Abstract
Vasculogenic mimicry (VM), the formation of vessel-like structures by highly invasive tumor cells, has been considered one of several mechanisms responsible for the failure of anti-angiogenesis therapy in glioma patients. Therefore, inhibiting VM formation might be an effective therapeutic method to antagonize the angiogenesis resistance. This study aimed to show that an extracellular protein called Tenascin-c (TNC) is involved in VM formation and that TNC knockdown inhibits VM in glioma. TNC was upregulated with an increase in glioma grade. TNC and VM formation are potential independent predictors of survival of glioma patients. TNC upregulation was correlated with VM formation, and exogenous TNC stimulated VM formation. Furthermore, TNC knockdown significantly suppressed VM formation and proliferation in glioma cells in vitro and in vivo, with a reduction in cellular invasiveness and migration. Mechanistically, TNC knockdown decreased Akt phosphorylation at Ser473 and Thr308 and subsequently downregulated matrix metalloproteinase 2 and 9, both of which are important proteins associated with VM formation and migration. Our results indicate that TNC plays an important role in VM formation in glioma, suggesting that TNC is a potential therapeutic target for anti-angiogenesis therapy for glioma.
Highlights
Glioma is the most common primary malignancy of the central nervous system
Anti-angiogenesis therapy might be a new method for high-grade glioma patients since Folkman et al proposed the tumor angiogenesis theory in 19711
Common genetic alterations in GBM like amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRVIII promote angiogenesis in GBM implying an important role of endothelial vessels in GBM development[29]
Summary
Glioma is the most common primary malignancy of the central nervous system. According to the WHO classification, gliomas are classified into four grades (grades I–IV), grades III and IV glioma are high-grade gliomas with poor prognosis. Excessive angiogenesis and adequate blood supply result in rapid proliferation and invasion in high-grade gliomas. Targeting angiogenesis may yield efficient anti-glioma therapies[1]. Receptor tyrosine kinase inhibitors (RTKIs) and recombinant humanized monoclonal antibodies have been widely studied in slightly contributed to progression-free survival (PFS) but not overall survival (OS) in glioma patients[3]. Several preclinical studies speculate that vasculogenic mimicry (VM) contributes to anti-angiogenesis therapeutic resistance[4,5,6]
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