CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer
Ling Lin1,2,3, Yong-Song Chen3, Yan-Dan Yao1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China.
Abstract:
The infiltration of tumor-associated macrophages (TAMs) is associated with extensive angiogenesis, which contributes to a poor prognosis in breast cancer. However, anti-angiogenic therapy with VEGF-specific monotherapy has been unsuccessful in treating breast cancer, and the molecular mechanisms associated with chemoresistance remain unclear. Here, we investigated whether CCL18, a chemokine produced by TAMs, can stimulate angiogenesis in breast cancer, as well as the underlying mechanisms. Double immunohistochemical staining for CCL18 and CD34/CD31/vWF was performed in 80 breast cancer samples to study the correlation between CCL18+ TAMs and microvascular density (MVD). Cocultures of TAMs with human umbilical vein endothelial cells (HUVECs) were used to model the inflammatory microenvironment, and CCL18-induced angiogenesis was evaluated both in vitro and in vivo. We demonstrated that CCL18+ TAM infiltration positively associated with MVD in breast cancer samples, which was correlated with tumor metastasis and poor prognosis. We confirmed, both in vitro and in vivo, that CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis. Conversely, blocking CCL18 or VEGF with neutralizing antibodies synergistically inhibited the promigratory effects of TAMs. Silencing PITPNM3, a putative CCL18 receptor, on the surface of HUVECs abrogated CCL18-mediated promigration and the enhancement of HUVEC tube formation, independently of VEGFR signaling. Moreover, CCL18 exposure induced the endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3β/Snail signaling in HUVECs, thereby contributing to its pro-angiogenic effects. In conclusion, our findings suggest that CCL18 released from TAMs promotes angiogenesis and tumor progression in breast cancer; thus, CCL18 may serve as a novel target for anti-angiogenic therapies.
Insights
Tumor-associated macrophages (TAMs) release CCL18, a chemokine that promotes breast cancer angiogenesis and progression. Blocking CCL18 offers a potential new strategy for anti-angiogenic therapy in breast cancer patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Tumor-associated macrophages (TAMs) drive angiogenesis in breast cancer, correlating with poor prognosis.
- VEGF-specific anti-angiogenic monotherapy has shown limited success in breast cancer.
- The role of TAM-derived chemokines, like CCL18, in breast cancer angiogenesis and chemoresistance is not fully understood.
Purpose of the Study:
- To investigate the role of CCL18, produced by TAMs, in promoting angiogenesis in breast cancer.
- To elucidate the molecular mechanisms underlying CCL18-induced angiogenesis.
- To evaluate CCL18 as a potential therapeutic target for anti-angiogenic therapy in breast cancer.
Main Methods:
- Analysis of CCL18 and microvascular density (MVD) in 80 breast cancer samples using immunohistochemistry.
- In vitro and in vivo co-culture models of TAMs and human umbilical vein endothelial cells (HUVECs).
- Assessment of endothelial cell migration, angiogenesis, endothelial-mesenchymal transition, and signaling pathways (ERK, Akt/GSK-3β/Snail) following CCL18 exposure or blockade.
Main Results:
- CCL18+ TAM infiltration positively correlated with MVD, tumor metastasis, and poor prognosis in breast cancer.
- CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis in vitro and in vivo.
- Blocking CCL18 or VEGF inhibited TAM-driven pro-angiogenic effects; silencing the putative CCL18 receptor PITPNM3 abrogated CCL18-mediated effects.
- CCL18 induced endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3β/Snail signaling in HUVECs.
Conclusions:
- CCL18 secreted by TAMs promotes angiogenesis and tumor progression in breast cancer.
- CCL18 acts via PITPNM3 to stimulate endothelial cell migration and angiogenesis, partly through endothelial-mesenchymal transformation.
- CCL18 represents a promising novel therapeutic target for developing anti-angiogenic strategies in breast cancer.
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