Macrophages activate ovarian tumor cell proliferation and migration during metastasis
Ovarian cancer is difficult to diagnose at early stages, and once it has metastasized, it is associated with a very high mortality rate. During transcoelomic metastasis, ovarian tumor cells detach from the primary tumor site and migrate to the peritoneal cavity, where their survival is supported by tumor-associated macrophages (TAMs). In the accompanying video, Yale University professor Wang Min describes how TAMs are recruited to ovarian tumor cells in the peritoneal environment to form spheroids that drive the early stages of metastasis. His recent study, published this week in the JCI, has shown that tumors attract macrophages by releasing cytokines. The macrophages then secrete growth factors such as EGF that promote tumor cell adhesion and proliferation, leading to the formation of tumor cell spheroids. This work elucidates a mechanism that may be a useful therapeutic target for treating ovarian and other transcoelomic metastatic cancers.
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Abstract
Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage–like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM. Moreover, EGF secreted by TAMs activated EGFR on tumor cells, which in turn upregulated VEGF/VEGFR signaling in surrounding tumor cells to support tumor cell proliferation and migration. Pharmacological blockade of EGFR or antibody neutralization of ICAM-1 in TAMs blunted spheroid formation and ovarian cancer progression in mouse models. These findings suggest that EGF secreted from TAMs plays a critical role in promoting early transcoelomic metastasis of ovarian cancer. As transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our findings uncover a mechanism for TAM-mediated spheroid formation and provide a potential target for the treatment of ovarian cancer and other transcoelomic metastatic cancers.
Authors
Mingzhu Yin, Xia Li, Shu Tan, Huanjiao Jenny Zhou, Weidong Ji, Stefania Bellone, Xiaocao Xu, Haifeng Zhang, Alessandro D. Santin, Ge Lou, Wang Min
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ISSN: 0021-9738 (print), 1558-8238 (online)