Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer
Mingzhu Yin, … , Ge Lou, Wang Min
Mingzhu Yin, … , Ge Lou, Wang Min
Published October 10, 2016
Citation Information: J Clin Invest. 2016;126(11):4157-4173. https://doi.org/10.1172/JCI87252.
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Research Article Inflammation Oncology

Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

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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Figure 9

A model for TAM–cancer cell interactions in spheroid formation.

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A model for TAM–cancer cell interactions in spheroid formation. (A) Duri...
(A) During early stages of OC transcoelomic metastasis and tumor growth, detached OC cells induce infiltration of macrophages into the peritoneal cavity. Interactions of macrophages with OC cells in the peritoneal environment form spheroids and skew macrophages into M2 subtype TAMs. TAMs located in the center of spheroids may provide initial matrix support for OC to avoid anoikis. Importantly, TAMs can secrete large amount of EGF and activate EGFR that is upregulated on tumor cells. The activated EGF/EGFR signaling can induce VEGF-C expression, which in turn activates VEGFR3 signaling and induces integrin/ICAM-1 expression in tumor cells to form a positive autocrine feedback loop, thus promoting tumor migration, adhesion, and spheroid formation. (B) Molecular interactions between TAMs and OC cells.