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TINT Tumor Indicating Normal Tissue: new field of diagnostic biomarkers for prostate cancer
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Prostate cancer is the most common cancer in Sweden. Due its highly variable behavior, multifocal nature, and insufficient diagnostic methods, prostate cancer is difficult to diagnose and prognosticate. Some patients have an aggressive lethal disease, but the majority of prostate cancer patients have slow-growing, non-lethal disease with long expected survival without treatment. Current diagnostic methods―serum levels of prostate-specific antigen (PSA) and histological grading of biopsied prostate tissue―often do not give the information required to be able to safely differentiate indolent tumors from potentially lethal ones. Many prostate cancers are difficult to detect by imaging, so tissue biopsy cannot be safely guided towards the tumor, and particularly not towards the most aggressive forms. To overcome this problem, multiple needle biopsies are taken from the organ, but biopsies are small and they sample less than 1% of the whole prostate. In this thesis, we explore the non-malignant prostate tissue adjacent to tumors, which is always sampled in biopsies, and we study adaptive changes in this tissue, which may provide new diagnostic and prognostic markers for prostate cancer. We have therefore proposed that this type of tissue should be termed TINT (Tumor Instructed/indicating Normal Tissue).

 Methods: In our studies, we used orthotopic rat prostate cancer models with tumors of different aggressiveness. We also used clinical materials from patients diagnosed with prostate cancer at transurethral resection (1975‒1990); the majority of these men were followed with watchful waiting. Analyses were performed with whole-genome expression array, quantitative real-time PCR, immunohistochemistry, and western blotting.

 Results: Using the animal model, we found that the presence of a tumor induces changes in gene expression in the surrounding tumor-bearing organ (TINT). The gene signature of TINT was linked to processes such as extracellular matrix organization, immune responses, and inflammation. We also showed that some of these adaptive TINT changes appear to be related to the aggressiveness and metastatic potential of the growing tumor, such as increases in macrophages, in mast cells, in vascular densities, and in vascular cell-proliferation. Some of these findings were confirmed by our observations in patient samples. We found that high staining of the extracellular matrix component hyaluronan in the stroma of the non-malignant prostate tissue was prognostic for short cancer-specific survival. We also found that an elevated proportion of C/EBP-beta positive epithelial cells in non-malignant (TINT) prostate tissue was associated with a good prognosis.

 Conclusions: Using animal experiments and patient samples, we showed that the presence of prostate cancer induces changes in the tumor-bearing organ, alterations associated with tumor aggressiveness, and that grading of these changes in TINT can be used to predict outcome in prostate cancer patients. 

Place, publisher, year, edition, pages
Umeå University , 2016. , 52 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1809
Keyword [en]
prostate cancer, biomarkers, TINT
National Category
Clinical Medicine
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-119706ISBN: 978-91-7601-470-7 (print)OAI: oai:DiVA.org:umu-119706DiVA: diva2:923228
Public defence
2016-05-20, Hörsal B Unod T 9, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2016-04-28 Created: 2016-04-25 Last updated: 2016-04-27Bibliographically approved
List of papers
1. Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ
Open this publication in new window or tab >>Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, e0130076Article in journal (Refereed) Published
Abstract [en]

Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating changes in the tumor-bearing organ, for example growth of the vasculature, an altered extracellular matrix, and influx of inflammatory cells. To investigate this response further, we compared prostate morphology and the gene expression profile of tumor-bearing normal rat prostate tissue (termed tumor-instructed/indicating normal tissue (TINT)) with that of prostate tissue from controls. Dunning rat AT-1 prostate cancer cells were injected into rat prostate and tumors were established after 10 days. As controls we used intact animals, animals injected with heat-killed AT-1 cells or cell culture medium. None of the controls showed morphological TINT-changes. A rat Illumina whole-genome expression array was used to analyze gene expression in AT-1 tumors, TINT, and in medium injected prostate tissue. We identified 423 upregulated genes and 38 downregulated genes (p<0.05, >= 2-fold change) in TINT relative to controls. Quantitative RT-PCR analysis verified key TINT-changes, and they were not detected in controls. Expression of some genes was changed in a manner similar to that in the tumor, whereas other changes were exclusive to TINT. Ontological analysis using GeneGo software showed that the TINT gene expression profile was coupled to processes such as inflammation, immune response, and wounding. Many of the genes whose expression is altered in TINT have well-established roles in tumor biology, and the present findings indicate that they may also function by adapting the surrounding tumor-bearing organ to the needs of the tumor. Even though a minor tumor cell contamination in TINT samples cannot be ruled out, our data suggest that there are tumor-induced changes in gene expression in the normal tumor-bearing organ which can probably not be explained by tumor cell contamination. It is important to validate these changes further, as they could hypothetically serve as novel diagnostic and prognostic markers of prostate cancer.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-106329 (URN)10.1371/journal.pone.0130076 (DOI)000356329900133 ()26076453 (PubMedID)
Available from: 2015-07-16 Created: 2015-07-10 Last updated: 2017-12-04Bibliographically approved
2. Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome
Open this publication in new window or tab >>Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome
Show others...
2011 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 4, 1961-1968 p.Article in journal (Refereed) Published
Abstract [en]

Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-48502 (URN)10.1016/j.ajpath.2011.06.005 (DOI)000298307400037 ()21854754 (PubMedID)
Available from: 2011-10-20 Created: 2011-10-20 Last updated: 2017-12-08Bibliographically approved
3. Adaptive (TINT) Changes in the Tumor Bearing Organ Are Related to Prostate Tumor Size and Aggressiveness
Open this publication in new window or tab >>Adaptive (TINT) Changes in the Tumor Bearing Organ Are Related to Prostate Tumor Size and Aggressiveness
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, e0141601Article in journal (Refereed) Published
Abstract [en]

In order to grow, tumors need to induce supportive alterations in the tumor-bearing organ, by us named tumor instructed normal tissue (TINT) changes. We now examined if the nature and magnitude of these responses were related to tumor size and aggressiveness. Three different Dunning rat prostate tumor cells were implanted into the prostate of immune-competent rats; 1) fast growing and metastatic MatLyLu tumor cells 2) fast growing and poorly metastatic AT-1 tumor cells, and 3) slow growing and non-metastatic G tumor cells. All tumor types induced increases in macrophage, mast cell and vascular densities and in vascular cell-proliferation in the tumor-bearing prostate lobe compared to controls. These increases occurred in parallel with tumor growth. The most pronounced and rapid responses were seen in the prostate tissue surrounding MatLyLu tumors. They were, also when small, particularly effective in attracting macrophages and stimulating growth of not only micro-vessels but also small arteries and veins compared to the less aggressive AT-1 and G tumors. The nature and magnitude of tumor-induced changes in the tumor-bearing organ are related to tumor size but also to tumor aggressiveness. These findings, supported by previous observation in patient samples, suggest that one additional way to evaluate prostate tumor aggressiveness could be to monitor its effect on adjacent tissues.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-112651 (URN)10.1371/journal.pone.0141601 (DOI)000364298400072 ()26536349 (PubMedID)
Available from: 2015-12-14 Created: 2015-12-11 Last updated: 2017-12-01Bibliographically approved
4. Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
Open this publication in new window or tab >>Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of a tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein-β (C/EBPβ). To explore this further, we examined C/EBPβ expression by quantitative RT-PCR, immunohistochemistry, and western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors―and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

In rats, C/EBPβ mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBPβ was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBPβ expression in the tumor-bearing prostates was associated with tumor size, with distance to the tumor, and with tumor cell metastatic capacity.

In prostate cancer patients, high expression of C/EBPβ in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and a favorable outcome. High expression of C/EBPβ in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, the presence of metastases at diagnosis, and poor outcome. 

Keyword
prostate cancer, biomarkers, TINT, C/EBPβ
National Category
Cancer and Oncology
Research subject
Pathology; Oncology
Identifiers
urn:nbn:se:umu:diva-119705 (URN)
Available from: 2016-04-25 Created: 2016-04-25 Last updated: 2016-04-27Bibliographically approved

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