Tenascin-C Downregulates Wnt Inhibitor Dickkopf-1, Promoting Tumorigenesis in a Neuroendocrine Tumor Model

Abstract

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.

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

“…In this context, tumor-derived Tnc has been found to promote the outgrowth of pulmonary lesions by enhancing Wnt and Notch signaling, thereby promoting the viability of cancer cells. Similar results were reported in a mouse model of pancreatic neuroendocrine cancer, in which Tnc was found to promote tumorigenesis and lung metastasis (38). These differing effects of Tnc on cancer may reflect the tumor typespecific or oncogene-specific roles of Tnc in cancer progression.…”

Tenascin-C: Exploitation and collateral damage in cancer management

“…Tenascin-C was among the most highly induced genes of the AngioMatrix and, in the absence of tenascin-C the angiogenic switch was significantly reduced whereas it was increased in comparison to control conditions with already high levels upon expression of additional tenascin-C from a transgene. 4,13 These observations suggest 2 things, that tenascin-C is important and that it may work in concert with other ECM molecules. Tenascin-C seems to be part of a complex ECM network that has been described as matrix tracks/channels in melanoma 17 and other cancers associated with enhanced metastasis, thus presumably generating physical niches with particular biochemical properties not only during angiogenesis but also during metastasis which may have an impact on drug responsiveness (see Spenle et al, this issue and reviews 18 and 19 ).…”

“…2,3 Formal evidence of its tumorigenesis promoting activity has recently been demonstrated in the first study using a stochastic murine multistage tumorigenesis model displaying either abundant or no tenascin-C. 4 Here tenascin-C promoted several events such as survival, proliferation, invasion, angiogenesis and lung metastasis formation by a mechanism that involved downregulation of Dickkopf-1 (DKK1) and activation of Wnt signaling. 4 Thus high expression of tenascin-C in malignant cancers might be useful for diagnosis. Indeed over the last years good antibodies have been generated that allow detection of tenascin-C expression by immunohistochemistry.…”

“…107 Whether these matrix sleeves contained tenascin-C had not been addressed but is likely since tenascin-C is found to be highly expressed around newly formed tumor blood vessels (reviewed in 19 , 2 ). Given its instrumental role in promoting tumor angiogenesis 4,13 it is an intriguing possibility that tenascin-C may also promote revascularization upon anti angiogenic treatment.…”

Tenascin-C: Form versus function

“…This collection of functions is reflected in the wide ranging consequences of genetic deletion of tenascin-C in mice. Reported abnormalities include reduced FN during dermal wound healing, 4 hyperactivity, 5 reduced kidney regeneration, 6 reduced haematopoiesis, 7 increased tumor monocyte population, 8 abnormal tumor organization and angiogenesis, 9,10 and aberrant immune responses, [11][12][13] among many others (reviewed in 14,15 ). Genetic variation at the human tenascin-C gene locus is associated with 6-fold increase in risk of Achilles tendon injury, 16 non-syndromic hearing loss, 17 and increased risk of developing adult asthma.…”