Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer
Mingzhu Yin, Xia Li, Shu Tan, Huanjiao Jenny Zhou, Weidong Ji, Stefania Bellone, Xiaocao Xu, Haifeng Zhang, Alessandro D. Santin, Ge Lou, Wang Min
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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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 6

Inhibition of EGFR reduces spheroid formation, cell proliferation, and ovarian tumor growth in mouse models.

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Inhibition of EGFR reduces spheroid formation, cell proliferation, and o...
An orthotopic mouse model was established by injecting human SKOV3 OCs i.p. into female recipient nude mice. Mice were then either untreated (CON) or treated with erlotinib i.p. (100 mg/kg body weight/d). LC was used as a treatment control. (A–E) Effects of erlotinib on SKOV3 tumor growth. (A and B) Mouse body weights were measured at indicated time points. Arrows indicate different starting times of treatment (2, 4, or 8 weeks after tumor cell implantation) with LC (A) or erlotinib (B). (C) Representative images of mouse bodies in control, LC-, and erlotinib-treated groups. (D and E) Ascitic fluid volumes and net tumor weights were measured at week 14. Data in A–E are presented as mean ± SEM. n = 10 for each group. ***P < 0.001. (F–H) Effects of erlotinib on SKOV3 spheroid formation. Spheroids from ascites were collected at week 14 and mounted on slides. Spheroids were examined by H&E staining (F). Scale bars: 100 μm. Total number (G) and size (H) of spheroids were quantified. (I and J) Effects of erlotinib on SKOV3 tumor cell proliferation. Spheroids collected at week 14 were subjected to immunostaining with anti-Ki67, anti-CD68, and DAPI, followed by confocal imaging. (I) Representative images of spheroids with Ki67+ tumor cells and CD68+ macrophages. (J) Ki67+ and CD68+ cells in spheroids were quantified. n = 5 mice and 10 spheroids from each mice. Data are presented as mean ± SEM. **P < 0.01;***P < 0.001 (2-sided Student’s t test).