Endosialin-positive stromal cells promote colorectal cancer progression by upregulating VEGF-driven angiogenesis

Abnormal angiogenesis is a hallmark of malignant tumors and drives sustained tumor growth and metastasis. Stromal cells play an important role in tumor angiogenesis; however, the detailed mechanism remains incompletely understood. Endosialin is a type I transmembrane glycoprotein highly expressed in stromal cells, including cancer associated fibroblasts (CAFs) and tumor associated pericytes (TAPs). However, whether these endosialin-positive stromal cells promote tumor angiogenesis and the underlying mechanism remain unknown. We analyzed the correlation between endosialin expression and angiogenesis-related genes in colorectal cancer (CRC) specimens from The Cancer Genome Atlas (TCGA). Subsequent in vitro and in vivo experiments were performed to explore the role of endosialin in angiogenesis. Additionally, we investigated the underlying molecular mechanisms by RNA sequencing. Finally, we evaluated the antitumor efficacy of an anti-endosialin antibody in comparison with other anti-angiogenic agents. In this study, we found that endosialin expression was associated with angiogenesis-related genes and closely correlated with poor prognosis in CRC patients. Using various mouse models, we demonstrated that endosialin deficiency, depletion of endosialin-positive cells, or endosialin knockdown in fibroblasts or pericytes all suppressed CRC progression and tumor angiogenesis. We further confirmed that conditioned medium (CM) from both endosialin-positive fibroblasts and pericytes promoted angiogenesis in vitro under hypoxia conditions. Mechanistically, we found that endosialin activated NF-κB signaling and upregulated hypoxia-inducible factor 1α (HIF-1α) expression. Both of these events stimulated VEGFA expression and secretion in fibroblasts and pericytes, thereby promoting tumor angiogenesis. Furthermore, we demonstrated that the anti-endosialin antibody IgG78 inhibited CRC growth and tumor angiogenesis in vivo, with potent therapeutic effects comparable to those of VEGFR inhibitor fruquintinib or anti-VEGFA antibody bevacizumab. Our study not only provides a mechanism by which endosialin-positive stromal cells promote CRC progression, but also identifies endosialin as an effective therapeutic target for CRC treatment.