Although shed syndecan-2 potentiated the tumorigenic activities of colon cancer cells, how shed syndecan-2 increases this tumorigenic potential remains unclear. Using an orthotopic mouse model of colon cancer, we show that shed syndecan-2 increases colon cancer progression by cooperatively promoting angiogenesis. Co-administration with a synthetic peptide of shed syndecan-2 (S2LQ) enhanced the survival and tumor engraftment of luciferase-expressing CT26 colon adenocarcinoma cells orthotopically implanted into the cecum of BALB/c mice. Intravenous injection of S2LQ further enhanced the growth of orthotopic tumors in the cecum, with increases in the tissue infiltration of macrophages and the formation of blood vessels, mainly in peripheral layers of the tumor facing the stroma. Furthermore, S2LQ stabilized HIF1α and enhanced the VEGF expression in human colon cancer cell lines, and increased the migration of RAW 264.7 murine macrophage cells and bone marrow-derived macrophages. Finally, S2LQ increased the tube formation of vascular endothelial cells in vitro. Together, these data demonstrate that shed syndecan-2 enhances tumorigenic activity by increasing the crosstalk of cancer cells with tumor-associated macrophages and endothelial cells to enhance angiogenesis for colon cancer progression in the tumor microenvironment.

尽管 shed syndecan-2 增强了结肠癌细胞的致瘤活性，但 shed syndecan-2 如何增加这种致瘤潜力仍不清楚。使用结肠癌的原位小鼠模型，我们表明 shed syndecan-2 通过协同促进血管生成来增加结肠癌的进展。与 shed syndecan-2 (S2LQ) 的合成肽共同给药增强了原位植入 BALB/c 小鼠盲肠的表达荧光素酶的 CT26 结肠腺癌细胞的存活和肿瘤移植。静脉注射 S2LQ 进一步促进了盲肠原位肿瘤的生长，巨噬细胞的组织浸润和血管的形成增加，主要在面向基质的肿瘤外周层。此外，S2LQ 稳定 HIF1α 并增强人结肠癌细胞系中的 VEGF 表达，并增加 RAW 264.7 鼠巨噬细胞和骨髓来源的巨噬细胞的迁移。最后，S2LQ 增加了血管内皮细胞的管形成体外。总之，这些数据表明，shed syndecan-2 通过增加癌细胞与肿瘤相关巨噬细胞和内皮细胞的串扰来增强肿瘤发生活性，从而增强肿瘤微环境中结肠癌进展的血管生成。