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.
The fly glial cell deficient/glial cell missing (glide/gcm) gene codes for a transcription factor that induces gliogenesis. Lack of its product eliminates lateral glial cells in the embryonic nervous system. Here we identify a second gene, glide2, that is homologous to glide/gcm in the binding domain and that is also necessary and sufficient to promote glial differentiation. glide2 codes for a transcription factor that displays a weaker and delayed expression compared with glide/gcm. The two genes, which are located 27 kb apart and share cis-regulatory elements, are able to auto- and cross-regulate, indicating that they form a gene complex. Finally, we show that lack of both products eliminates all lateral glial cells, which means that the two genes contain all the fly lateral glial promoting activity.
Tenascin-C, an extracellular matrix molecule of the tumorspecific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin A 5 B 1 /syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C-induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH 2 -terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis. [Cancer Res 2007;67(13):6163-73]
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