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Basement membrane collagens in pancreatic cancer: novel stroma-derived tumor markers and regulators of cancer cell growth
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Basalmembranskollagener vid pankreascancer : utgör nya stromala tumörmarkörer och reglerar cancercellstillväxt (Swedish)
Abstract [en]

Background: Among the common malignancies, pancreatic cancer has the shortest long-term survival. The aggressive, rapid, and infiltrative growth pattern of pancreatic cancer, together with the lack of specific symptoms, often leads to late diagnosis. Metastases are frequently found at the time of diagnosis, which prevents curative surgical treatment. Good tumor markers would enable early detection, thus improving the prognosis. Unfortunately, no such markers are available in the clinic.

The tumor stroma is defined as the non-malignant cells and the extracellular matrix (ECM) of a cancer. Pancreatic cancer is characterized by an abundant tumor stroma, rich in ECM proteins such as collagens, which have been shown to play important roles in tumor progression. Furthermore, pancreatic cancer cells produce large quantities of ECM proteins, especially the basement membrane (BM) protein type IV collagen. All epithelial cells are anchored to a BM, which must be degraded in order for an in situ cancer to become invasive. Matrix metalloproteinases (MMPs) are enzymes involved in BM degradation.

In this thesis, the tumor stroma of pancreatic cancer is studied, focusing on the BM proteins type IV and type XVIII collagen, with the aim to clarify if the stroma could be a source of novel tumor markers for this form of cancer. Additionally, the role of type IV collagen produced by the cancer cells is studied.

Methods: Expression patterns of type IV and type XVIII collagen, MMPs involved in collagen degradation, and collagen receptors (integrins) were studied by immunoflourescence in both normal and pancreatic cancer tissue, and in pancreatic cancer cell lines. Circulating plasma levels of type IV and type XVIII collagen and conventional tumor markers (TPS, Ca 19-9, CEA and Ca 125) were measured in controls and pancreatic cancer patients at the time of diagnosis and after treatment.

The role of cancer cell produced type IV collagen was studied in human pancreatic cancer cell lines by functional blocking of integrin receptors (integrin a1, a2 and b1) and integrin-binding sites on type IV collagen, and by siRNA-induced down-regulation of type IV collagen synthesis. Proliferation was analyzed by a luminescence based cell viability assay, migration by time-lapse microscopy, and apoptosis by M30-neoepitope detection.

Results: MMPs involved in BM degradation were upregulated in pancreatic cancer tissue. The expression of type XVIII collagen shifted from a general BM expression pattern in normal tissue, to mainly being found in the tumor vasculature in pancreatic cancer. Type IV collagen, on the other hand, remained highly expressed in the vicinity of the cancer cells. The a1, a2, and b1 integrin receptors were highly expressed at the cancer cell surface.

Both down-regulation of type IV collagen synthesis and blocking the integrin/type IV collagen interaction decreased cell proliferation and migration. The proliferative capacity was rescued by the addition of exogenous type IV collagen.

Furthermore, the circulating levels of both type IV and type XVIII collagen were increased in pancreatic cancer patients at the time of diagnosis compared to controls. After treatment, the levels were normalized for type XVIII collagen, whereas the levels of type IV collagen remained high after surgery. High postoperative levels of type IV collagen were associated with short overall survival. A similar association to short survival was found for preoperative type XVIII collagen levels. No such associations to survival could be detected for the conventional markers.

 

Conclusion: The results of this thesis show that type IV and type XVIII collagens can serve as tumor markers for pancreatic cancer with advantages compared to conventionally used markers. Additionally, evidence is provided of an autocrine loop, involving type IV collagen and its integrin receptors, with importance for retaining a proliferative and migratory phenotype in pancreatic cancer cells.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2010. , 84 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1385
Keyword [en]
Pancreatic cancer, tumor marker, basement membrane, type IV collagen, type XVIII collagen, matrix metalloproteinase, integrin, autocrine loop, tumor stroma
Research subject
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-37555ISBN: 978-91-7459-109-5 (print)OAI: oai:DiVA.org:umu-37555DiVA: diva2:369575
Public defence
2010-12-03, Sal B, byggnad 1D, 9 tr, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2010-11-12 Created: 2010-11-08 Last updated: 2010-11-12Bibliographically approved
List of papers
1. Expression pattern and circulating levels of endostatin in patients with pancreas cancer
Open this publication in new window or tab >>Expression pattern and circulating levels of endostatin in patients with pancreas cancer
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2008 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 122, no 12, 2805-2810 p.Article in journal (Refereed) Published
Abstract [en]

Endostatin is a potent inhibitor of angiogenesis that is cleaved from the basement membrane protein type XVIII collagen. Expression of endostatin has recently been shown by Western blot analysis of tissue lysates in normal pancreas and pancreas cancer tissue. We show here that the expression pattern of type XVIII collagen/endostatin is shifted from a general basement membrane staining and is mainly located in the vasculature during tumor progression. This shift in type XVIII collagen/endostatin expression pattern coincides with an up-regulation of MMPs involved in endostatin processing in the tumor microenvironment, such as MMP-3, MMP-9 and MMP-13. The circulating levels of endostatin was analyzed in patients with pancreas cancer and compared to that of healthy controls, as well as after surgical treatment or in a group of nonoperable patients after intraperitoneal fluorouracil (5-FU) chemotherapy. The results show that patients with pancreas cancer have increased circulating levels of endostatin and that these levels are normalized after surgery or intraperitoneal chemotherapy. These findings indicate that endostatin could be used as a biomarker for pancreas cancer progression.

Keyword
Blotting; Western, Endostatins/*blood/genetics, Female, Humans, Immunohistochemistry, Male, Matrix Metalloproteinases/metabolism, Pancreatic Neoplasms/*blood/genetics/therapy, Up-Regulation
Identifiers
urn:nbn:se:umu:diva-10601 (URN)10.1002/ijc.23468 (DOI)18360823 (PubMedID)
Available from: 2008-10-08 Created: 2008-10-08 Last updated: 2017-12-14Bibliographically approved
2. Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer
Open this publication in new window or tab >>Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer
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2009 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 1, 91-97 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Pancreas cancer is a dreaded disease with high mortality, despite progress in surgical and oncological treatments in recent years. The field is hampered by a lack of good prognostic and predictive tumour biomarkers to be used during follow-up of patients.

METHODS: The circulating level of type IV collagen was measured by ELISA in pancreas cancer patients and controls. The expression pattern of type IV collagen in normal pancreas, pancreas cancer tissue and in pancreas cancer cell lines was studied by immunofluorescence and Western blot techniques.

RESULTS: Patients with pancreas cancer have significantly increased circulating levels of type IV collagen. In pancreas cancer tissue high levels of type IV collagen expression was found in close proximity to cancer cells in the tumour stroma. Furthermore, pancreas cancer cells were found to produce and secrete type IV collagen in vitro, which in part can explain the high type IV collagen expression observed in pancreas cancer tissue, and the increased circulating levels in pancreas cancer patients. Of clinical importance, our results show that the circulating level of type IV collagen after surgery is strongly related to prognosis in patients treated for pancreas cancer by pancreatico-duodenectomy with curative intent. Persisting high levels of circulating type IV collagen after surgery indicates a quick relapse in disease and poor survival.

CONCLUSION: Our results most importantly show that stroma related substances can be evaluated as potential cancer biomarkers, and thereby underline the importance of the tumour microenvironment also in this context.

Keyword
extracellular matrix, basement membrane, surgery, circulation, biomarker, pancreas
Identifiers
urn:nbn:se:umu:diva-33778 (URN)10.1038/sj.bjc.6605107 (DOI)19491897 (PubMedID)
Available from: 2010-05-06 Created: 2010-05-06 Last updated: 2017-12-12Bibliographically approved
3. Basement membrane fragments as pancreatic tumour markers: a comparison to conventional markers
Open this publication in new window or tab >>Basement membrane fragments as pancreatic tumour markers: a comparison to conventional markers
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(English)Manuscript (preprint) (Other academic)
Keyword
pancreatic adenocarcinoma, tumour markers, type IV collagen, type XVIII collagen, endostatin, TPS, Ca 125, TPS, Ca 19-9, CEA
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-37656 (URN)
Available from: 2010-11-11 Created: 2010-11-11 Last updated: 2010-11-12Bibliographically approved
4. Type IV collagen enhances pancreatic cancer cell proliferation and migration through an autocrine loop
Open this publication in new window or tab >>Type IV collagen enhances pancreatic cancer cell proliferation and migration through an autocrine loop
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(English)Manuscript (preprint) (Other academic)
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-37659 (URN)
Available from: 2010-11-11 Created: 2010-11-11 Last updated: 2010-11-12Bibliographically approved

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