Extracellular Vesicles Derived from Ovarian Cancer Cells Promote Tumor Progression through M2 Macrophage Polarization and Enhanced Angiogenesis

Abstract Background: Ovarian cancer, among the most lethal gynecologic malignancies globally, features a tumor microenvironment crucial to disease progression. Extracellular vesicles (EVs) function as key intercellular communication mediators, though their role in ovarian cancer advancement via macrophage regulation remains inadequately characterized. Methods: EVs isolated from ovarian cancer cell lines (SKOV3, HO8910, ID8) underwent characterization through transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Macrophage polarization was evaluated following co-culture with cancer cells or their derived EVs. HUVEC angiogenic activity was assessed through tube formation, proliferation, and VEGFR expression analyses. In vivo studies examined tumor growth, macrophage infiltration, and angiogenesis in nude mice bearing SKOV3 tumors treated with cancer-derived EVs. Results: Ovarian cancer patients demonstrated significantly elevated M2 macrophage proportions in peripheral blood and tumor tissues compared to controls (p<0.05), with increased CD31 expression correlating with poor prognosis. In vitro, cancer cells and their derived EVs induced significant M2 polarization (p<0.0001) and enhanced HUVEC tube formation through VEGFR upregulation. The mouse model confirmed that cancer-derived EVs significantly promoted tumor growth (p<0.0001), M2 macrophage infiltration, and CD31 expression. Conclusions: This study demonstrates that ovarian cancer-derived EVs enhance tumor progression by inducing M2 macrophage polarization and stimulating angiogenesis, elucidating a novel tumor-microenvironment interaction mechanism and suggesting EV-targeted therapeutic approaches for ovarian cancer.