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The extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC's functions in cancer, we established an immune-competent transgenic mouse model of pancreatic β-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.

Original publication

DOI

10.1016/j.celrep.2013.09.014

Type

Journal

Cell Rep

Publication Date

31/10/2013

Volume

5

Pages

482 - 492

Keywords

Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Disease Models, Animal, Down-Regulation, Human Umbilical Vein Endothelial Cells, Humans, Intercellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Pathologic, Neuroendocrine Tumors, Signal Transduction, Tenascin, Wnt Proteins