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  • 1.
    Adamo, Hanibal
    et al.
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Hammarsten, Peter
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Hägglöf, Christina
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Scherdin, Tove Dahl
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Egevad, Lars
    Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Bergström, Sofia Halin
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Bergh, Anders
    Umea Univ, Dept Med Biosci, Pathol, 6M, Umea, Sweden.
    Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 5, p. 435-445Article in journal (Refereed)
    Abstract [en]

    Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

    Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

    Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

    Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

  • 2.
    Adamo, Hanibal Hani
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Scherdin, Tove Dahl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Egevad, Lars
    Stattin, Paer
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 5Article in journal (Refereed)
    Abstract [en]

    Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

    Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

    Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

    Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

  • 3.
    Adolfsson, Per
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlstrand, Christer
    Linköping University, Department of Clinical and Experimental Medicine, Urology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Clinical and Experimental Medicine, Urology. Linköping University, Faculty of Health Sciences.
    Svensson, Samuel
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lysophosphatidic acid stimulates proliferation of cultured smooth muscle cells from human BPH tissue: Sildenafil and papaverin generate inhibition2002In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 51, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Background The endogenous substance lysophosphatidic acid (LPA) has been found to generate proliferation of cultured smooth muscle cells (SMC). Therefore, the effect of LPA on human benign prostate hyperplasia (BPH) could be of interest.

    Methods The proliferative effect of LPA on cultured human prostatic SMC from specimens obtained at trans-urethral resection of the prostate (TURP) because of BPH, was analyzed by [3H]-thymidine and [35S]-methionine incorporation. In addition, LPA stimulated BPH SMC were treated with papaverin, forskolin, sildenafil or zaprinast, well known to increase the intracellular level of cAMP or cGMP.

    Results LPA produced a dose-dependent increase in BPH SMC, both regarding DNA- and protein-synthesis with EC50 values of 3 and 10 μM, respectively. Furthermore, both papaverin, a general phosphodiesterase inhibitor regarding cAMP hydrolyzes, and forskolin, an adenylyl cyclase stimulating agent, inhibited the LPA-stimulated DNA replication in a dose dependent manner with IC50  = 2.5, and 0.35 μM, respectively. cGMP increasing agents, such as the NO-donors SIN-1 and SNAP, produced a weak anti-proliferative response. However, both phosphodiesterase 5 inhibitors sildenafil (Viagra®) and zaprinast efficiently blocked DNA replication. In addition, when the protein synthesis was examined, we found that the LPA response was significantly inhibited by forskolin and papaverin.

    Conclusions The major conclusion of this investigation is that the endogenous serum component LPA, is able to promote human BPH SMC growth. In addition, our study indicates that cyclic nucleotides can inhibit this effect. Future clinical studies will be needed to determine if different specific phosphodiesterase inhibitors per se or in combination could represent a new therapeutic possibility for the treatment of BPH.

  • 4. Babiker, A A
    et al.
    Hamad, O A
    Sanchez, J
    Ronquist, G
    Nilsson, B
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Prothrombotic Effect of Prostasomes of Metastatic Cell and Seminal Origin2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, p. 378-388Article in journal (Refereed)
  • 5.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Prothrombotic effect of prostasomes of metastatic cell and seminal origin2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, p. 378-388Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Prostasomes are secretory granules produced by the glandular epithelial cells of the prostate. Seminal prostasomes contain high amounts of Tissue Factor (TF) but no studies of TF on malignant cell prostasomes have been made. Here we compare the expression, phosphorylation, and function of TF on prostasomes of different origin. METHODS. TF was detected on prostasomes isolated from seminal fluid and human prostate cancer cell lines (PC-3, DU145, and LNCaP) using FACS and enzyme immunoassay (EIA). Incubation of prostasomes with radioactive ATP under conditions favoring protein kinase A activity led to phosphorylation of TF as detected by immunoprecipitation and SDS-PAGE. The prothrombotic effect of prostasomes was investigated in whole blood and recalcified plasma. Blocking experiments were performed using anti-TF antibodies and corn trypsin inhibitor. RESULTS. TF was expressed on all tested prostasome preparations with lowest values found for seminal ones. Prostasomal TF was the main endogenous substrate for prostasomal protein kinase A. All tested prostasome preparations greatly enhanced the rate of clot formation in a dose-dependent fashion, that is, the clotting capability of prostasomes seemed to be related to the extent of their expression of TF. In addition, the density of the clot varied between different prostasome preparations. When incubated in whole blood, prostasomes were found to associate to WBC thereby inducing them to express and release TF. CONCLUSIONS. These data show that TF is overexpressed and also subjected to phosphorylation by malignant cell prostasomes. This suggests major roles for prostasomes in thrombotic events that occur in some advanced cases of prostate cancer.

  • 6.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mapping pro- and antiangiogenic factors on the surface of prostasomes of normal and malignant cell origin2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 8, p. 834-847Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS: VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS: VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS: Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

  • 7. Babiker, Adil A
    et al.
    Magnusson, Peetra U
    Ronquist, Gunnar
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Mapping Pro- and Antiangiogenic Factors on the Surface of Prostasomes of Normal and Malignant Cell Origin2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 8, p. 834-847Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis.

    METHODS. VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy.

    RESULTS. VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy.

    CONCLUSIONS. Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

  • 8.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attck2005In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 62, no 2, p. 105-114Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostasomes are secretory granules produced, stored, and released, by the glandular epithelial cells of the prostate. They express the glycosylphosphatidylinositol (GPI)-anchored complement regulatory protein CD59, which has been shown to be transferred to spermatozoa and erythrocytes.

    METHODS: The CD59 content of prostasomes isolated from seminal fluid and malignant prostate cells (PC-3, DU145, and LNCaP) and the transfer of prostasomal CD59 to rabbit erythrocytes (RE) and to PIPLC-treated and unmanipulated cancer cells were investigated using FACS. All prostasomes were also incubated with RE and tested in a hemolytic assay.

    RESULTS: Prostasomes from cancer cells had higher expression of CD59 than those of normal cells. Prostasomal CD59 of different origin could be transferred to RE, malignant cell lines stripped of CD59 by PIPLC, or unmanipulated LNCaP cells. Malignant cell prostasomes had an increased ability to inhibit complement-mediated lysis compared to those from non-malignant cells.

    CONCLUSIONS: These results point to a novel mechanism by which prostasomes can protect prostatic malignant cells from complement attack.

  • 9.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 7, p. 675-686Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prostasomes are secretory granules produced, stored, and released by the glandular epithelial cells of the prostate. They express numerous enzymes whose physiological roles have so far not been fully evaluated. In this study, we investigated the expression and function of prostasomal protein kinases and ATPase.

    METHODS:

    The protein kinase activities of prostasomes isolated from seminal fluid and malignant prostate cell lines (PC-3, DU145, and LNCaP) were investigated using the model phosphorylation substrates histone and casein, as well as the plasma proteins C3 and fibrinogen, in combination with specific protein kinase inhibitors. The prostasomal ATPase activity was also evaluated. The expression of protein kinases and ATPase on prostasomes was verified by flow cytometry.

    RESULTS:

    Prostasomes (intact or solubilized with octylglucoside or saponin) from prostate cancer cells had higher expression of protein kinases A, C, and casein kinase II compared to prostasomes isolated from seminal plasma, resulting in higher phosphorylation of both exogenous and endogenous substrates. Using intact prostasomes, it was found that prostasomes of metastatic origin had lower ATPase activity, resulting in higher residual ATP available for the phosphorylation reaction. Finally, complement component C3 and fibrinogen (two proteins whose activities are modulated by phosphorylation) were identified as physiologically relevant phosphorylation substrates.

    CONCLUSIONS:

    These results indicate that prostasomes are capable of modifying proteins possibly involved in the innate response by extracellular phosphorylation mediated by ecto-kinases. This is a novel mechanism by which prostatic malignant cells may interact with their environment.

  • 10.
    Beshara, Soheir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Letocha, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wikström, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandhagen, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Danielson, Bo G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Anemia associated with advanced prostatic adenocarcinoma: Effects of recombinant human erythropoietin1997In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 31, no 3, p. 153-160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND METHODS: Nine patients with hormone-refractory metastatic prostatic adenocarcinoma and anemia were treated with recombinant human erythropoietin (rHuEpo) at a median dose of 150 U/kg BW 3 times a week subcutaneously. Baseline hemoglobin (Hb) ranged from 70 to 116 g/L, and the study duration was 12 weeks (median patient participation period was 8 weeks). RESULTS: Four patients demonstrated a median Hb increase of 20 g/L and were considered responders. Three patients showed a median increase of 17 g/L but required blood transfusion once, and were therefore considered as partial responders. Baseline erythropoietic status showed a significant correlation between serum Epo and Hb. Inadequate Epo production, evaluated by the observed/predicted log Epo ratio, was found in two patients. Defective bone marrow activity, demonstrated by low transferrin receptor (TfR), and hypoferremia in spite of abundant iron stores were also shown. Hemorheological investigations showed elevated plasma viscosity. CONCLUSIONS: Our results indicate that suppression of erythropoiesis can be mainly explained by the depressed marrow activity. The altered hemorheology might contribute to the anemia. This anemia could possibly be corrected with rHuEpo.

  • 11.
    Bylund, Annika
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    Zhang, Jie-Xian
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Bergh, Anders
    Damber, Jan-Erik
    Widmark, Anders
    Johansson, Anders
    Adlercreutz, Herman
    Åman, Per
    Shepherd, Martin J
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Rye bran and soy protein delay growth and increase apoptosis of human LNCaP prostate adenocarcinoma in nude mice2000In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 42, no 4, p. 304-314Article in journal (Refereed)
  • 12.
    Cantarutti, Anna
    et al.
    Univ Milano Bicocca, Dept Stat & Quantitat Methods, I-20126 Milan, Italy.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Bonn, Stephanie E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gronberg, Henrik
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Bellocco, Rino
    Univ Milano Bicocca, Dept Stat & Quantitat Methods, I-20126 Milan, Italy.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Bälter, Katarina
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Body mass index and mortality in men with prostate cancer2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 11, p. 1129-1136Article in journal (Refereed)
    Abstract [en]

    BACKGROUNDBody Mass index (BMI) has been shown to affect risk and mortality of several cancers. Prostate cancer and obesity are major public health concerns for middle-aged and older men. Previous studies of pre-diagnostic BMI have found an increased risk of prostate cancer mortality in obese patients. OBJECTIVETo study the associations between BMI at time of prostate cancer diagnosis and prostate cancer specific and overall mortality. METHODSBMI was analyzed both as a continuous variable and categorized into four groups based on the observed distribution in the cohort (BMI<22.5, 22.5<25, 25<27.5 and 27.5kg/m(2)). The association between BMI and mortality was assessed using stratified Cox proportional hazards models and by fitting regression splines for dose response analysis in 3,161 men diagnosed with prostate cancer. After 11 years of follow up via linkage to the population-based cause of death registry, we identified 1,161 (37%) deaths off which 690 (59%) were due to prostate cancer. RESULTSHigh BMI (BMI27.5kg/m(2)) was associated with a statistically significant increased risk of prostate cancer specific mortality (HR:1.44, 95%CI: 1.09-1.90) and overall mortality (HR:1.33, 95%CI: 1.09-1.63) compared to the reference group (BMI 22.5<25kg/m(2)). Additionally, men with a low BMI (<22.5kg/m(2)), had a statistically significant increased risk of prostate cancer specific mortality (HR:1.33, 95%CI: 1.02-1.74) and overall mortality (HR:1.36, 95%CI: 1.11-1.67) compared to the reference. However, this effect disappeared when men who died within the first two years of follow-up were excluded from the analyses while the increased risk of prostate cancer specific mortality and overall mortality remained statistically significant for men with a BMI27.5kg/m(2) (HR:1.44, 95%CI: 1.09-1.90 and HR: 1.33, 95%CI: 1.09-1.63, respectively). CONCLUSIONThis study showed that a high BMI at time of prostate cancer diagnosis was associated with increased overall mortality. Prostate 75: 1129-1136, 2015. (c) 2015 Wiley Periodicals, Inc.

  • 13.
    Carlsson, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Forsberg, Ole
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Characterization of human prostate and breast cancer cell lines for experimental T cell-based immunotherapy2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, p. 389-395Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. In order to develop experimental immunotherapy for prostate and breast cancer it is of outmost importance to have representative target cell lines that through human leukocyte antigen (HLA) class I molecules present relevant levels of peptides from tumor-associated antigens for cytotoxic T lymphocyte (CTL) recognition. METHODS. We sequenced the HLA-A and HLA-B loci of eight commonly used prostate and breast cancer cell lines and analyzed the surface expression of HLA-ABC, HLA-DR, CD40, CD80, CD86, and CD54 by flow cytometry. We also analyzed the cell lines for mRNA expression from 25 genes reported to be specifically or preferentially expressed by prostate cells. RESULTS. Among the analyzed cell lines we found that LNCaP, PC-346C and MCF-7 are HLA-A*0201 positive. However, the HLA-A2 expression level is low and only MCF-7 upregulates HLA-A2 in response to IFN-γ stimulation. MCF-7 also expresses high levels of CD54, which further improve its value as a CTL target cell line. On the other hand, LNCaP and PC-346C express 25 and 23 out of 25 prostate-related genes, respectively, while MCF-7 expresses 16 out of 25 genes. CONCLUSIONS. None of the analyzed prostate cancer cell lines are optimal CTL target cells. However, MCF-7 could in many cases be used as a complement to HLA-A*0201 positive prostate cancer cells. The LNCaP and PC-346C cell lines are rich sources of prostate-related antigens that may be valuable for cancer vaccine development.

  • 14.
    Carlsson, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Tötterman, Thomas H.
    Essand, Magnus
    Generation of cytotoxic T lymphocytes specific for the prostate and breast tissue antigen TARP2004In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 61, no 2, p. 161-170Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Expansion of cytotoxic T lymphocytes (CTL) directed against peptide epitopes from antigens that are specifically expressed by normal and neoplastic prostate epithelial cells has during the last years emerged as an interesting therapeutic approach to treat advanced prostate cancer. TCRgamma alternate reading frame protein (TARP) is a protein that in males is specifically expressed by normal prostate epithelial cells and prostate cancer cells. We have evaluated TARP for human leukocyte antigen (HLA)-A*0201-restricted peptides capable of triggering TARP-specific CTL. METHODS: Dendritic cells (DC) were pulsed either with synthetic peptides derived from the natural amino acid sequence of TARP or with cognate peptides having enhanced affinity for HLA-A*0201 due to an N-terminal anchor residue substitution. The peptide-pulsed DC were used to stimulate autologous T cells ex vivo. RESULTS: We were able to generate T cells against TARP(27-35) and TARP(4-13) and their mutated counterparts TARP(V28L)(27-35) and TARP(P5L)(4-13). The use of affinity-enhanced peptides resulted in the generation of T cells recognizing target cells displaying either wild-type or mutated peptide. We further show that TARP-specific T cells can be tetramer-sorted and subsequently expanded to large numbers by general T cell stimulation, with retained specificity and activity. Sorted and expanded T cells, obtained by stimulation with TARP(P5L)(4-13), exert moderate lysis of the TARP-expressing prostate cancer cell line, LNCaP, and breast cancer cell line, MCF-7, indicating that the TARP(4-13) epitope may be endogenously processed and presented by TARP-positive, HLA-A*0201-positive cells. CONCLUSIONS: Our findings suggest that synthetic TARP peptides, such as TARP(P5L)(4-13), may play a role in prostate and breast cancer immunotherapy.

  • 15. Christensen, G Bryce
    et al.
    Baffoe-Bonnie, Agnes B
    George, Asha
    Powell, Isaac
    Bailey-Wilson, Joan E
    Carpten, John D
    Giles, Graham G
    Hopper, John L
    Severi, Gianluca
    English, Dallas R
    Foulkes, William D
    Maehle, Lovise
    Moller, Pal
    Eeles, Ros
    Easton, Douglas
    Badzioch, Michael D
    Whittemore, Alice S
    Oakley-Girvan, Ingrid
    Hsieh, Chih-Lin
    Dimitrov, Latchezar
    Xu, Jianfeng
    Stanford, Janet L
    Johanneson, Bo
    Deutsch, Kerry
    McIntosh, Laura
    Ostrander, Elaine A
    Wiley, Kathleen E
    Isaacs, Sarah D
    Walsh, Patrick C
    Isaacs, William B
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Hebbring, Scott
    Schaid, Daniel J
    Lange, Ethan M
    Cooney, Kathleen A
    Tammela, Teuvo L J
    Schleutker, Johanna
    Paiss, Thomas
    Maier, Christiane
    Grönberg, Henrik
    Wiklund, Fredrik
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Farnham, James M
    Cannon-Albright, Lisa A
    Camp, Nicola J
    Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, p. 735-744Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS: We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS: Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS: Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate (c) 2010 Wiley-Liss, Inc.

  • 16.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Ohlson, Anna-Lena
    Department of Laboratory Medicine, Pathology, University Hospital Örebro, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giunchi, Francesca
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Rider, Jennifer R.
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Fiorentino, Michelangelo
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer2018In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 1, p. 40-47Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer.

    METHODS: Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area.

    RESULTS: In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart.

    CONCLUSIONS: Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established.

  • 17. de la Torre, M.
    et al.
    Eklöv, S.
    Häggman, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Björk, P.
    Busch, C.
    Nilsson, S.
    Elevated expression of estramustine binding protein (EMBP) in prostatic intraepithelial neoplasia (PIN) compared with malignant and benign prostatic epithelia1994In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 25, no 3, p. 125-31Article in journal (Refereed)
    Abstract [en]

    The expression of estramustine-binding protein (EMBP) was studied immunohistochemically in whole-mount prostate sections. Specimens were taken from the prostates of 15 patients who had undergone total prostatectomy due to localized (TOd-T2 NO MO) prostatic cancer (PC). Almost all the examined whole-mount sections displayed areas with prostatic intraepithelial neoplasia (PIN). PIN is regarded as the main precursor of invasive PC. High- and low-grade PIN expressed EMBP. The average positively stained areas accounted for averages of 69.2% and 48.7%, respectively. High-grade PIN contained the highest EMBP levels of all the investigated (benign and malignant) epithelia, followed by moderately differentiated PC. With regard to areas with PC, the highest levels of EMBP expression (61.3%) were observed in moderately differentiated PC; poorly differentiated PC came second. Of all the examined epithelia, EMBP levels were lowest in well-differentiated PC (25.8%). Normal prostatic epithelia and hyperplasia were characterized by low EMBP expression, although somewhat higher than well-differentiated PC. A moderate expression (45%) was observed in the seminal vesicles. According to these results, EMBP was expressed mainly in the diseased peripheral zone (PZ), where PIN and prostatic cancer have their highest prevalence.

  • 18.
    Djusberg, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lundberg, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases2017In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 6, p. 625-638Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

  • 19.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Kharaziha, Pedram
    Chioureas, Dimitris
    Meersman, Niels
    Panaretakis, Theocharis
    Ronquist, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Malignant Cell-Derived Extracellular Vesicles Express Different Chromogranin Epitopes Compared to Prostasomes2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 10, p. 1063-1073Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS. We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS. A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION. Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers.

  • 20.
    Dzojic, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Loskog, Angelica
    Tötterman, Thomas H.
    Essand, Magnus
    Adenovirus-Mediated CD40 Ligand Therapy Induces Tumor Cell Apoptosis and Systemic Immunity in the TRAMP-C2 Mouse Prostate Cancer Model2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 8, p. 831-838Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The interaction between CD40 ligand (CD40L) and CD40 on antigen presenting cells is essential for the initiation of antigen-specific T-cell responses, whereas CD40L stimulation of CD40+ tumor cells can induce cellular apoptosis. We investigated the anti-tumor effects induced by CD40L gene transfer into the mouse prostate adenocarcinoma cell line TRAMP-C2, both in vitro and in vivo.

    METHODS: TRAMP-C2 cells were transduced with an adenoviral vector encoding CD40L (AdCD40L). The induced expression of co-stimulatory molecules and cell viability was analyzed. AdCD40L-transduced TRAMP-C2 cells were used in prophylactic vaccination studies, while therapeutic studies were performed using peritumoral injections of AdCD40L.

    RESULTS: AdCD40L yielded reduced TRAMP-C2 cell viability and induced apoptosis in vitro. Vaccination with CD40L-expressing TRAMP-C2 cells induced anti-tumor immunity and peritumoral AdCD40L injections induced tumor growth suppression.

    CONCLUSIONS: Our observations highlight the therapeutic potential of using AdCD40L as a monotherapy or in combination with conventional chemotherapy or novel therapies (e.g., oncolytic viruses). The use of AdCD40L offers an attractive option for future clinical trials.

  • 21.
    Eriksson, Margaretha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Wedel, Hans
    Nordic School of Public Health, Gothenburg.
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Krakau, Ingvar
    Department of Internal Medicine, General Medicine Unit, Karolinska Institute, Stockholm.
    Hugosson, Jonas
    Department of Urology, The Sahlgrenska Academy at Göteborg University.
    Carlsson, Sture
    Department of Surgery, Kungälv Hospital.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    The impact of birth weight on prostate cancer incidence and mortality in a population-based study of men born in 1913 and followed up from 50 to 85 years of age2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 11, p. 1247-1254Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Insulin-like growth factor-I (IGF-I) hormone is directly associated with birth weight (BW), and high IGF-I measured in adults is associated with increased risk of prostate cancer (PCA). Whether BW and PCA are related is inconclusive to date. METHODS: BW and PCA incidence and mortality data for a population-based cohort of 1,436 singleton Swedish men born in 1913 and followed until 85 years of age were obtained. RESULTS: BW > or = 4,250 g was associated with significantly higher PCA incidence [62% (CI: 4%-151%)] and PCA mortality [82% (CI: 3%-221%)] than BW 3,001-4,249 g, even when other potential effect modifiers were taken into account. The hazards ratio for PCA incidence fell from approximately 3 at age 50 to unity at age 85. Approximately one out of every six PCA incident cases between 50 and 70 years of age could be attributed to BW > or = 4,250 g. CONCLUSIONS: In the current study PCA incidence and mortality rate appears to increase with BW.

  • 22.
    Erlandsson, Ann
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology.
    Lundholm, Marie
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Fält, Anna
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Andersson, Sven-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    M2 macrophages and regulatory T cells in lethal prostate cancer2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 4, p. 363-369Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs) can contribute to cancer progression by suppressing the anti‐tumor immune response. This study investigated the number of CD163‐positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs.

    METHODS: were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.

    RESULTS: showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis.

    CONCLUSIONS: Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs , promote an immunosuppressive environment.

  • 23. Erlandsson, Ann
    et al.
    Carlsson, Jessica
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fält, Anna
    Andersson, Sven-Olof
    Andrén, Ove
    Davidsson, Sabina
    M2 macrophages and regulatory T cells in lethal prostate cancer2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 4, p. 363-369Article in journal (Refereed)
    Abstract [en]

    Background: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs) can contribute to cancer progression by suppressing the anti‐tumor immune response. This study investigated the number of CD163‐positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs.

    Methods: This nested case‐control study included subjects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infiltrating CD163‐positive M2 macrophages and FOXP3/CD4‐positive Tregs in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and Tregs were assessed using Spearman's rank‐order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.

    Results: The number of M2 macrophages and Tregs showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23‐3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis.

    Conclusions: Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs, promote an immunosuppressive environment.

  • 24.
    Erlandsson, Ann
    et al.
    Örebro University.
    Carlsson, Jessica
    Örebro University.
    Lundholm, Marie
    Umeå University.
    Fält, Anna
    Örebro University.
    Andersson, Sven-Olof
    Örebro University.
    Andrén, Ove
    Örebro University.
    Davidsson, Sabina
    Örebro University.
    M2 macrophages and regulatory T cells in lethal prostate cancer.2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 4, p. 363-369Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs ) can contribute to cancer progression by suppressing the anti-tumor immune response. This study investigated the number of CD163-positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs .

    METHODS: This nested case-control study included subjects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infiltrating CD163-positive M2 macrophages and FOXP3/CD4-positive Tregs in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and Tregs were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.

    RESULTS: The number of M2 macrophages and Tregs showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis.

    CONCLUSIONS: Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs , promote an immunosuppressive environment.

  • 25.
    Fall, Katja
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Stark, J. R.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Laboratory, Department of Medicine, Brigham Women’s Hospital and Harvard Medical School, Boston, USA.
    Mucci, L. A.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Chan, J.
    Departments of Epidemiology & Biostatistics and Urology, University of California, San Francisco, USA.
    Stampfer, M. J.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Kurth, T.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Febbo, P. G.
    Duke University School of Medicine, Durham, USA.
    Kantoff, P.
    Division of Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA.
    Ma, J.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    No association between a polymorphic variant of the IRS-1 gene and prostate cancer risk2008In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 68, no 13, p. 1416-20Article in journal (Refereed)
    Abstract [en]

    Objective: Insulin receptor substrate-1 (IRS-1) acts as a docking protein between the insulin-like growth factor-1 (IGF-1) receptor and intracellular signaling molecules in the IGF-1 signaling pathway. Accumulating data support a role of IGF-1 in prostate carcinogenesis. We assessed the influence of the most common IRS-1 gene polymorphism (Gly972Arg) on prostate cancer risk, alone and in combination with IGF-1 and other components in the IGF-1 signaling pathway.

    Materials and methods: In a nested case-control study within the Physicians' Health Study, the IRS-1 polymorphism was assayed from prospectively collected samples from 564 incident prostate cancer cases and 758 controls matched on age and smoking. We calculated relative risks (RR) and 95% confidence intervals (CI) using conditional logistic regression.

    Results: Among the controls, 0.8% were homozygous (AA) and 12% were heterozygous (GA) for the polymorphic allele. There was no association between carriage of the A allele and total prostate cancer risk (RR = 1.1 95% CI = 0.8-1.5), advanced disease (stage C or D or lethal prostate cancer, RR = 1.3 95% CI = 0.8-2.3), or plasma IGF-1 levels. We explored possible interactions with body mass index and components in the IGF-1 pathway including IGFBP3, PI3k, and PTEN but none of these factors influenced the relation between IRS-1 genotype and prostate cancer risk.

    Conclusions: Our data do not support an association between carriage of the variant IRS-1 gene and prostate cancer risk.

  • 26.
    Forsberg, Ole
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    High frequency of prostate antigen-directed T cells in cancer patients compared to healthy age-matched individuals2009In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, no 1, p. 70-81Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. In order to obtain a sustained cytotoxic T lymphocyte (CTL) response against cancer cells it is preferable to have CTLs directed against multiple peptide epitopes from numerous tumor-associated antigens.

    METHODS. We used a flow cytometry-based interferon (IFN)-g secretion assay to analyze whether CD8+ T cells directed against any of 24 HLA-A*0201-binding peptides from 15 prostate-associated proteins can be found in the peripheral blood of patients with localized prostate cancer. We also investigated whether multiple prostate antigen-specific CD8+ T cells can be generated simultaneously, from a naïve T cell repertoire. In that case, dendritic cells (DCs) from peripheral blood of healthy donors were divided in six portions and separately pulsed with six peptides. The peptide-pulsed DCs were then pooled and used to stimulate autologous T cells. The T cells were re-stimulated with peptide-pulsed monocytes.

    RESULTS. We found prostate antigen-restricted CD8+ T cells in the peripheral blood in 48 out of 184 (26.1%) analyzed samples from 25 cancer patients. This is significantly higher than 17 out of 214 analyzed samples (7.9%) from 10 healthy age-matched male individuals (p = 0.0249). In the cases when antigen-specific T cells could not be detected, we were able to generate IFN-g-producing CD8+ T cells specific for up to three prostate antigens simultaneously from a naïve T cell repertoire.

    CONCLUSIONS. CD8+ T cells directed against prostate antigen peptides can be found in, or generated from, peripheral blood. This indicates that such T cells could be expanded ex vivo for adoptive transfer to prostate cancer patients.

  • 27.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Järemo, Helena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adamo, Hanibal Hani
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate tumors downregulate microseminoprotein-beta (MSMB) in the surrounding benign prostate epithelium and this response is associated with tumor aggressiveness2018In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 4, p. 257-265Article in journal (Refereed)
    Abstract [en]

    Background: Microseminoprotein-beta (MSMB) is a major secretory product from prostate epithelial cells. MSMB synthesis is decreased in prostate tumors in relation to tumor grade. MSMB levels are also reduced in the circulation and MSMB is therefore used as a serum biomarker for prostate cancer. We hypothesized that cancers induce a reduction in MSMB synthesis also in the benign parts of the prostate, and that the magnitude of this response is related to tumor aggressiveness. Reduced levels of MSMB in the circulation could therefore be a consequence of reduced MSMB expression not only in tumor tissue but also in the benign prostate tissue.

    Methods: MSMB expression was analyzed in prostatectomy specimens from 36 patients using immunohistochemistry and qRT-PCR. MSMB expression in the benign prostate tissue was analyzed in relation to Gleason score, tumor stage, and distance to the tumor. Furthermore, Dunning rat prostate tumors with different aggressiveness were implanted into the prostate of Copenhagen rats to study if this affected the MSMB expression in the tumor-adjacent benign rat prostate tissue.

    Results: In prostatectomy specimens, MSMB expression was reduced in prostate tumors but also in the tumor-adjacent benign parts of the prostate. The reduction in tumor MSMB was related to tumor grade and stage, and the reduction in the benign parts of the prostate to tumor grade, stage, and distance to the tumor. Implantation of Dunning cancer cells into the rat prostate resulted in reduced MSMB protein levels in the tumor-adjacent benign prostate tissue. Rapidly growing and metastatic MatLyLu tumors had a more pronounced effect than slow-growing non-metastatic G tumors.

    Conclusion: Our data suggest that aggressive prostate tumors suppress MSMB synthesis in the benign prostate and that this could explain why serum levels of MSMB are decreased in prostate cancer patients. This study suggests that markers for aggressive cancer can be found among factors altered in parallel in prostate tumors and in the adjacent benign tissue.

  • 28.
    Halin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Androgen-insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment.2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, p. 370-7Article in journal (Refereed)
  • 29. Hedelin, Maria
    et al.
    Bälter Augustsson, Katarina
    Karolinska institutet, Sweden.
    Chang, Ellen T.
    Bellocco, Rino
    Klint, Asa
    Johansson, Jan-Erik
    Wiklund, Fredrik
    Thellenberg-Karlsson, Camilla
    Adami, Hans-Olov
    Gronberg, Henrik
    Dietary intake of phytoestrogens, estrogen receptor-beta polymorphisms and the risk of prostate cancer2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 14, p. 1512-1520Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. The causes of prostate cancer are poorly understood, but genetic factors may be more important than for many other malignancies, and dietary phytoestrogens may be protective. Because phytoestrogens bind tightly to the estrogen receptor-beta, we conducted an epiderniologic investigation of synergistic effects between phytoestrogen intake and estrogen receptor-beta gene polymorphisms. METHODS. We performed a population-based case-control study in Sweden. All participants reported their phytoestrogen intake and donated a blood sample. We identified four haplotype-tagging single nucleotide polymorphisms (htSNPs) and genotyped these htSNPs in 1314 prostate cancer patients and 782 controls. Odds ratios were estimated by multivariate logistic regression. Interactions between phytoestrogen intake and estrogen receptor-beta SNPs on prostate cancer risk were evaluated considering both multiplicative and additive effect scales. RESULTS. We found a significant multiplicative interaction (P = 0.04) between dietary intake of phytoestrogens and a promoter SNP in the estrogen receptor-beta gene (rs 2987983-13950), but not with any of the three other htSNPs (P = 0.11, 0.69, 0.85). Among carriers of the variant promoter alleles, we found strong inverse associations with increasing intake of total phytoestrogens (odds ratio for highest vs. lowest quartile = 0.43; P for trend < 0.001), isoflavonoids (odds ratio = 0.63; P for trend = 0.05), and coumestrol (odds ratio = 0.57; P for trend = 0.003). We found no association between phytoestrogens and prostate cancer among carriers homozygous for the wild-type allele (TT). CONCLUSIONS. Our study provides strong evidence that high intake of phytoestrogens substantially reduce prostate cancer risk among men with specific polymorphic variation in the promoter region of the estrogen receptor-beta gene.

  • 30. Hedelin, Maria
    et al.
    Bälter, Katarina Augustsson
    Chang, Ellen T.
    Bellocco, Rino
    Klint, Åsa
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Wiklund, Fredrik
    Thellenberg-Karlsson, Camilla
    Adami, Hans-Olov
    Grönberg, Henrik
    Dietary intake of phytoestrogens, estrogen receptor-beta polymorphisms and the risk of prostate cancer2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 14, p. 1512-1520Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The causes of prostate cancer are poorly understood, but genetic factors may be more important than for many other malignancies, and dietary phytoestrogens may be protective. Because phytoestrogens bind tightly to the estrogen receptor-beta, we conducted an epidemiologic investigation of synergistic effects between phytoestrogen intake and estrogen receptor-beta gene polymorphisms. METHODS: We performed a population-based case-control study in Sweden. All participants reported their phytoestrogen intake and donated a blood sample. We identified four haplotype-tagging single nucleotide polymorphisms (htSNPs) and genotyped these htSNPs in 1314 prostate cancer patients and 782 controls. Odds ratios were estimated by multivariate logistic regression. Interactions between phytoestrogen intake and estrogen receptor-beta SNPs on prostate cancer risk were evaluated considering both multiplicative and additive effect scales. RESULTS: We found a significant multiplicative interaction (P = 0.04) between dietary intake of phytoestrogens and a promoter SNP in the estrogen receptor-beta gene (rs 2987983-13950), but not with any of the three other htSNPs (P = 0.11, 0.69, 0.85). Among carriers of the variant promoter alleles, we found strong inverse associations with increasing intake of total phytoestrogens (odds ratio for highest vs. lowest quartile = 0.43; P for trend <0.001), isoflavonoids (odds ratio = 0.63; P for trend = 0.05), and coumestrol (odds ratio = 0.57; P for trend = 0.003). We found no association between phytoestrogens and prostate cancer among carriers homozygous for the wild-type allele (TT). CONCLUSIONS: Our study provides strong evidence that high intake of phytoestrogens substantially reduce prostate cancer risk among men with specific polymorphic variation in the promoter region of the estrogen receptor-beta gene.

  • 31.
    Horning, Aaron M.
    et al.
    University of Texas Health Science Center, San Antonio, USA.
    Awe, Julius Adebayo
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada / Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wang, Chiou-Miin
    University of Texas Health Science Center, San Antonio, USA.
    Liu, Joseph
    University of Texas Health Science Center, San Antonio, USA.
    Lai, Zhao
    University of Texas Health Science Center, San Antonio, USA.
    Wang, Vickie Yao
    University of Texas Health Science Center, San Antonio, USA.
    Jadhav, Rohit R.
    University of Texas Health Science Center, San Antonio, USA.
    Louie, Anna D.
    University of Texas Health Science Center, San Antonio, USA.
    Lin, Chun-Lin
    University of Texas Health Science Center, San Antonio, USA.
    Kroczak, Tad
    University of Manitoba, Winnipeg, Manitoba, Canada.
    Chen, Yidong
    University of Texas Health Science Center, San Antonio, USA.
    Jin, Victor X.
    University of Texas Health Science Center, San Antonio, USA.
    Abboud-Werner, Sherry L.
    University of Texas Health Science Center, San Antonio, USA.
    Leach, Robin J.
    University of Texas Health Science Center, San Antonio, USA.
    Hernandez, Javior
    University of Texas Health Science Center, San Antonio, USA.
    Thompson, Ian M.
    University of Texas Health Science Center, San Antonio, USA.
    Saranchuk, Jeff
    University of Manitoba, Winnipeg, Canada.
    Drachenberg, Darrel
    University of Manitoba, Winnipeg, Canada.
    Chen, Chun-Liang
    University of Texas Health Science Center, San Antonio, USA.
    Mai, Sabine
    University of Manitoba, Winnipeg, Canada.
    Huang, Tim Hui-Ming
    University of Texas Health Science Center, San Antonio, USA.
    DNA Methylation Screening of Primary Prostate Tumors Identifies SRD5A2 and CYP11A1 as Candidate Markers for Assessing Risk of Biochemical Recurrence2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 15, p. 1790-1801Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Altered DNA methylation in CpG islands of gene promoters has been implicated in prostate cancer (PCa) progression and can be used to predict disease outcome. In this study, we determine whether methylation changes of androgen biosynthesis pathway (ABP)-related genes in patients' plasma cell-free DNA (cfDNA) can serve as prognostic markers for biochemical recurrence (BCR). METHODS. Methyl-binding domain capture sequencing (MBDCap-seq) was used to identify differentially methylated regions (DMRs) in primary tumors of patients who subsequently developed BCR or not, respectively. Methylation pyrosequencing of candidate loci was validated in cfDNA samples of 86 PCa patients taken at and/or post-radical prostatectomy (RP) using univariate and multivariate prediction analyses. RESULTS. Putative DMRs in 13 of 30 ABP-related genes were found between tumors of BCR (n = 12) versus no evidence of disease (NED) (n = 15). In silico analysis of The Cancer Genome Atlas data confirmed increased DNA methylation of two loci-SRD5A2 and CYP11A1, which also correlated with their decreased expression, in tumors with subsequent BCR development. Their aberrant cfDNA methylation was also associated with detectable levels of PSA taken after patients' post-RP. Multivariate analysis of the change in cfDNA methylation at all of CpG sites measured along with patient's treatment history predicted if a patient will develop BCR with 77.5% overall accuracy. CONCLUSIONS. Overall, increased DNA methylation of SRD5A2 and CYP11A1 related to androgen biosynthesis functions may play a role in BCR after patients' RP. The correlation between aberrant cfDNA methylation and detectable PSA in post-RP further suggests their utility as predictive markers for PCa recurrence. (C) 2015 Wiley Periodicals, Inc.

  • 32.
    Häggström, Jenny
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Plym Forshell, Linus
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stella, Nephi
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: A Bayesian network analysis of data from a tissue microarray2014In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 74, no 11, p. 1107-1117Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors.

  • 33.
    Häggström, S
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Vascular endothelial growth factor content in metastasizing and nonmetastasizing Dunning prostatic adenocarcinoma.2000In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 45, no 1, p. 42-50Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tumor angiogenesis is important in progressive tumor growth and metastasis. In the normal rat prostate and in androgen-sensitive prostate tumors androgen ablation causes an involution of the vasculature and a decrease in the vascular endothelial growth factor (VEGF) levels before regression of the prostate gland. To examine whether angiogenesis and metastasis are regulated by VEGF in androgen-insensitive and metastasizing prostate tumors, five Dunning rat prostate cancer sublines were tested; the androgen-sensitive, nonmetastasizing R3327 PAP, and the androgen-insensitive, low metastasizing AT-1, and the three androgen-insensitive, metastasizing AT-2, AT-3, and MatLyLu Dunning prostatic adenocarcinomas.

    METHODS: VEGF levels were quantified in the rat dorsolateral prostate and in the five Dunning sublines using competitive RT-PCR, Western blot, and Elisa. Vascular density was determined by factor VIII staining.

    RESULTS: VEGF mRNA was increased in all tumors compared with normal prostates. The two metastatic sublines AT-3 and MatLyLu and the nonmetastatic subline AT-1 showed the highest VEGF mRNA expression. VEGF protein levels in the prostate gland showed increased expression in the metastatic sublines, AT-2, AT-3, and MatLyLu, compared with the nonmetastatic AT-1 subline and the ventral prostate. VEGF proteins in serum were highest in the metastatic AT-3 subline. The vessel density was highest in the two highly metastatic sublines AT-3 and MatLyLu.

    CONCLUSIONS: Our results suggest that VEGF levels are associated with microvessel density and the previously established metastatic pattern of these rat prostate tumor systems.

  • 34.
    Häggström, S
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, P
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Expression of vascular endothelial growth factor and its receptors in the rat ventral prostate and Dunning R3327 PAP adenocarcinoma before and after castration.1998In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 36, no 2, p. 71-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiogenesis is important for prostate organogenesis and prostate cancer progression. It is not yet known whether androgens promote part of their control of prostate structure and function by influencing angiogenesis. The aim of this study was to explore the possible androgenic regulation of the angiogenic factor vascular endothelial growth factor (VEGF) and its receptors flt-1 and flk-1/KDR in the rat ventral prostate (VP) and Dunning R3327 PAP adenocarcinoma.

    METHODS: RNA was prepared from VP and tumors of intact and castrated rats. VEGF, flt-1, and flk-1/KDR mRNA levels were determined using competitive RT-PCR.

    RESULTS: VEGF121, VEGF165, and VEGF189 together with flt-1 and flk-1/KDR mRNA were detected. The VEGF, but not flt-1 mRNA levels were significantly decreased in the VP after castration. The Dunning tumor expressed high levels of mRNA for VEGF and its receptors compared to the VP. The flt-1 mRNA level in the tumor increased after castration, while the VEGF mRNA levels were unchanged.

    CONCLUSIONS: Decreased mRNA expression of VEGF, but not flt-1, was found in the rat VP after castration. However, in the Dunning tumor, castration did not alter the expression of VEGF mRNA. Moreover, elevated levels of both mRNA for VEGF and its receptors relative to the VP were observed, indicating that the VEGF system may be important for Dunning tumor development.

  • 35.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Jones, Jonathan
    Umeå University, Faculty of Medicine, Radiation Sciences. Umeå University, Faculty of Medicine, Radiation Sciences, Diagnostic Radiology.
    Pietras, Kristian
    Kilter, Sigrid
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Skytt, Asa
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rudolfsson, Stina Häggström
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model.2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 15, p. 1664-1676Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma. METHODS: Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies. RESULTS: In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone. CONCLUSIONS: The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.

  • 36.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research against Cancer, Lyon, France.
    McKay, James D
    Rinaldi, Sabina
    Wiklund, Fredrik
    Adami, Hans-Olov
    Grönberg, Henrik
    Kaaks, Rudolf
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival2009In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, no 12, p. 1281-1291Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival. MATERIALS AND METHODS: Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register. RESULTS: We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (P(trend) = 9 x 10(-8)), but not intact IGFBP3 (P(trend) = 0.16). Elevated levels of total- (P(trend) = 0.03) and intact IGFBP3 (P(trend) = 6 x 10(-14)) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (P(trend-adjusted) = 0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (P(trend-adjusted) = 0.0003), and among patients who had not been treated (P(trend-adjusted) = 0.02). CONCLUSIONS: Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death.

  • 37.
    Josefsson, Andreas
    et al.
    Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Linder, Anna
    Flondell Site, Despina
    Canesin, Giacomo
    Stiehm, Anna
    Anand, Aseem
    Bjartell, Anders
    Damber, Jan-Erik
    Welén, Karin
    Circulating Tumor Cells as a Marker for Progression-free Survival in Metastatic Castration-naïve Prostate Cancer2017In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 8, p. 849-858Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Analysis of circulating tumor cells (CTC) is a promising prognostic marker in castration-resistant prostate cancer (CRPC). The aim of this study was to investigate CTC detection and phenotyping as prognostic biomarkers for response to primary androgen deprivation therapy (ADT) of metastatic prostate cancer (PC).

    METHODS: PC patients presenting with a prostate specific antigen (PSA) >80 ng/ml and/or metastatic disease, intended for ADT were enrolled in the study. CTCs were analysed for expression of PSA prostate specific membrane antigen (PSMA) and epidermal growth factor receptor (EGFR) before and three months after ADT and related to progression.

    RESULTS: At inclusion, 46 out of 53 patients (87%) were CTC-positive with a sensitivity and specificity for distant metastases (M1) of 98% and 75%, respectively. In patients with M1-disease, EGFR-detection in CTC was an independent prognostic marker for progression-free survival, whereas PSA and alkaline phosphatase serum levels, Gleason score, or T-stage were not. EGFR-positive patients had significantly shorter time to progression (5 months) compared to EGFR-negative patients (11 months) (P < 0.05).

    CONCLUSIONS: In this explorative study, CTCs were detected in 98% of M1 patients and detection of EGFR in CTCs was strongly associated with poor outcome, which indicated that phenotypical analysis of CTC could be a promising prognostic marker of ADT-response in castration-naïve metastatic PC patients. Prostate 77:849-858, 2017. © 2017 Wiley Periodicals, Inc.

  • 38.
    Karlsson, Terese
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Osteoblast-derived factors promote metastatic potential in human prostate cancer cells, in part via non-canonical transforming growth factor β (TGFβ) signaling2018In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 6, p. 446-456Article in journal (Refereed)
    Abstract [en]

    Background: Transforming growth factor β (TGFβ) functions as a double-edged sword in prostate cancer tumorigenesis. In initial stages of the disease, TGFβ acts as a growth inhibitor upon tumor cells, whereas it in later stages of disease rather promotes invasion and metastatic potential. One well-known cellular source of TGFβ in the bone metastatic site is the bone-forming osteoblasts. Here we have studied the effects by osteoblast-derived factors on metastatic potential in several human prostate cancer cell lines.

    Methods: Effects on metastatic potential in prostate cancer cells by osteoblast-derived factors were studied in vitro using several methods, including Transwell migration and evaluation of formation of pro-migratory protrusions. Confocal microscopy was used to evaluate possible changes in differentiation state in tumor cells by analysis of markers for epithelial-to-mesenchymal transition (EMT). The Matrigel-on-top 3D culture method was used for further assessment of metastatic characteristics in tumor cells by analysis of formation of filopodium-like protrusions (FLPs).

    Results: Osteoblast-derived factors increased migration of PC-3U cells, an effect less prominent in cells overexpressing a mutated type I TGFβ receptor (TβRI) preventing non-canonical TRAF6-dependent TGFβ signaling. Osteoblast-derived factors also increased the formation of long protrusions and loss of cell-cell contacts in PC-3U cells, suggesting induction of a more aggressive phenotype. In addition, treatment with TGFβ or osteoblast-derived factors of PC-3U cells in Matrigel-on-top 3D cultures promoted formation of FLPs, previously shown to be essential for metastatic establishment.

    Conclusions: These findings suggests that factors secreted from osteoblasts, including TGFβ, can induce several cellular traits involved in metastatic potential of PC-3U cells, further strengthening the role for bone cells to promote metastatic tumor cell behavior.

  • 39. Källberg, Eva
    et al.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ivars, Fredrik
    Leanderson, Tomas
    Indoleamine 2,3-dioxygenase (IDO) activity influence tumor growth in the TRAMP prostate cancer model2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 13, p. 1461-1470Article in journal (Refereed)
    Abstract [en]

    Our results argue for a role for IDO mediated immune suppression in the early stages of prostate cancer progression. However, since the intra-tumor IDO expression in J(-/-) mice was indistinguishable from that of C57BL/6 animals the IDO expression in the tumor tissue appears to be irrelevant for TRAMP tumor incidence.

  • 40.
    Lindmark, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Zheng, S Lilly
    Meyers, Deborah A
    Xu, Jianfeng
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer.2004In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 59, no 2, p. 132-140Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The macrophage scavenger receptor 1 (MSR1) gene on chromosome 8p22 was recently reported as a candidate gene for hereditary prostate cancer (HPC). Here, we further elucidate the role of MSR1 in both Swedish families with HPC and in a cohort of unselected prostate cancer. METHODS: DNA samples from 83 Swedish HPC families and 215 unselected population based cases of prostate cancer as well as 425 age-matched controls were genotyped. RESULTS: A total of 18 variants were identified, including 2 exonic, 7 intronic changes, and 9 changes in the 5'- or 3'-uncoding region. Of the two exonic changes, one previously reported truncation mutation was identified, a R293X nonsense mutation. This mutation was found in 2 of the 83 (2.4%) HPC families. The R293X mutation was found more frequently in men with PC (4.9%) than in unaffected men (2.7%), consistent with previous published results, however our results were not significant (P = 0.16). To additionally test for potential association of common sequence variants and increased risk for the disease, five common polymorphisms (PRO3, INDEL1, IVS5-57, P275A, INDEL7) were genotyped in the group of 215 prostate cancer cases and 425 age-matched controls. No association between any of the five common sequence variants and prostate cancer were found. CONCLUSION: Our results suggest that mutations in MSR1 gene might play a role in prostate cancer susceptibility, particularly the R293X mutation. This study warrants further investigations of the role of MSR1 in prostate cancer etiology.

  • 41. Lindstrom, Sara
    et al.
    Zheng, S. Lilly
    Wiklund, Fredrik
    Jonsson, Bjoern-Anders
    Adami, Hans-Olov
    Bälter, Katarina
    Brookes, Anthony J.
    Sun, Jielin
    Chang, Bao-Li
    Liu, Wennuan
    Li, Ge
    Isaacs, William B.
    Adolfsson, Jan
    Gronberg, Henrik
    Xu, Jianfeng
    Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 16, p. 1729-1743Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND. Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS. We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS. We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1. gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS. Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.

  • 42.
    Lindström, Sara
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Zheng, S Lilly
    Wiklund, Fredrik
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Adami, Hans-Olov
    Augustsson Bälter, Katarina
    Brookes, Anthony J
    Sun, Jielin
    Chang, Bao-Li
    Liu, Wennuan
    Li, Ge
    Isaacs, William B
    Adolfsson, Jan
    Grönberg, Henrik
    Xu, Jianfeng
    Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway.2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 16, p. 1729-1743Article in journal (Refereed)
  • 43. Lu, Lingyi
    et al.
    Cancel-Tassin, Geraldine
    Valeri, Antoine
    Cussenot, Olivier
    Lange, Ethan M.
    Cooney, Kathleen A.
    Farnham, James M.
    Camp, Nicola J.
    Cannon-Albright, Lisa A.
    Tammela, Teuvo L. J.
    Schleutker, Johanna
    Hoegel, Josef
    Herkommer, Kathleen
    Maier, Christiane
    Vogel, Walther
    Wiklund, Fredrik
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Groenberg, Henrik
    Wiley, Kathleen E.
    Isaacs, Sarah D.
    Walsh, Patrick C.
    Helfand, Brian T.
    Kan, Donghui
    Catalona, William J.
    Stanford, Janet L.
    FitzGerald, Liesel M.
    Johanneson, Bo
    Deutsch, Kerry
    McIntosh, Laura
    Ostrander, Elaine A.
    Thibodeau, Stephen N.
    McDonnell, Shannon K.
    Hebbring, Scott
    Schaid, Daniel J.
    Whittemore, Alice S.
    Oakley-Girvan, Ingrid
    Hsieh, Chih-Lin
    Powell, Isaac
    Bailey-Wilson, Joan E.
    Cropp, Cheryl D.
    Simpson, Claire
    Carpten, John D.
    Seminara, Daniela
    Zheng, S. Lilly
    Xu, Jianfen
    Giles, Graham G.
    Severi, Gianluca
    Hopper, John L.
    English, Dallas R.
    Foulkes, William D.
    Maehle, Lovise
    Moller, Pal
    Badzioch, Michael D.
    Edwards, Steve
    Guy, Michelle
    Eeles, Ros
    Easton, Douglas
    Isaacs, William B.
    Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG2012In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 72, no 4, p. 410-426Article in journal (Refereed)
    Abstract [en]

    BACKGROUND In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD?=?1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS. In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS. Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD cores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS. These results will be useful in prioritizing future susceptibility gene discovery efforts in thiscommon cancer. Prostate 72: 410-426, 2012. (C) 2011 Wiley Periodicals, Inc.

  • 44.
    Markt, Sarah C.
    et al.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston, USA.
    Rider, Jennifer R.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston, USA; Dept Med, Channing Div Network Med, Brigham & Womens Hosp, Boston, USA; Sch Med, Harvard Univ, Boston, USA .
    Penney, Kathryn L.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston, USA; Dept Med, Channing Div Network Med, Brigham & Womens Hosp, Boston, USA; Sch Med, Harvard Univ, Boston, USA .
    Schumacher, Fredrick R.
    Keck Sch Med, Dept Prevent Med, Univ So Calif, Los Angeles, USA.
    Epstein, Mara M.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston, USA; Dept Med, Channing Div Network Med, Brigham & Womens Hosp, Boston, USA; Sch Med, Harvard Univ, Boston, USA .
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Epidemiology, Harvard School of Public Health, Boston MA, United States.
    Sesso, Howard D.
    Dept Med, Div Prevent Med, Brigham & Womens Hosp, Boston, USA; Sch Med, Harvard Univ, Boston, USA .
    Stampfer, Meir J.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston, USA; Dept Med, Channing Div Network Med, Brigham & Womens Hosp, Boston, USA; Sch Med, Harvard Univ, Boston, USA .
    Mucci, Lorelei A.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston, USA; Dept Med, Channing Div Network Med, Brigham & Womens Hosp, Boston, USA; Sch Med, Harvard Univ, Boston, USA .
    Genetic Variation Across C-Reactive Protein and Risk of Prostate Cancer2014In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 74, no 10, p. 1034-1042Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Inflammation has been hypothesized to play an important etiological role in the initiation or progression of prostate cancer. Circulating levels of the systemic inflammation marker C-reactive protein (CRP) have been associated with increased risk of prostate cancer. We investigated the role of genetic variation in CRP and prostate cancer, under the hypothesis that variants may alter risk of disease.

    METHODS. We undertook a case-control study nested within the prospective Physicians' Health Study among 1,286 men with incident prostate cancer and 1,264 controls. Four single-nucleotide polymorphisms (SNPs) were selected to capture the common genetic variation across CRP (r(2) > 0.8). We used unconditional logistic regression to assess the association between each SNP and risk of prostate cancer. Linear regression models explored associations between each genotype and plasma CRP levels.

    RESULTS. None of the CRP SNPs were associated with prostate cancer overall. Individuals with one copy of the minor allele (C) in rs1800947 had an increased risk of high-grade prostate cancer (OR: 1.7; 95% CI: 1.1-2.8), and significantly lower mean CRP levels (P-value < 0.001), however, we found no significant association with lethal disease. Mean CRP levels were significantly elevated in men with one or two copies of the minor allele in rs3093075 and rs1417939, but these were unrelated to prostate cancer risk.

    CONCLUSION. Our findings suggest that SNPs in the CRP gene are not associated with risk of overall or lethal prostate cancer. Polymorphisms in CRP rs1800947 may be associated with higher grade disease, but our results require replication in other cohorts.

  • 45. Markt, Sarah C.
    et al.
    Shui, Irene M.
    Unger, Robert H.
    Urun, Yuksel
    Berg, Christine D.
    Black, Amanda
    Brennan, Paul
    Bueno-de-Mesquita, H. Bas
    Gapstur, Susan M.
    Giovannucci, Edward
    Haiman, Christopher
    Henderson, Brian
    Hoover, Robert N.
    Hunter, David J.
    Key, Timothy J.
    Khaw, Kay-Tee
    Canzian, Federico
    Larranga, Nerea
    Le Marchand, Loic
    Ma, Jing
    Naccarati, Alessio
    Siddiq, Afshan
    Stampfer, Meir J.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stevens, Victoria L.
    Stram, Daniel O.
    Tjonneland, Anne
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Ziegler, Regina G.
    Lindstrom, Sara
    Kraft, Peter
    Mucci, Lorelei A.
    Choueiri, Toni K.
    Wilson, Kathryn M.
    ABO Blood Group Alleles and Prostate Cancer Risk: results from the Breast and Prostate Cancer Cohort Consortium (BPC3)2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 15, p. 1677-1681Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer. METHODS. We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score >= 8 or locally advanced/metastatic disease (stage T3/T4/N1/M1). RESULTS. We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95% CI = 0.87-1.08; Type B: OR = 0.92, 95% CI = n0.77-1.09; Type AB: OR = 1.25, 95% CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk. CONCLUSIONS. ABO blood type was not associated with risk of aggressive prostate cancer. Prostate 75: 1677-1681, 2015. (C) 2015 Wiley Periodicals, Inc.

  • 46. Markt, Sarah C
    et al.
    Shui, Irene M
    Unger, Robert H
    Urun, Yuksel
    Berg, Christine D
    Black, Amanda
    Brennan, Paul
    Bueno-de-Mesquita, H Bas
    Gapstur, Susan M
    Giovannucci, Edward
    Haiman, Christopher
    Henderson, Brian
    Hoover, Robert N
    Hunter, David J
    Key, Timothy J
    Khaw, Kay-Tee
    Canzian, Federico
    Larranga, Nerea
    Le Marchand, Loic
    Ma, Jing
    Naccarati, Alessio
    Siddiq, Afshan
    Stampfer, Meir J
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Stevens, Victoria L
    Stram, Daniel O
    Tjønneland, Anne
    Travis, Ruth C
    Trichopoulos, Dimitrios
    Ziegler, Regina G
    Lindstrom, Sara
    Kraft, Peter
    Mucci, Lorelei A
    Choueiri, Toni K
    Wilson, Kathryn M
    ABO blood group alleles and prostate cancer risk: Results from the breast and prostate cancer cohort consortium (BPC3)2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 15, p. 1677-81Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer.

    METHODS: We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score ≥8 or locally advanced/metastatic disease (stage T3/T4/N1/M1).

    RESULTS: We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95%CI = 0.87-1.08; Type B: OR = 0.92, 95%CI =n0.77-1.09; Type AB: OR = 1.25, 95%CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk.

    CONCLUSIONS: ABO blood type was not associated with risk of aggressive prostate cancer.

  • 47. Matsuyama, Hideyasu
    et al.
    Pan, Yi
    Yoshihiro, Satoru
    Kudren, David
    Naito, Katsusuke
    Bergerheim, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Ekman, Peter
    Clinical significance of chromosome 8p, 10q, and 16q deletions in prostate cancer2003In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 54, p. 103-111Article in journal (Refereed)
  • 48.
    Ohlson, Nina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Persson, Malin Lindhagen
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice.2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 16, p. 1687-1697Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The mechanisms by which castration induces prostate involution are largely unknown. METHODS: Early responses to castration in mouse ventral prostate (VP) were explored by quantitative microscopy, cDNA array expression, quantitative RT-PCR, and Western blot analysis. As several changes occurred in the insulin-like growth factor (IGF) system this was studied in more detail. Laser micro-dissection was used to localize sites of IGF-1 and IGF-1 receptor (IGF-R1) production. IGF-1 protein levels and IGF-R1 mediated signaling via insulin regulated substrate 1 and 2 (IRS-1 and 2) were examined. IGF-1 was injected into the VP in intact, and castrated mice and effects studied 1 day later. RESULTS: IGF-1 and IGF binding protein 2 (IGFBP-2) mRNA were rapidly reduced whereas IGFBP-3 and IGF-R1 mRNA were increased after castration. IGF-1 was principally produced in the stromal compartment, while IGF-R1 was produced in both epithelial and stromal cells. IGF-1 and IRS-1 protein levels were decreased 1 and 3 days after castration, respectively, while IRS-2 was unchanged. Inactivating phosphorylation of IRS-1 at serine 307 was increased 1 day after castration, and activating phosphorylation at tyrosine 612 was decreased 2 days later. These changes were accompanied by decreased cell proliferation and increased cell death in the glandular and vascular compartment. Local injection of IGF-1 increased vascular density and epithelial cell proliferation in intact mice, but had no effect in castrated animals. CONCLUSION: Decreased IGF-1 levels and action may mediate some of the key features of castration-induced prostate involution.

  • 49.
    Ohlson, Nina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Cell proliferation and apoptosis in prostate tumors and adjacent non-malignant prostate tissue in patients at different time-points after castration treatment.2005In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 62, no 4, p. 307-315Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Androgen ablation is the standard treatment for advanced prostate cancer but the short-term cellular effects are largely unknown. METHODS: Sextant prostate biopsies were taken from 77 prostate cancer patients before and 1-10 days after castration treatment. Apoptosis, cell proliferation, and morphology were studied in malignant and non-malignant tissue, using stereological and immunohistochemical methods. RESULTS: Epithelial cell proliferation was significantly decreased both in non-malignant and malignant epithelium already 1 day after therapy. It remained low until day 7, but increased thereafter in the remaining non-malignant epithelial cells and in some tumors. Epithelial cell apoptosis was significantly increased during the first week and then returned to basal levels. The maximal apoptotic indexes, seven- and two-times the intact levels in the non-malignant and malignant glands, respectively, were found at days 3-4 or even earlier in the tumors. Signs of tumor shrinkage such as glandular collapse and decreased tumor cell size were observed from day 3 in most tumors. DISCUSSION: The present study shows that the magnitude and kinetics of the response to castration in the normal human prostate is very similar to the response previously described in rodents. We also demonstrate that most human prostate tumors rapidly respond to castration indicating the need for further evaluation of when and how to best monitor the effects of hormone ablation therapy in prostate cancer patients. (c) 2004 Wiley-Liss, Inc.

  • 50.
    Olsson, Mats
    et al.
    Karolinska University Hospital, Stockholm.
    Gustafsson, Ove
    Skogastierna, Cristine
    Tolf, Anna
    Karolinska University Hospital, Stockholm.
    Rietz, Barbara Du
    Morfin, Robert
    Rane, Anders
    Ekström, Lena
    Regulation and expression of human CYP7B1 in prostate: overexpression of CYP7B1 during progression of prostatic adenocarcinoma.2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 13, p. 1439-46Article in journal (Refereed)
    Abstract [en]

    This is the first report showing that CYP7B1 is overexpressed in high-grade PIN and in prostate cancer and that local methylation of CYP7B1 promoter region may have significant effect on gene transcription.

12 1 - 50 of 70
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