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Tenascins : prominent molecules in tumor stroma

Degen, Martin. Tenascins : prominent molecules in tumor stroma. 2007, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8199

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Abstract

A very special connective tissue surrounds and interweaves solid tumors, the tumor stroma. Initially thought to only have a passive role, there is now more and more evidence accumulating that the tumor stroma plays an active function in the process of tumor progression as well as tumor initiation. Activated stromal cells express pro-proliferative paracrine signals to the epithelial cells, stimulate angiogenesis and can even show loss of tumor suppressor genes. Therefore, understanding the complex crosstalk between the epithelium and the tumor stroma might reveal novel therapeutic targets. Tenascin-C is known to be specifically expressed in the stroma of a variety of tumors triggering different stromal reactions required for tumorigenesis such as angiogenesis. We found in the stroma of mouse mammary tumors the induction of a second member of the tenascin family, tenascin-W. Moreover, we detected human tenascin-W in different human neoplasms, and could correlate its expression in breast cancers with tumor grade. Tenascin-W is enriched in low-grade breast cancers whereas the presence of tenascin-C does not correlate with tumor grade. Functionally, we could show that presence of tenascin-W does influence the cellular behavior of cancer cells. Fibroblasts adhere on tenascin-W in a β1-integrin-dependent way, and cancer cell migration towards fibronectin is stimulated by addition of tenascin-W. In order to evaluate the significance of tenascin-W to act as tumor marker, we established a sensitive sandwich-ELISA to measure serum tenascin-W levels. By screening sera of healthy volunteers and sera from cancer patients, we could detect elevated serum tenascin-W levels in non-metastatic colorectal and non-metastatic breast cancer patients. However, not all cancer patients did show this increase. Furthermore, we found high tenascin-W expression in a large fraction of colorectal cancer extracts, but complete absence in normal colon mucosae. This suggests that tenascin-W is a better tumor marker for colorectal cancer than tenascin-C, which is also expressed in the normal colon mucosa. These observations warrant a follow-up study to evaluate the potential diagnostic or prognostic relevance of tenascin-W in colorectal cancer. Glioblastomas are very aggressive human cancers. We found that glioblastomas frequently harbor amplifications at the Notch2 locus and express high levels of Notch2 protein, which coincided with the presence of tenascin-C, an established prognostic marker for glioblastomas. A conserved potential RBPJk binding motif was found in the tenascin-C
promoter sequence, and by luciferase assays we could identify tenascin-C as a new RBPJkdependent
Notch-2 target. Furthermore, we could induce endogenous tenascin-C by
transfecting fibroblasts with the intracellular Notch2 domain. These data imply a novel
oncogenic function of Notch2 by inducing tenascin-C, a molecule enhancing cancer cell
motility.
Advisors:Chiquet-Ehrismann, Ruth
Committee Members:Hynes, Nancy and Rüegg, Markus A.
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI
UniBasel Contributors:Rüegg, Markus A.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8199
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:202
Language:English
Identification Number:
Last Modified:22 Apr 2018 04:30
Deposited On:13 Feb 2009 16:21

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