AngioMatrix, a signature of the tumor angiogenic switch-specific matrisome, correlates with poor prognosis for glioma and colorectal cancer patients

Abstract

Angiogenesis represents a rate-limiting step during tumor progression. Targeting angiogenesis is already applied in cancer treatment, yet limits of anti-angiogenic therapies have emerged, notably because tumors adapt and recur after treatment. Therefore, there is a strong need to better understand the molecular and cellular mechanisms underlying tumor angiogenesis. Using the RIP1-Tag2 transgenic murine model, we identified 298 genes that are deregulated during the angiogenic switch, revealing an ingression/expansion of specific stromal cell types including endothelial cells and pericytes, but also macrophages and perivascular mesenchymal cells. Canonical TGF-β signaling is up-regulated during the angiogenic switch, especially in tumor-associated macrophages and fibroblasts. The matrisome, comprising extracellular matrix (ECM) and ECM-associated molecules, is significantly enriched, which allowed us to define the AngioMatrix signature as the 110 matrisomal genes induced during the RIP1-Tag2 angiogenic switch. Several AngioMatrix molecules were validated at expression level. Ablation of tenascin-C, one of the most highly induced ECM molecules during the switch, resulted in reduced angiogenesis confirming its important role. In human glioma and colorectal samples, the AngioMatrix signature correlates with the expression of endothelial cell markers, is increased with tumor progression and finally correlates with poor prognosis demonstrating its diagnostic and therapeutic potential.

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

“…Interestingly of the 20 proteins that we found in higher abundance in the ECM signature of KP lung tumors (compared with normal lung), nine (Col12a1, Col14a1, Col18a1, Col8a1, Fbln2, Fn1, Ltbp2, Nid1, and Tnc) were encoded by genes that are part of the AngioMatrix signature, an ensemble of matrisome genes whose up-regulation at the mRNA has been associated with the induction of angiogenesis in the RIP1-Tag2 mouse model of pancreatic neuroendocrine cancer (27). Tnc was identified as an important component of the AngioMatrix in driving the angiogenesis in the neuroendocrine tumor model; the AngioMatrix also has negative predictive value in patients with glioma and colorectal carcinoma (27). The partial overlap between the lung tumor matrisome factors we have identified and the AngioMatrix raises the possibility of an angiogenic component to our ECM signature in lung tumors, which warrants further investigation.…”

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 ).…”

“…Importantly, this gene signature had diagnostic value since its high expression correlated with shorter survival of colon cancer and glioma patients. 13 Thus we may need to revisit these results to define a limited number of genes that altogether could have the potential as diagnostic tool for the development of cancer blood screening tests in the future.…”

“…Pharmacological ALK5 inhibition restored radiation induced inhibition of endothelial cell migration and sprouting in vitro, and impairment of angiogenesis in vivo. 102 Since tenascin-C enhances TGFb signaling 98 , binds TGFb 99 and is upregulated during the angiogenic switch 13 it will be interesting to see whether tenascin-C potentiates the TGFb effect on new blood vessel formation post irradiation.…”

“…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.…”