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  • 1.
    Ahnström, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, Tommy
    Karolinska University Hospital.
    Skoog, Lambert
    Karolinska University Hospital.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer2009In: International Journal of Oncology, ISSN 1019-6439, Vol. 34, no 2, p. 441-448Article in journal (Refereed)
    Abstract [en]

    Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G(1) phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.93) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).

  • 2. Akhtar, Monira
    et al.
    Holmgren, Claes
    Gondor, Anita
    Vesterlund, Mattias
    Kanduri, Chandrasekhar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Catharina
    Ekström, Tomas J.
    Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity2012In: International Journal of Oncology, ISSN 1019-6439, Vol. 41, no 6, p. 1959-1966Article in journal (Refereed)
    Abstract [en]

    The fetal transcription factor PLAG1 is found to be overexpressed in cancers, and has been suggested to bind the insulin like growth factor 2 (IGF2) P3 promoter, and to activate the IGF2 gene. The expression of IGF2 has partly been linked to loss of CTCF-dependent chromatin insulator function at the H19 imprinting control region (ICR). We investigated the role of PLAG1 for IGF2 regulation in Hep3B and JEG-3 cell lines. Chromatin immunoprecipitation revealed cell type-specific binding of PLAG1 to the IGF2 P3 promoter, which was substantially insensitive to recombinant PLAG1 overexpression in the endogenous context. We hypothesized that the H19 chromatin insulator may be involved in the cell type-specific PLAG1 response. By using a GFP reporter gene/insulator assay plasmid construct with and without the H19 ICR and/or an SV40 enhancer, we confirm that the effect of the insulator is specifically associated with the activity of the IGF2 P3 promoter in the GFP reporter system, and furthermore, that the reporter insulator is functional in JEG-3 but not in Hep3B cells. FACS analysis was used to assess the function of PLAG1 in low endogenously expressing, but Zn-inducible stable PLAG1 expressing JEG-3 cell clones. Considerable increase in IGF2 expression upon PLAG1 induction with a partial insulator overriding activity was found using the reporter constructs. This is in contrast to the effect of the endogenous IGF2 gene which was insensitive to PLAG1 expression in JEG-3, while modestly induced the already highly expressed IGF2 gene in Hep3B cells. We suggest that the PLAG1 binding to the IGF2 P3 promoter and IGF2 expression is cell type-specific, and that the PLAG1 transcription factor acts as a transcriptional facilitator that partially overrides the insulation by the H19 ICR.

  • 3. Alimov, A
    et al.
    Sundelin, B
    Bergerheim, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Pavlenko, M
    Pisa, P
    Zetterberg, A
    Larsson, C
    Lagercrantz, S
    Molecular cytogenetic characterization shows higher genetic homogeneity in conventional renal cell carcinoma compared to other kidney cancers2004In: International Journal of Oncology, ISSN 1019-6439, Vol. 25, p. 955-960Article in journal (Refereed)
  • 4. Alimov, Andrei
    et al.
    Sundelin, Birgitta
    Wang, Naining
    Larsson, Catharina
    Bergerheim, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Loss of 14q31-q32.2 in renal cell carcinoma is associated with high malignancy grade and poor survival2004In: International Journal of Oncology, ISSN 1019-6439, Vol. 25, p. 179-185Article in journal (Refereed)
  • 5.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 3, p. 1185-1194Article in journal (Refereed)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 6. Altai, Mohamed
    et al.
    Liu, Hao
    KTH, School of Biotechnology (BIO), Protein Technology.
    Orlova, Anna
    Tolmachev, Vladimir
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Protein Technology.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 3, p. 1185-1194Article in journal (Refereed)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide In-111. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)(3) purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, In-111-(HE)(3)-Z(HER2)-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 7.
    Andersson, Jennie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Yavari, Nazila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    In Vitro Therapy Modeling of HER2 Targeting Therapy in Disseminated Prostate Cancer2014In: International Journal of Oncology, ISSN 1019-6439, Vol. 45, no 5, p. 2153-2158Article in journal (Refereed)
    Abstract [en]

    Prostate cancer (PCa) is the most common cancer type among men. Treatments against advanced PCa are limited and in many cases only palliative. In a later, androgent independent, stage of PCa androgen receptors can be activated without interaction with ligand, i.e., by receptors of tyrosine kinase (RTK) family in the outlaw pathway. Human epidermal growth factor receptors HER2 and EGFR belong to RTK-family. HER2 is one of the main actors in the outlaw pathway with EGFR as the preferable heterodimerizing partner. We hypothesized that information on HER2 expression in advanced PCa could be useful for selection of patients for anti-RTK therapy and monitoring of therapy response. A panel of PCa cell lines (LNCap, PC3, DU-145) was subjected to a 8-week treatment using drugs influencing the RTK: trastuzumab (anti‑HER2), 17-DMAG (Hsp90 inhibitor), alone or in combination, and their HER2 and EGFR expressions were compared with non-treated cells. Treatment with trastuzumab decreased proliferation of LNCap and DU-145 cell lines, while 17-DMAG and trastuzumab/17‑DMAG combination affected all three cell lines. HER2 expression was significantly increased in PC3 cells, the most resistant cell line. On the contrary, in responding cells (LNCap and DU-145) HER2 expression decreased, accompanied by increased EGFR expression. However, additional treatment of cells with cetuximab (anti‑EGFR) did not give any additive effect to trastuzumab. In this study the response to anti-RTK therapy proved to vary between different PCa cell lines. We have demonstrated that RTK targeting treatments may affect the phenotypic profile of PCa tumor cells that correlates with therapy outcome. Observation of such changes during treatment could be used for monitoring and an improved therapy outcome.

  • 8.
    Andersson, Ken G.
    et al.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Oroujeni, Maryam
    Garousi, Javad
    Mitran, Bogdan
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Orlova, Anna
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, Vladimir
    Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR:2377 affibody molecule labeled with Tc-99m using a peptide-based cysteine-containing chelator2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 6, p. 2285-2293Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide Tc-99m should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with Tc-99m using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, Tc-99m-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that Tc-99m-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6 1 and 2.5 0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8 0.4 and 8 3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of Tc-99m-labeled ZEGFR:2377 for imaging of EGFR in vivo.

  • 9.
    Au, Gough G
    et al.
    The University of Newcastle.
    Lindberg, A Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Barry, Richard D
    The University of Newcastle.
    Shafren, Darren R
    The University of Newcastle.
    Oncolysis of vascular malignant human melanoma tumors by Coxsackievirus A21.2005In: International Journal of Oncology, ISSN 1019-6439, Vol. 26, no 6, p. 1471-6Article in journal (Refereed)
    Abstract [en]

    Cultured melanoma cell lines despite exhibiting similar in vitro morphology, display significant phenotypic and growth rate differences when propagated as in vivo xenografts. Previously we have shown that Coxsackievirus A21 (CVA21) lytically infects in vitro cultures of malignant melanoma cells and is efficient at reducing the tumor burden of mice bearing slow-growing SK-Mel-28 melanoma xenografts. The oncolytic activity of CVA21 against in vivo melanoma xenografts, which possess rapid growth rates and more extensive vascular structure than SK-Mel-28 xenografts warrants further investigation. In the present study we evaluated the oncolytic action of CVA21 against rapidly growing melanoma xenografts (ME4405) which exhibit a highly vascular phenotype. Flow cytometric analysis indicated that in vitro cultures of ME4405 cells expressed comparable levels of the CVA21 cellular receptors, ICAM-1 (intercellular adhesion molecules-1) and DAF (decay accelerating factor) to SK-Mel-28 cells. Despite similar levels of CVA21 receptor expression, SK-Mel-28 cells appear to be more susceptible to viral lysis than ME4405 cells, even though the kinetics of virus replication in both lines was comparable. Intratumoral, intraperitoneal or intravenous administration of CVA21 were equally effective in reducing the tumor volume of ME4405 xenografts in immunodeficient mice, and provides further evidence for the use of CVA21 as a novel oncolytic agent against varying phenotypes of malignant melanoma.

  • 10. Barta, Pavel
    et al.
    Malmberg, Jennie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Melicharova, Ludmila
    Strandgård, John
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Laznicek, Milan
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Protein interactions with HER-family receptors can have different characteristics depending on the hosting cell line2012In: International Journal of Oncology, ISSN 1019-6439, Vol. 40, no 5, p. 1677-1682Article in journal (Refereed)
    Abstract [en]

    Cell lines are common model systems in the development of therapeutic proteins and in the research on cellular functions and dysfunctions. In this field, the protein interaction assay is a frequently used tool for assessing the adequacy of a protein for diagnostic and therapeutic purposes. In this study, we investigated the extent to which the interaction characteristics depend on the choice of cell line for HER-family receptors. The interaction characteristics of two therapeutic antibodies (trastuzumab and cetuximab) and one Affibody molecule (ZHER2:342), interacting with the intended receptor were characterized with high precision using an automated real-time interaction method, in different cell lines (HaCaT, A431, HEP-G2, SKOV3, PC3, DU-145). Clear differences in binding affinity and kinetics, up to one order of magnitude, were found for the interaction of the same protein binding to the same receptor on different cells for all three proteins. For HER-family receptors, it is therefore important to refer to the measured affinity for a protein-receptor interaction together with the hosting cell line. The ability to accurately measure affinity and kinetics of a protein-receptor interaction on cell lines of different origins may increase the understanding of underlying receptor biology, and impact the selection of candidates in the development of therapeutic or diagnostic agents.

  • 11. Belpomme, D.
    et al.
    Irigaray, P.
    Sasco, A. J.
    Newby, J. A.
    Howard, V.
    Clapp, R.
    Hardell, Lennart
    Örebro University, Department of Natural Sciences.
    The growing incidence of cancer: Role of lifestyle and screening detection (Review)2007In: International Journal of Oncology, ISSN 1019-6439, Vol. 30, no 5, p. 1037-1049Article in journal (Refereed)
    Abstract [en]

    The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population, as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed: i) over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased; ii) obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other lifestyle-related factors; iii) there is evidence that the environment has changed over the same time scale as the recent rise in cancer incidence, and that this change included the accumulation of many new carcinogenic factors in the environment; iv) genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through gene-environment interactions; v) age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children; vi) the fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical window period may explain why current epidemiological studies may be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment contributes to the rising trend in cancer incidence.

  • 12.
    Benetkiewicz, Magdalena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Díaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jankowski, Michal
    Bala, Dariusz
    Hoffman, Jacek
    Srutek, Ewa
    Laskowski, Ryszard
    Zegarski, Wojciech
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity2006In: International Journal of Oncology, ISSN 1019-6439, Vol. 29, no 4, p. 935-945Article in journal (Refereed)
    Abstract [en]

    Breast cancer is a common malignancy and the second most frequent cause of death among women. Our aim was to perform DNA copy number profiling of 22q in breast tumors using a methodology which is superior, as compared to the ones applied previously. We studied 83 biopsies from 63 tumors obtained from 60 female patients. A general conclusion is that multiple distinct patterns of genetic aberrations were observed, which included deletion(s) and/or gain(s), ranging in size from affecting the whole chromosome to only a few hundred kb. Overall, the analysis revealed genomic imbalances of 22q in 22% (14 out of 63) of tumors. The predominant profile (11%) was monosomy 22. The smallest identified candidate region, in the vicinity of telomere of 22q, encompasses approximately 220 kb and was involved in all but one of the tumors with aberrations on chromosome 22. This segment is dense in genes and contains 11 confirmed and one predicted gene. The availability of multiple biopsies from a single tumor provides an excellent opportunity for analysis of possible intra-tumor differences in genetic profiles. In 15 tumors we had access to two or three biopsies derived from the same lesion and these were studied independently. Four out of 15 (26.6%) tumors displayed indications of clonal intra-tumor genotypic differences, which should be viewed as a high number, considering that we studied in detail only a single human chromosome. Our results open up several avenues for continued genetic research of breast cancer.

  • 13. Bogaerts, Eliene
    et al.
    Heindryckx, Femke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vandewynckel, Yves-Paul
    Van Grunsven, Leo A.
    Van Vlierberghe, Hans
    The roles of transforming growth factor- similar to, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours ( Review)2014In: International Journal of Oncology, ISSN 1019-6439, Vol. 44, no 4, p. 1015-1022Article, review/survey (Refereed)
    Abstract [en]

    Primary liver tumours have a high incidence and mortality. The most important forms are hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both can occur together in the mixed phenotype hepatocellular-cholangiocarcinoma. Liver progenitor cells (LPCs) are bipotential stem cells activated in case of severe liver damage and are capable of forming both cholangiocytes and hepatocytes. Possibly, alterations in Wnt, transforming growth factor-, Notch and hypoxia pathways in these LPCs can cause them to give rise to cancer stem cells, capable of driving tumourigenesis. In this review, we summarize and discuss current knowledge on the role of these pathways in LPC activation and differentiation during hepatocarcinogenesis.

  • 14.
    Bohl Kullberg, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
    Capala, J
    Sjöberg, S
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Introductory experiments on ligand liposomes as delivery agents for boronneutron capture therapy2003In: International Journal of Oncology, ISSN 1019-6439, Vol. 23, no 2, p. 461-467Article in journal (Refereed)
    Abstract [en]

    Liposomes are, when coupled to receptor ligands, candidates for receptor mediated delivery of boron for tumour therapy since they have capacity to deliver large amounts of boron per receptor interaction. With EGF-liposomes we present a pegylated ligand liposome delivery vehicle, containing water soluble boronated phenanthridine, WSP1, or water soluble boronated acridine, WSA1, for EGFR targeting. In the case of WSA1 a ligand dependent uptake was obtained and the boron uptake was as good as if free WSA1 was given. No ligand dependent boron uptake was seen for WSP1 containing liposomes. Thus, WSA1 is a candidate for further studies. Approximately 10(5) boron atoms were in each liposome. A critical assessment indicates that after optimization up to 10(6) boron atoms can be loaded. Since it is known that, for therapeutic effect, approximately 10(8)-10(9) boron atoms are needed in a single tumour cell it is realized that 10(2)-10(3) receptor interactions are needed to meet the demand. Tests applying cultured glioma cells indicate, without optimization of the delivery conditions, a boron uptake in the ppm range, which is necessary for successful BNCT. Thus, it seems possible to kill micro-invasive tumour cells with targeted liposomes if the delivery conditions are optimal.

  • 15.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Coates, Philip J
    Hedberg, Ylva
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Clinical Microbiology, Biomedical Laboratory Science.
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Dahlqvist, Åke
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Expression of p63, COX-2, EGFR and beta-catenin in smokers and patients with squamous cell carcinoma of the head and neck reveal variations in non-neoplastic tissue and no obvious changes in smokers.2005In: International Journal of Oncology, ISSN 1019-6439, Vol. 27, no 6, p. 1661-1667Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common malignancy in the world, is associated with smoking and has a low 5-year survival rate. Various changes have been described at different stages of SCCHN tumour development, including overexpression of p63, a protein important for development of normal epidermal structures. p63 has been suggested to activate beta-catenin, and nuclear accumulation of beta-catenin is an important event in many cancers. Elevated COX-2 activity and overexpression of EGFR protein has been shown in a variety of human cancers, including SCCHN. An important question for the pathogenesis of SCCHN is when the genetic changes take place during the natural course of the disease, and whether they appear in clinically normal oral mucosa to predispose tumour development. We mapped the expression of p63, COX-2, EGFR, beta-catenin, and PP2A in oral mucosa from smokers/non-smokers and from patients with SCCHN. We also considered if changes occurring in tumours are present in the clinically normal tissue adjacent to the tumour. No direct influence of heavy smoking on the levels of the proteins studied could be seen. Tumours and clinically normal non-neoplastic tissue from SCCHN patients showed increased expression of COX-2 and PP2A. Interestingly, non-neoplastic tissue adjacent to SCCHN also showed increased beta-catenin, although this was not seen in tumours. The data support the notion that pre-existing alterations in clinically normal epithelium exist in patients with SCCHN and could be important for the pathogenesis of the disease and for local recurrences.

  • 16. Cui, Baoxia
    et al.
    Zheng, Biying
    Zhang, Xi
    Stendahl, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Sonia
    Wallin, Keng-Ling
    Mutation of PIK3CA: possible risk factor for cervical carcinogenesis in older women2009In: International Journal of Oncology, ISSN 1019-6439, Vol. 34, no 2, p. 409-416Article in journal (Refereed)
    Abstract [en]

    PIK3CA encodes the p110alpha catalytic subunit of PI 3-kinase, which regulates signaling pathways important for neoplasia, cell proliferation and apoptosis. Somatic mutations in this gene have been detected in several solid human tumors. We investigated these mutations in cervical carcinoma and its precursors, and their association with HPV infection and patient clinical data. The mutations were analyzed using post-PCR direct genomic DNA sequencing. Samples included 9 cervical cancer cell lines, 184 invasive cervical carcinomas, and 30 cervical neoplasias. Missense mutations of PIK3CA were identified in 15/184 (8.15%) invasive cervical carcinomas. One novel mutation G1638C (Q546H) was found. Three mutations were identified in the cervical cancer lines. No mutations were found in the precursors. The difference in mutation frequency between invasive and pre-invasive lesions was not significant (p=0.1372). In relation to age and HPV, the mutation rate was significantly higher in patients>or=60 years (p=0.001), while the rate of HPV infection was higher in patients

  • 17.
    Dimberg, Jan
    et al.
    University College of Health Sciences, Jönköping, Sweden.
    Dienus, Olaf
    Ryhov County Hospital, Jönköping, Sweden.
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden.
    Expression and gene polymorphisms of the chemokine CXCL5 in colorectal cancer patients2007In: International Journal of Oncology, ISSN 1019-6439, Vol. 31, no 1, p. 97-102Article in journal (Refereed)
    Abstract [en]

    Several studies indicate that chemokines play important roles in colorectal mucosal immunity by recruiting leukocytes into and out of the lamina propria adjacent to the epithelium. The chemokine CXCL5 which is expressed by epithelial cells within colorectal mucosa is a chemoattractant for neutrophils and has been implicated in Crohns disease and ulcerative colitis. In addition, CXCL5 is one chemokine which promote angiogenesis related to cancer. The objective of this study was to determine by ELISA assay whether CXCL5 protein level is altered in colorectal cancer (CRC) tissues (n=80) compared with paired normal mucosa. Furthermore, the plasma CXCL5 levels from CRC patients (n=62) compared with controls (n=71) were also examined. Using a TaqMan system we screened for -156G -greater than C and +398G -greater than A CXCL5 gene variants in CRC patients (n=228) and a control group (n=231) to assess the role of CXCL5 genotype in CRC. The analyses showed that CXCL5 protein level in colorectal tumours was significantly (P less than 0.0001) higher than in normal tissue and was lower in plasma in CRC patients compared with controls (P=0.026). Immunohistochemistry revealed CXCL5 immunoreactivity mainly in epithelial cells of the colorectal carcinoma and in normal epithelial cells. Furthermore, patients who were -156C carriers had higher CXCL5 protein concentration compared with -156G carriers in normal tissue (P=0.027) and CXCL5 protein levels in cancerous tissue tended to be higher for the patient -156C carriers (P=0.059). To our knowledge this is the first report on the influence of CXCL5 gene variants and their relation to expression of CXCL5 protein in human CRC.

  • 18.
    Dimberg, Jan
    et al.
    Jönköping University, School of Health Science, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health Science, HHJ. Ageing - living conditions and health. Jönköping University, School of Health Science, HHJ. Biomedical Platform.
    Dienus, Olaf
    Löfgren, Sture
    Hugander, Anders
    Wågsäter, Dick
    Expression and gene polymorphisms of the chemokine CXCL5 in colorectal cancer patients2007In: International Journal of Oncology, ISSN 1019-6439, Vol. 31, no 1, p. 97-102Article in journal (Other academic)
  • 19.
    Dimberg, Jan
    et al.
    University College of Health Sciences, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Wågsäter, Dick
    University of Örebro, Sweden.
    Protein expression of the chemokine, CCL28, in human colorectal cancer2006In: International Journal of Oncology, ISSN 1019-6439, Vol. 28, no 2, p. 315-319Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence points out that chemokines play important roles in colorectal mucosal immunity by recruiting leukocytes into and out of the lamina propria adjacent to the epithelium. The chemokine, CCL28, which is expressed by epithelial cells within colorectal mucosa is thought to have dual roles as a chemoattractant for leukocytes expressing CCR10 and/or CCR3 and a mediator of antimicrobial activity. To date, there is little known about the presence of CCL28 in colorectal cancer. The objective of this study was to determine whether the CCL28 protein level is altered in colorectal tumours (n=76) compared with paired normal mucosa. Further, the plasma CCL28 levels from patients with colon and rectal cancer were also examined. Immunohistochemistry revealed heterogeneous CCL28 protein expression in tumour and normal epithelial cells. Analyses by ELISA showed that the CCL28 protein level in colon tumours was significantly (P less than 0.001) lower than in normal tissue and that the difference in CCL28 protein level between rectal tumour and normal tissue was not significant. Patients with a tumour localized in the colon had significantly (P less than 0.05) higher plasma CCL28 protein levels than patients with a tumour localized in the rectum. These discrepancies may suggest that there are different mechanisms and signalling pathways involved in the pathogenesis of cancer in the colon and rectum and thereby differentially promote the expression and secretion of CCL28 protein. Further studies on CCL28 protein in colorectal cancer with an extended number of patients are necessary to conclude whether tissue levels and plasma concentrations carry significant clinical relevance.

  • 20.
    Dimberg, Jan
    et al.
    Jönköping University, School of Health Science, HHJ, Dep. of Natural Science and Biomedicine. Jönköping University, School of Health Science, HHJ. Ageing - living conditions and health. Jönköping University, School of Health Science, HHJ. Biomedical Platform.
    Hugander, Anders
    Wågsäter, Dick
    Protein expression of the chemokine, CCL28, in human colorectal cancer.2006In: International Journal of Oncology, ISSN 1019-6439, Vol. 28, no 2, p. 315-319Article in journal (Other academic)
  • 21.
    Ekberg, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Engström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue2005In: International Journal of Oncology, ISSN 1019-6439, Vol. 26, no 5, p. 1177-85Article in journal (Refereed)
    Abstract [en]

    The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2, HER3, and HER4 were evaluated by immunohistochemistry in 19 cases of metastatic squamous cell carcinoma of the oral cavity and base of tongue. EGFR had a similar and high expression in both primary tumours and the corresponding metastases, while the expression in normal epithelium was lower in most cases. HER2 was not expressed to the same extent as EGFR. However, when HER2 was well expressed, it was in most cases expressed to the same extent and intensity in the primary tumours, metastases, and normal epithelium. The expression of HER3 and HER4 varied and was mainly cytoplasmic in all cases studied. No overexpression of HER3 and HER4 in tumours was seen as compared to normal epithelium. In order to further investigate the distribution of HER3, two HER3 expressing cell lines originating from tongue cancer were analysed in vitro, using radiolabelled anti-HER3 antibodies directed to the extracellular domains of the receptor. The results indicated that HER3 was not present in measurable amounts in the cellular membrane. There is a need for improved diagnostics and therapy for the studied type of tumours, e.g. using radiolabelled antibodies or ligands, and EGFR seemed suitable as target since the expression was high, membrane associated and similar in the primary tumours and the corresponding metastases.

  • 22.
    El-Salhy, Magdy
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Hilding, L
    Royson, H
    Tjomsland, Veronica
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology.
    Comparison between triple therapy with octreotide, galanin and serotonin vs. irinotecan or oxaliplatin in combination with 5-fluorouracil/leukovorin in human colon cancer.2005In: International Journal of Oncology, ISSN 1019-6439, Vol. 27, no 3, p. 687-691Article in journal (Refereed)
    Abstract [en]

    Human colon cancer cells were injected sub-cutaneously into 30 nude mice. After 8 days, the animals were divided into 3 equal groups. The first and second groups received an i.p. injection with 5-fluorouracil/leukovorin (5-FU/LV) for 5 days (20 mg and 10 mg/kg body weight respectively). On the first day of 5-FU/LV treatment, the first group received an i.p. injection of irinotecan (2.5 mg/kg body weight), and the second group received an i.p. injection with oxaliplatin (1 mg/kg body weight). The third group were injected i.p. with 100 microl saline solution containing octreotide, galanin and serotonin. Injections were given 3 times daily for 5 days with a total dose of 150 microg/kg body weight/day. Three days after the treatment, the animals were sacrificed. Whereas the animals treated with triple therapy held a stable body weight, animals treated with 5-FU/LV-irinotecan and 5-FU/LV-oxaliplatin had gradual weight loss, which amounted to approximately 25% of their body weight at the end of the experiment. Moreover, 2 mice in the group treated with 5-FU/LV-irinotecan died, most probably due to side effects. There was no statistically significant difference between the 3 groups regarding tumour proliferation, apoptosis, blood vessel density, EGF- and VEGF-expression. Treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable to 5-FU/LV in combination with irinotecan and oxaliplatin. However, triple therapy seems to have a better safety profile.

  • 23.
    Engström, Alexander
    et al.
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Erlandsson, Ann
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Delbro, Dick
    Örebro University, School of Medicine, Örebro University, Sweden.
    Wijkander, Jonny
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Conditioned media from macrophages of M1, but not M2 phenotype, inhibit the proliferation of the colon cancer cell lines HT-29 and CACO-22014In: International Journal of Oncology, ISSN 1019-6439, Vol. 44, no 2, p. 385-392Article in journal (Refereed)
    Abstract [en]

    Solid tumors are infiltrated by stroma cells including macrophages and these cells can affect tumor growth, metastasis and angiogenesis. We have investigated the effects of conditioned media (CM) from different macrophages on the proliferation of the colon cancer cell lines HT-29 and CACO-2. CM from THP-1 macrophages and monocyte-derived human macrophages of the M1 phenotype, but not the M2 phenotype, inhibited proliferation of the tumor cells in a dose-dependent manner. Lipopolysaccaharide and interferon gamma was used for differentiation of macrophages towards the M1 phenotype and CM were generated both during differentiation (M1(DIFF)) and after differentiation (M1). M1 and M1(DIFF) CM as well as THP-1 macrophage CM resulted in cell cycle arrest in HT-29 cells with a decrease of cells in S phase and an increase in G(2)/M phase. Treatment of HT-29 cells with M1(DIFF), but not M1 or THP-1 macrophage CM, resulted in apoptosis of about 20% of the tumor cells and this was accompanied by lack of recovery of cell growth after removal of CM and subsequent culture in fresh media. A protein array was used to identify cytokines released from M1 and M2 macrophages. Among the cytokines released by M1 macrophages, tumor necrosis factor alpha and CXCL9 were tested by direct addition to HT-29 cells, but neither affected proliferation. Our results indicate that M1 macrophages inhibit colon cancer cell growth and have the potential of contributing to reducing tumor growth in vivo.

  • 24.
    Engström, Alexander
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Erlandsson, Ann
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Delbro, Dick
    School of Health and Medical Sciences, Örebro University.
    Wijkander, Jonny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Conditioned media from macrophages of M1, but not M2 phenotype, inhibit the proliferation of the colon cancer cell lines HT-29 and CACO-22014In: International Journal of Oncology, ISSN 1019-6439, Vol. 44, no 2, p. 385-392Article in journal (Refereed)
    Abstract [en]

    Solid tumors are infiltrated by stroma cells including macrophages and these cells can affect tumor growth, metastasis and angiogenesis. We have investigated the effects of conditioned media (CM) from different macrophages on the proliferation of the colon cancer cell lines HT-29 and CACO-2. CM from THP-1 macrophages and monocyte-derived human macrophages of the M1 phenotype, but not the M2 phenotype, inhibited proliferation of the tumor cells in a dose-dependent manner. Lipopolysaccaharide and interferon γ was used for differentiation of macrophages towards the M1 phenotype and CM were generated both during differentiation (M1DIFF) and after differentiation (M1). M1 and M1DIFF CM as well as THP-1 macrophage CM resulted in cell cycle arrest in HT-29 cells with a decrease of cells in S phase and an increase in G2/M phase. Treatment of HT-29 cells with M1DIFF, but not M1 or THP-1 macrophage CM, resulted in apoptosis of about 20% of the tumor cells and this was accompanied by lack of recovery of cell growth after removal of CM and subsequent culture in fresh media. A protein array was used to identify cytokines released from M1 and M2 macrophages. Among the cytokines released by M1 macrophages, tumor necrosis factor α and CXCL9 were tested by direct addition to HT-29 cells, but neither affected proliferation. Our results indicate that M1 macrophages inhibit colon cancer cell growth and have the potential of contributing to reducing tumor growth in vivo.

  • 25.
    Evertsson, Sofia
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Bartik, Zsuzsa
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Zhang, Hong
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Jansson, Agneta
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Apoptosis in relation to proliferating cell nuclear antigen and Dukes' stage in colorectal adenocarcinoma1999In: International Journal of Oncology, ISSN 1019-6439, Vol. 15, no 1, p. 53-58Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer is a disease that is associated with default in the balance of apoptotic regulation. In the present study apoptosis was examined in 158 colorectal adenocarcinomas using the terminal deoxynucleotidyl transferase mediated digoxigenin nick end labeling (TUNEL) method. The median apoptotic index (AI) was 0.95% (range 0-6. 68%). Eighty-two tumours exhibited AI 0.95%. We revealed a positive correlation between apoptosis and proliferation determined as the expression of proliferating cell nuclear antigen (PCNA, p=0.002). The frequency of apoptosis increased from Dukes' stage A, B, C to D (p=0.01). No correlations were found between apoptosis and the patients' sex, age, tumour location, growth pattern, differentiation, prognosis, bcl-2, p53 or K-ras. Our findings suggest that we should further investigate the relationship between apoptosis and cellular proliferative activity in colorectal cancer to evaluate whether this might provide additional information in the selection of patients for effective adjuvant therapy.

  • 26.
    Fransson, Susanne
    et al.
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
    Abel, Frida
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
    Kogner, Per
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
    Martinsson, Tommy
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Stage-dependent expression of PI3K/Akt‑pathway genes in neuroblastoma2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 42, no 2, p. 609-616Article in journal (Refereed)
    Abstract [en]

    The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival and has also been implicated in the development of the childhood cancer neuroblastoma. In neuroblastoma high mRNA expression of the PI3K catalytic isoform PIK3CD is associated to favorable disease. Yet, activation of Akt is associated with poor prognosis. Since the contribution of the numerous members of this pathway to neuroblastoma pathogenesis is mainly unknown, genes of the PI3K/Akt pathway were analyzed at the mRNA level through microarrays and quantitative real-time RT-PCR (TaqMan) and at the protein level using western blot analysis. Five genes showed lower mRNA expression in aggressive compared to more favorable neuroblastomas (PRKCZ, PRKCB1, EIF4EBP1, PIK3RI and PIK3CD) while the opposite was seen for PDGFRA. Clustering analysis shows that the expression levels of these six genes can predict aggressive disease. At the protein level, p110δ (encoded by PIK3CD) and p85α isomers (encoded by PIK3R1) were more highly expressed in favorable compared to aggressive neuroblastoma. Evaluation of the expression of these PI3K genes can predict aggressive disease, and indicates stage-dependent involvement of PI3K-pathway members in neuroblastoma.

  • 27. Garousi, Javad
    et al.
    Anderson, Ken G.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Mitran, Bogdan
    Pichl, Marie-Louise
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Orlova, Anna
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, Vladimir
    PET imaging of epidermal growth factor receptor expression in tumours using Zr-89-labelled ZEGFR:2377 affibody molecules2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 48, no 4, p. 1325-1332Article in journal (Refereed)
    Abstract [en]

    Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a radionuclide Zr-89. The Zr-89-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160 +/- 60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, Zr-89-DFO-ZEGFR: 2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6 +/- 0.5% ID/g and tumour-to-blood ratio of 3.7 +/- 0.6 at 24 h after injection. Zr-89-DFO-ZEGFR: 2377 provides higher tumour-to-organ ratios than anti-EGFR antibody Zr-89-DFO-cetuximab at 48 h after injection. EGFR-expressing tumours were clearly visualized by microPET using Zr-89-DFO-ZEGFR: 2377 at both 3 and 24 h after injection. In conclusion, Zr-89-DFO-ZEGFR: 2377 is a potential probe for PET imaging of EGFR-expression in vivo.

  • 28.
    Gothlin Eremo, Anna
    et al.
    University of Örebro, Sweden.
    Tina, Elisabet
    Örebro University Hospital, Sweden.
    Wegman, Pia
    Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fransen, Karin
    University of Örebro, Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
    Wingren, Sten
    University of Örebro, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed)
    Abstract [en]

    The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (Pless than0.0005), PgR-negativity (Pless than0.0005), tumor size greater than20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

  • 29.
    Graflund, Marianne
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Örebro University Hospital, Örebro, Sweden.
    MIB-1, p53, bcl-2, and WAF-1 expression in pelvic lymph nodes and primary tumors in early stage cervical carcinomas: correlation with clinical outcome2002In: International Journal of Oncology, ISSN 1019-6439, Vol. 20, no 5, p. 1041-1047Article in journal (Refereed)
    Abstract [en]

    A complete series of 40 cervical carcinomas with pelvic lymph node metastases were analysed immunohistochemically for prognostic markers. The aims of this study were to examine whether the detection of MIB-1, p53, bcl-2, and WAF-1 could be used as a prognostic marker for tumor recurrence and survival rate. During the period of observation (mean 222, range 72-360 months) 22 (55%) recurrences were encountered and 20 patients died of the disease. There were 35 squamous cell carcinomas (87.5%), 2 adenosquamous carcinomas (5.0%), and 3 pure adenocarcinomas (7.5%). One tumor (2.5%) was well differentiated, 12 tumors (30%) were moderately differentiated, and 27 tumors (67.5%) were poorly differentiated. The primary tumor grade (P=0.037) and radicality of the surgical margins (P=0.021) were significant prognostic factors with regard to tumor recurrence. The site and number of lymph nodes with metastases had no prognostic value. P53, bcl-2, and WAF-1 were not predictive factors for recurrences or the cancer-specific survival rate. The concordant expression of WAF-1 in the primary tumor and in lymph node metastases was lower than for p53 and bcl-2. The proliferative activity (MIB-1) seemed to be lower in tumor cells metastasized to the pelvic lymph nodes than in cells of the primary tumor. Expression of MIB-1 in lymph nodes was predictive of disease-free survival in both univariate and multivariate proportional hazard Cox analyses.

  • 30.
    Göstring, Lovisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Chew, Ming Tsuey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Höidén-Guthenberg, Ingmarie
    Wennborg, Anders
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Quantification of internalization of EGFR-binding Affibody molecules: Methodological aspects2010In: International Journal of Oncology, ISSN 1019-6439, Vol. 36, no 4, p. 757-763Article in journal (Refereed)
    Abstract [en]

    Tumor cell internalization of targeting agents is of interest, since internalization influences the local retention time of a radionuclide and thereby imaging quality in PET and SPECT and effects of radionuclide therapy. In cases where nuclear methods are not applicable at the cellular level, quantitative fluorescent techniques are useful as described in this article. Two fluorescence-based methods to study cellular internalization were applied: the CypHer and the Alexa488-quenching methods, both utilized in fluorescence microscopy and flow cytometry. Two EGFR-binding Affibody molecules were analyzed in A431 cells: the monomer Z1907 and the dimer (Z1907)2. EGF, cetuximab and non-specific Affibody molecules were used as controls. For comparison, internalization of 111In-labeled Z1907 was studied with the acid wash internalization assay. The Cypher method is straightforward, but requires equal labeling of all compounds for accurate quantification. The Alexa488-quenching method is preferable since it is independent of the dye-to-protein ratio. According to this method, about 45% of EGF and 19-24% of the bound Affibody molecules and cetuximab were internalized within one hour. Similar results were seen with 111In-Z1907 in the acid wash method, while (Z1907)2 was not removed by acid and thus could not be studied this way. The fluorescence-based Alexa488-quenching method is well suited to quantitatively analyze internalization of targeting agents, also those that resist acid wash. The internalized fraction showed that both the monomeric and dimeric Affibody molecules are expected to give good uptake and thereby good retention of metallic radionuclides which will render good tumor to background values.

  • 31.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Wegman, Pia
    Department of Clinical Genetics, University Hospital, Linköping, Sweden.
    Stål, Olle
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden; Regional Cancer Center Stockholm-Gotland, Stockholm, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed)
    Abstract [en]

    The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (P<0.0005), PgR-negativity (P<0.0005), tumor size >20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

  • 32. Hallak, Sorana
    et al.
    Ladi, Luz
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences.
    Prophylactic inguinal-femoral irradiation as an alternative to primary lymphadenectomy in treatment of vulvar carcinoma2007In: International Journal of Oncology, ISSN 1019-6439, Vol. 31, no 5, p. 1077-1085Article in journal (Refereed)
    Abstract [en]

    In a complete geographic series of 294 cases of primary vulvar carcinomas prophylactic inguinal-femoral irradiation was used as a standard postoperative therapy. Inguinal lymph node dissection was performed in only 27 cases (9%) and was not part of the standard surgery. The histology was squamous cell carcinoma in 269 cases (92%). The primary surgery was total vulvectomy, partial vulvectomy, or local resection of the tumor. The main type of radiotherapy was adjuvant inguinal irradiation. Two separate, symmetrical and rectangular inguinal fields were irradiated with combined photon and electron beams. In the complete series 127 recurrences (43%) were recorded. Local (24%) and regional recurrences (19%) were most frequent. Type of surgery was not associated with the risk of tumor recurrence. The 5-year overall survival rate was 53% and the relapse-free survival (RFS) rate was 55%. Tumor grade was significantly (P=0.007) associated with the RFS. The inguinal RFS rate was 75% both for patients treated with adjuvant inguinal irradiation without lymphadenectomy and patients treated with primary lymph adenectomy +/- inguinal irradiation. Postoperative complications were recorded in 22%. Postoperative complications occurred most frequently in the subgroup undergoing inguinal lymphadenectomy. Chronic lymph edemas were the most serious late tissue reactions.

  • 33. Hardell, Lennart
    et al.
    Carlberg, Michael
    Hansson Mild, Kjell
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Pooled analysis of case-control studies on malignant brain tumours and the use of mobile and cordless phones including living and deceased subjects2011In: International Journal of Oncology, ISSN 1019-6439, Vol. 38, no 5, p. 1465-1474Article in journal (Refereed)
    Abstract [en]

    We studied the association between use of mobile and cordless phones and malignant brain tumours. Pooled analysis was performed of two case-control studies on patients with malignant brain tumours diagnosed during 1997-2003 and matched controls alive at the time of study inclusion and one case-control study on deceased patients and controls diagnosed during the same time period. Cases and controls or relatives to deceased subjects were interviewed using a structured questionnaire. Replies were obtained for 1,251 (85%) cases and 2,438 (84%) controls. The risk increased with latency period and cumulative use in hours for both mobile and cordless phones. Highest risk was found for the most common type of glioma, astrocytoma, yielding in the >10 year latency group for mobile phone use odds ratio (OR) = 2.7, 95% confidence interval (CI) = 1.9-3.7 and cordless phone use OR = 1.8, 95% CI = 1.2-2.9. In a separate analysis, these phone types were independent risk factors for glioma. The risk for astrocytoma was highest in the group with first use of a wireless phone before the age of 20; mobile phone use OR = 4.9, 95% CI = 2.2-11, cordless phone use OR = 3.9, 95% CI = 1.7-8.7. In conclusion, an increased risk was found for glioma and use of mobile or cordless phone. The risk increased with latency time and cumulative use in hours and was highest in subjects with first use before the age of 20.

  • 34. Hardell, Lennart
    et al.
    Carlberg, Michael
    Soderqvist, Fredrik
    Hansson Mild, Kjell
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 43, no 6, p. 1833-1845Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the hand-held phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04-3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15-20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis.

  • 35.
    Hardell, Lennart
    et al.
    Dept Oncol, Örebro University Hospital, Örebro, Sweden.
    Carlberg, Michael
    Dept Oncol, Örebro University Hospital, Örebro, Sweden.
    Soderqvist, Fredrik
    Dept Oncol, Örebro University Hospital, Örebro, Sweden.
    Mild, Kjell Hansson
    Dept Radiat Phys, Umeå University, Umeå, Sweden.
    Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997-2003 and 2007-2009 and use of mobile and cordless phones2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 43, no 4, p. 1036-1044Article in journal (Refereed)
    Abstract [en]

    We previously conducted a case-control study of acoustic neuroma. Subjects of both genders aged 20-80 years, diagnosed during 1997-2003 in parts of Sweden, were included, and the results were published. We have since made a further study for the time period 2007-2009 including both men and women aged 18-75 years selected from throughout the country. These new results for acoustic neuroma have not been published to date. Similar methods were used for both study periods. In each, one population-based control, matched on gender and age (within five years), was identified from the Swedish Population Registry. Exposures were assessed by a self-administered questionnaire supplemented by a phone interview. Since the number of acoustic neuroma cases in the new study was low we now present pooled results from both study periods based on 316 participating cases and 3,530 controls. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index (SEI). Use of mobile phones of the analogue type gave odds ratio (OR) = 2.9, 95% confidence interval (CI) = 2.0-4.3, increasing with >20 years latency (time since first exposure) to OR = 7.7, 95% CI = 2.8-21. Digital 20 mobile phone use gave OR = 1.5, 95% CI = 1.1-2.1, increasing with latency >15 years to an OR = 1.8, 95% CI = 0.8-4.2. The results for cordless phone use were OR = 1.5, 95% CI = 1.1-2.1, and, for latency of >20 years, OR = 6.5, 95% CI = 1.7-26. Digital type wireless phones (20 and 3G mobile phones and cordless phones) gave OR = 1.5, 95% CI = 1.1-2.0 increasing to OR = 8.1,95% CI = 2.0-32 with latency >20 years. For total wireless phone use, the highest risk was calculated for the longest latency time >20 years: OR = 4.4, 95% CI = 2.2-9.0. Several of the calculations in the long latency category were based on low numbers of exposed cases. Ipsilateral use resulted in a higher risk than contralateral for both mobile and cordless phones. OR increased per 100 h cumulative use and per year of latency for mobile phones and cordless phones, though the increase was not statistically significant for cordless phones. The percentage tumour volume increased per year of latency and per 100 h of cumulative use, statistically significant for analogue phones. This study confirmed previous results demonstrating an association between mobile and cordless phone use and acoustic neuroma.

  • 36. Hardell, Lennart
    et al.
    Carlberg, Michael
    Söderqvist, Fredrik
    Department of Oncology, University Hospital, Örebro, Sweden.
    Hansson Mild, Kjell
    Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 43, no 6, p. 1833-1845Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the handheld phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a 'possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04‑3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15-20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis.

  • 37. Hardell, Lennart
    et al.
    Carlberg, Michael
    Söderqvist, Fredrik
    Örebro University, School of Health and Medical Sciences.
    Hansson Mild, Kjell
    Meta-analysis of long-term mobile phone use and the association with brain tumours2008In: International Journal of Oncology, ISSN 1019-6439, Vol. 32, no 5, p. 1097-1103Article in journal (Refereed)
    Abstract [en]

    We evaluated long-term use of mobile phones and the risk for brain tumours in case-control studies published so far on this issue. We identified ten studies on glioma and meta-analysis yielded OR = 0.9, 95% CI = 0.8-1.1. Latency period of > or =10-years gave OR = 1.2, 95% CI = 0.8-1.9 based on six studies, for ipsilateral use (same side as tumour) OR = 2.0, 95% CI = 1.2-3.4 (four studies), but contralateral use did not increase the risk significantly, OR = 1.1, 95% CI = 0.6-2.0. Meta-analysis of nine studies on acoustic neuroma gave OR = 0.9, 95% CI = 0.7-1.1 increasing to OR = 1.3, 95% CI = 0.6-2.8 using > or =10-years latency period (four studies). Ipsilateral use gave OR = 2.4, 95% CI = 1.1-5.3 and contra-lateral OR = 1.2, 95% CI = 0.7-2.2 in the > or =10-years latency period group (three studies). Seven studies gave results for meningioma yielding overall OR = 0.8, 95% CI = 0.7-0.99. Using > or =10-years latency period OR = 1.3, 95% CI = 0.9-1.8 was calculated (four studies) increasing to OR = 1.7, 95% CI = 0.99-3.1 for ipsilateral use and OR = 1.0, 95% CI = 0.3-3.1 for contralateral use (two studies). We conclude that this meta-analysis gave a consistent pattern of an association between mobile phone use and ipsilateral glioma and acoustic neuroma using > or =10-years latency period.

  • 38. Hardell, Lennart
    et al.
    Carlberg, Michael
    Söderqvist, Fredrik
    Department of Oncology, University Hospital, Örebro.
    Hansson Mild, Kjell
    Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997-2003 and 2007-2009 and use of mobile and cordless phones2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 43, no 4, p. 1036-1044Article in journal (Refereed)
    Abstract [en]

    We previously conducted a case-control study of acoustic neuroma. Subjects of both genders aged 20-80 years, diagnosed during 1997-2003 in parts of Sweden, were included, and the results were published. We have since made a further study for the time period 2007-2009 including both men and women aged 18-75 years selected from throughout the country. These new results for acoustic neuroma have not been published to date. Similar methods were used for both study periods. In each, one population-based control, matched on gender and age (within five years), was identified from the Swedish Population Registry. Exposures were assessed by a self-administered questionnaire supplemented by a phone interview. Since the number of acoustic neuroma cases in the new study was low we now present pooled results from both study periods based on 316 participating cases and 3,530 controls. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index (SEI). Use of mobile phones of the analogue type gave odds ratio (OR) = 2.9, 95% confidence interval (CI) = 2.0-4.3, increasing with >20 years latency (time since first exposure) to OR = 7.7, 95% CI = 2.8-21. Digital 2G mobile phone use gave OR = 1.5, 95% CI = 1.1-2.1, increasing with latency >15 years to an OR = 1.8, 95% CI = 0.8-4.2. The results for cordless phone use were OR = 1.5, 95% CI = 1.1-2.1, and, for latency of >20 years, OR = 6.5, 95% CI = 1.7-26. Digital type wireless phones (2G and 3G mobile phones and cordless phones) gave OR = 1.5, 95% CI = 1.1-2.0 increasing to OR = 8.1, 95% CI = 2.0-32 with latency >20 years. For total wireless phone use, the highest risk was calculated for the longest latency time >20 years: OR = 4.4, 95% CI = 2.2-9.0. Several of the calculations in the long latency category were based on low numbers of exposed cases. Ipsilateral use resulted in a higher risk than contralateral for both mobile and cordless phones. OR increased per 100 h cumulative use and per year of latency for mobile phones and cordless phones, though the increase was not statistically significant for cordless phones. The percentage tumour volume increased per year of latency and per 100 h of cumulative use, statistically significant for analogue phones. This study confirmed previous results demonstrating an association between mobile and cordless phone use and acoustic neuroma.

  • 39.
    Hardell, Lennart
    et al.
    Department of Oncology, University Hospital, Örebro, Sweden.
    Carlberg, Michael
    Department of Oncology, University Hospital, Örebro, Sweden.
    Söderqvist, Fredrik
    Department of Oncology, University Hospital, Örebro, Sweden.
    Hansson Mild, Kjell
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997-2003 and 2007-2009 and use of mobile and cordless phones2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 43, no 4, p. 1036-1044Article in journal (Refereed)
    Abstract [en]

    We previously conducted a case-control study of acoustic neuroma. Subjects of both genders aged 20-80 years, diagnosed during 1997-2003 in parts of Sweden, were included, and the results were published. We have since made a further study for the time period 2007-2009 including both men and women aged 18-75 years selected from throughout the country. These new results for acoustic neuroma have not been published to date. Similar methods were used for both study periods. In each, one population-based control, matched on gender and age (within five years), was identified from the Swedish Population Registry. Exposures were assessed by a self-administered questionnaire supplemented by a phone interview. Since the number of acoustic neuroma cases in the new study was low we now present pooled results from both study periods based on 316 participating cases and 3,530 controls. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index (SEI). Use of mobile phones of the analogue type gave odds ratio (OR) = 2.9, 95% confidence interval (CI) = 2.0-4.3, increasing with >20 years latency (time since first exposure) to OR = 7.7, 95% CI = 2.8-21. Digital 20 mobile phone use gave OR = 1.5, 95% CI = 1.1-2.1, increasing with latency >15 years to an OR = 1.8, 95% CI = 0.8-4.2. The results for cordless phone use were OR = 1.5, 95% CI = 1.1-2.1, and, for latency of >20 years, OR = 6.5, 95% CI = 1.7-26. Digital type wireless phones (20 and 3G mobile phones and cordless phones) gave OR = 1.5, 95% CI = 1.1-2.0 increasing to OR = 8.1,95% CI = 2.0-32 with latency >20 years. For total wireless phone use, the highest risk was calculated for the longest latency time >20 years: OR = 4.4, 95% CI = 2.2-9.0. Several of the calculations in the long latency category were based on low numbers of exposed cases. Ipsilateral use resulted in a higher risk than contralateral for both mobile and cordless phones. OR increased per 100 h cumulative use and per year of latency for mobile phones and cordless phones, though the increase was not statistically significant for cordless phones. The percentage tumour volume increased per year of latency and per 100 h of cumulative use, statistically significant for analogue phones. This study confirmed previous results demonstrating an association between mobile and cordless phone use and acoustic neuroma.

  • 40.
    Hardell, Lennart
    et al.
    Örebro University Hospital. Dept Oncol, Örebro University Hospital, Örebro, Sweden.
    Carlberg, Michael
    Dept Oncol, Örebro University Hospital, Örebro, Sweden.
    Söderqvist, Fredrik
    Dept Oncol, Örebro University Hospital, Örebro, Sweden.
    Mild, Kjell Hansson
    Dept Radiat Sci, Umeå University, Umeå, Sweden.
    Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 43, no 6, p. 1833-1845Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the hand-held phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04-3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15-20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis.

  • 41.
    Hardell, Lennart
    et al.
    Örebro Universitet.
    Koppel, Tarmo
    Tallinn University of Technology, Estonia.
    Carlberg, Michael
    Örebro Universitet.
    Ahonen, Mikko
    Institute of Environmental Health and Safety,Tallinn, Estonia.
    Hedendahl, Lena
    Independent Environment and Health Research Luleå.
    Radiofrequency radiation at Stockholm Central Railway Station in Sweden and some medical aspects on public exposure to RF fields2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 4, p. 1315-1324Article in journal (Refereed)
    Abstract [en]

    The Stockholm Central Railway Station in Sweden was investigated for public radiofrequency (RF) radiation exposure. The exposimeter EME Spy 200 was used to collect the RF exposure data across the railway station. The exposimeter covers 20 different radiofrequency bands from 88 to 5,850 MHz. In total 1,669 data points were recorded. The median value for total exposure was 921 µW/m2 (or 0.092 µW/cm2; 1 µW/m2=0.0001 µW/cm2) with some outliers over 95,544 µW/m2 (6 V/m, upper detection limit). The mean total RF radiation level varied between 2,817 to 4,891 µW/m2 for each walking round. High mean measurements were obtained for GSM + UMTS 900 downlink varying between 1,165 and 2,075 µW/m2. High levels were also obtained for UMTS 2100 downlink; 442 to 1,632 µW/m2. Also LTE 800 downlink, GSM 1800 downlink, and LTE 2600 downlink were in the higher range of measurements. Hot spots were identified, for example close to a wall mounted base station yielding over 95,544 µW/m2 and thus exceeding the exposimeter's detection limit. Almost all of the total measured levels were above the precautionary target level of 3-6 µW/m2 as proposed by the BioInitiative Working Group in 2012. That target level was one-tenth of the scientific benchmark providing a safety margin either for children, or chronic exposure conditions. We compare the levels of RF radiation exposures identified in the present study to published scientific results reporting adverse biological effects and health harm at levels equivalent to, or below those measured in this Stockholm Central Railway Station project. It should be noted that these RF radiation levels give transient exposure, since people are generally passing through the areas tested, except for subsets of people who are there for hours each day of work.

  • 42. Haylock, Anna-Karin
    et al.
    Spiegelberg, Diana
    Mortensen, Anja C.
    Selvaraju, Ram K.
    Nilvebrant, Johan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Erikson, Olof
    Tolmachev, Vladimir
    Nestor, Marika V.
    Evaluation of a novel type of imaging probe based on a recombinant bivalent mini-antibody construct for detection of CD44v6-expressing squamous cell carcinoma2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 48, no 2, p. 461-470Article in journal (Refereed)
    Abstract [en]

    We have developed the CD44v6-targeting human bivalent antibody fragment AbD19384, an engineered recombinant human bivalent Fab antibody formed via dimerization of dHLX (synthetic double helix loop helix motif) domains, for potential use in antibody-based molecular imaging of squamous cell carcinoma in the head and neck region. This is a unique construct that has, to the best of our knowledge, never been assessed for molecular imaging in vivo before. The objective of the present study was to evaluate for the first time the in vitro and in vivo binding properties of radio-iodinated AbD19384, and to assess its utility as a targeting agent for molecular imaging of CD44v6-expressing tumors. Antigen specificity and binding properties were assessed in vitro. In vivo specificity and biodistribution of I-125-AbD19384 were next evaluated in tumor-bearing mice using a dual-tumor setup. Finally, AbD19384 was labeled with I-124, and its imaging properties were assessed by small animal PET/CT in tumor bearing mice, and compared with 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG). In vitro studies demonstrated CD44v6-specific binding with slow off-rate for AbD19384. A favorable biodistribution profile was seen in vivo, with tumor-specific uptake. Small animal PET/CT images of I-124-AbD19384 supported the results through clearly visible high CD44v6-expressing tumors and faintly visible low expressing tumors, with superior imaging properties compared to 18F-FDG. Tumor-to-blood ratios increased with time for the conjugate (assessed up to 72 h p.i.), although 48 h p.i. proved best for imaging. Biodistribution and small-animal PET studies demonstrated that the recombinant Fab-dHLX construct AbD19384 is a promising tracer for imaging of CD44v6 antigen expression in vivo, with the future aim to be used for individualized diagnosis and early detection of squamous cell carcinomas in the head and neck region. Furthermore, this proof-of-concept research established the feasibility of using recombinant Fab-dHLX constructs for in vivo imaging of tumor biomarkers.

  • 43.
    Hedbrant, Alexander
    et al.
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Erlandsson, Ann
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Delbro, Dick
    Örebro University, School of Medicine, Örebro University, Sweden.
    Wijkander, Jonny
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5-fluorouracil on the HT-29 colon cancer cell line2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 46, no 1, p. 37-46Article in journal (Refereed)
    Abstract [en]

    Resistance of tumor cells to chemotherapy, such as 5-fluorouracil (5-FU), is an obstacle for successful treatment of cancer. As a follow-up of a previous study we have investigated the effect of conditioned media (CM) from macrophages of M1 or M2 phenotypes on 5-FU cytotoxicity on the colon cancer cell lines HT-29 and CACO-2. HT-29 cells, but not CACO-2 cells, having been treated with a combination of M1 CM and 5-FU recovered their cell growth to a much larger extent compared to cells having been treated with 5-FU alone when further cultured for 7 days in fresh media. M1 CM treatment of HT-29, but not CACO-2 cells, induced cell cycle arrest in the G(0)/G(1) and G(2)/M phases. 5-FU treatment induced accumulation of cells in S-phase in both HT-29 and CACO-2 cells. This accumulation of cells in S-phase was attenuated by combined M1 CM and 5-FU treatment in HT-29 cells, but not in CACO-2 cells. The mRNA expression of cell cycle regulatory proteins and 5-FU metabolic enzymes were analyzed in an attempt to find possible mechanisms for the M1 CM induced attenuation of 5-FU cytotoxicity in HT-29. Thymidylate synthetase (TS) and thymidine phosphorylase (TP) were found to be substantially downregulated and upregulated, respectively, in HT-29 cells treated with M1 CM, making them unlikely as mediators of reduced 5-FU cytotoxicity. Among cell cycle regulating proteins, p21 was induced in HT-29 cells, but not in CACO-2 cells, in response to M1 CM treatment. However, small interfering RNA (siRNA) knockdown of p21 had no effect on the M1 CM induced cell cycle arrest seen in HT-29 and neither did it change the growth recovery after combined treatment of HT-29 cells with M1 CM and 5-FU. In conclusion, treatment of HT-29 cells with M1 CM reduces the cytotoxic effect of 5-FU and this is mediated by a M1 CM induced cell cycle arrest in the G(0)/G(1) and G(2)/M phases. So far, we lack an explanation why this action is absent in the CACO-2 cells. The current findings may be important for optimization of chemotherapy in colon cancer.

  • 44.
    Hedbrant, Alexander
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Erlandsson, Ann
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Delbro, Dick
    Örebro university.
    Wijkander, Jonny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5‑fluorouracil on the HT‑29 colon cancer cell line2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 46, no 1, p. 37-46Article in journal (Refereed)
    Abstract [en]

    Resistance of tumor cells to chemotherapy, such as 5‑fluorouracil (5‑FU), is an obstacle for successful treatment of cancer. As a follow‑up of a previous study we have investigated the effect of conditioned media (CM) from macrophages of M1 or M2 phenotypes on 5‑FU cytotoxicity on the colon cancer cell lines HT‑29 and CACO‑2. HT‑29 cells, but not CACO‑2 cells, having been treated with a combination of M1 CM and 5‑FU recovered their cell growth to a much larger extent compared to cells having been treated with 5‑FU alone when further cultured for 7 days in fresh media. M1 CM treatment of HT‑29, but not CACO‑2 cells, induced cell cycle arrest in the G0/G1 and G2/M phases. 5‑FU treatment induced accumulation of cells in S‑phase in both HT‑29 and CACO‑2 cells. This accumulation of cells in S‑phase was attenuated by combined M1 CM and 5‑FU treatment in HT‑29 cells, but not in CACO‑2 cells. The mRNA expression of cell cycle regulatory proteins and 5‑FU metabolic enzymes were analyzed in an attempt to find possible mechanisms for the M1 CM induced attenuation of 5‑FU cytotoxicity in HT‑29. Thymidylate synthetase (TS) and thymidine phosphorylase (TP) were found to be substantially downregulated and upregulated, respectively, in HT‑29 cells treated with M1 CM, making them unlikely as mediators of reduced 5‑FU cytotoxicity. Among cell cycle regulating proteins, p21 was induced in HT‑29 cells, but not in CACO‑2 cells, in response to M1 CM treatment. However, small interfering RNA (siRNA) knockdown of p21 had no effect on the M1 CM induced cell cycle arrest seen in HT‑29 and neither did it change the growth recovery after combined treatment of HT‑29 cells with M1 CM and 5‑FU. In conclusion, treatment of HT‑29 cells with M1 CM reduces the cytotoxic effect of 5‑FU and this is mediated by a M1 CM induced cell cycle arrest in the G0/G1 and G2/M phases. So far, we lack an explanation why this action is absent in the CACO‑2 cells. The current findings may be important for optimization of chemotherapy in colon cancer.

  • 45. Holmberg, Anders R
    et al.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Alayia, Ayodele A
    Al-Mohanna, Mai
    Adra, Chaker
    Marquez, Marcela
    Meurling, Lennart
    Nilsson, Sten
    Development of a novel poly bisphosphonate conjugate for treatment of skeletal metastasis and osteoporosis2010In: International Journal of Oncology, ISSN 1019-6439, Vol. 37, no 3, p. 563-567Article in journal (Refereed)
    Abstract [en]

    Advanced stage prostate and breast cancer frequently metastasize to the skeleton (approximately 75%). An additional complication in these patients, that further affects the bones, is that their hormonal treatment, induces osteoporosis. Bisphosphonates (bpns) are standard drugs against osteoporosis and have been shown to have clinically significant anti-tumor effects. This study describes the development of a new polybisphosphonate conjugate (ODX) with enhanced dual efficacy i.e. with anti-bone resorption and anti-tumor properties. Zoledronic acid (Zometa) was used as a positive control (at equimolar concentrations). Alendronic acid and aminoguanidine were conjugated to oxidized dextran with subsequent reductive amination (on average approximately 8 alendronate and approximately 50 guanidine moieties per conjugate). ODX was tested in a bone resorption assay for its capacity to inhibit bone resorbing osteoclasts (bone organ culture from neonatal mice, 45Ca labelled bone mineral). Tumor cell toxicity was studied on prostate (PC3) and breast cancer (MDA231, MDA453) cell cultures. Two methods were employed, a fluorescent cytotoxicity assay (FMCA) and an apoptosis assay (Annexin V assay). In the bone resorption assay, Zometa and ODX showed very similar potency with 50% osteoclast inhibition at approximately 20 nM and 100% at 0.2 microM. In the FMCA, IC50 for ODX was at approximately 2 microM and 25 microM for Zometa (PC3). In the apoptosis assay, ODX induced approximately 85-97% apoptosis at 10 microM in both cell lines, while Zometa failed to induce any significant apoptosis in any of the cell lines at the tested concentration range (10 nM-10 microM). ODX appears to be a promising drug candidate with high dual efficacy for the treatment of bone metastasis and osteoporosis. It has both potent osteoclast inhibiting properties and enhanced anti-tumor efficacy.

  • 46.
    Honarvar, Hadis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gunneriusson, Elin
    Höidén-Guthenberg, Ingmarie
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Widström, Charles
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Frejd, Fredrik Y
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Imaging of CAIX-expressing xenografts in vivo using 99mTc-HEHEHE-ZCAIX: 1 Affibody molecule2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 46, no 2, p. 513-20Article in journal (Refereed)
    Abstract [en]

    Carbonic anhydrase IX (CAIX) is a transmembrane enzyme involved in regulation of tissue pH balance. In cancer, CAIX expression is associated with tumor hypoxia. CAIX is also overexpressed in renal cell carcinoma and is a molecular target for the therapeutic antibody cG250 (girentuximab). Radionuclide imaging of CAIX expression might be used for identification of patients who may benefit from cG250 therapy and from treatment strategies for hypoxic tumors. Affibody molecules are small (7 kDa) scaffold proteins having a high potential as probes for radionuclide molecular imaging. The aim of the present study was to evaluate feasibility of in vivo imaging of CAIX-expression using radiolabeled Affibody molecules. A histidine-glutamate-histidine-glutamate-histidine-glutamate (HE)3-tag-containing CAIX-binding Affibody molecule (HE)3-ZCAIX:1 was labeled with [99mTc(CO)3]+. Its binding properties were evaluated in vitro using CAIX-expressing SK-RC-52 renal carcinoma cells. 99mTc-(HE)3-ZCAIX:1 was evaluated in NMRI nu/nu mice bearing SK-RC-52 xenografts. The in vivo specificity test confirmed CAIX-mediated tumor targeting. 99mTc-(HE)3-ZCAIX:1 cleared rapidly from blood and normal tissues except for kidneys. At optimal time-point (4 h p.i.), the tumor uptake was 9.7±0.7% ID/g, and tumor-to-blood ratio was 53±10. Experimental imaging of CAIX-expressing SK-RC-52 xenografts at 4 h p.i. provided high contrast images. The use of radioiodine label for ZCAIX:1 enabled the reduction of renal uptake, but resulted in significantly lower tumor uptake and tumor-to-blood ratio. Results of the present study suggest that radiolabeled Affibody molecules are promising probes for imaging of CAIX-expression in vivo.

  • 47.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mortensen, Anja C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael K. R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells2017In: International Journal of Oncology, ISSN 1019-6439, Vol. 50, no 1, p. 5-14Article in journal (Refereed)
    Abstract [en]

    AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT'/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.

  • 48.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines2012In: International Journal of Oncology, ISSN 1019-6439, Vol. 40, no 1, p. 176-184Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2 in combination with external radiation and the possible inhibitory effects in the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116. The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase inhibitors (erlotinib and sunitinib). These cell lines are genotypically different with respect to e.g. KRAS and BRAF mutational status, recently shown to be of clinical significance for therapeutic effects. Both cell lines express approximately 100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28 and HT-29, SF2=0.70). Exposure to (ZEGFR:1907)2 produced a small, but significant, reduction in survival in HCT116 but did not affect HT-29 cells. Similar results were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor sunitinib reduced survival in both cell lines. However, none of the drugs had any significant radiosensitizing effects in combination with radiation. Akt and Erk are central proteins in the EGFR downstream signalling and in the cellular response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/Tyr204) by radiation was both dose- and time-dependent. However the activation of EGFR was not clearly affected by radiation. Neither (ZEGFR:1907)2 nor any of the other drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was activated. Overall the results illustrate the complexity in response to radiation and drugs in cells with differential phenotypic status.

  • 49. Ifversen, Marianne RS
    et al.
    Kågedal, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Christensen, Lisa D
    Rechnitzer, Catherine
    Petersen, Bodil L
    Heilmann, Carsten
    Comparison of immunocytochemistry, real-time quantitative RT-PCR and flow cytometry for detection of minimal residual disease in neuroblastoma2005In: International Journal of Oncology, ISSN 1019-6439, Vol. 27, no 1, p. 121-129Article in journal (Refereed)
  • 50.
    Ihnatko, Robert
    et al.
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Kubes, Miroslav
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Takacova, Martina
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Sedlakova, Olga
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Sedlak, Jan
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Pastorek, Jaromir
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Kopacek, Juraj
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Pastorekova, Silvia
    Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
    Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia2006In: International Journal of Oncology, ISSN 1019-6439, Vol. 29, no 4, p. 1025-33Article in journal (Refereed)
    Abstract [en]

    Most solid tumors display extracellular acidosis, which only partially overlaps with hypoxia and induces distinct adaptive changes leading to aggressive phenotype. Although acidosis is mainly attributable to excessive production of lactic acid, it also involves carbonic anhydrase (CA) IX-mediated conversion of CO(2) to an extracellular proton and a bicarbonate ion transported to cytoplasm. CA IX is pre-dominantly expressed in tumors with poor prognosis and its transcription and activity are induced by hypoxia. Here we investigated whether low extracellular pH in absence of hypoxia can influence CA IX expression in cell lines derived from glioblastoma, a tumor type particularly linked with acidosis. Our data show that extracellular acidosis increased the level of CA IX protein, mRNA and the activity of minimal CA9 promoter that contains binding sites for HIF-1 and SP-1 transcription factors. Mutation within each of these two biding sites reduced the promoter activity, but did not eliminate the increase by acidosis. Transfection of HIF-1alpha cDNA produced additive inducing effect with acidosis. Normoxic acidosis was accompanied by HIF-1alpha protein accumulation and transiently increased phosphorylation of ERK1/2. Expression of a dominant-negative mutant of ERK2 reduced the CA9 promoter activity in both standard and acidic conditions. Similar result was obtained by inhibitors of MAPK and PI3K pathways, whose combination completely suppressed CA IX expression and abolished induction by acidosis. Altogether, our results suggest that acidosis increases the CA IX expression via a hypoxia-independent mechanism that operates through modulation of the basic CA9 transcriptional machinery.

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