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Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer
Po-Chun Chen1, Hsu-Chen Cheng, John Wang
1Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Abstract:
Tumor-associated macrophages (TAMs) are M2-polarized macrophages that infiltrate the tumor microenvironment and promote tumorigenesis. However, the mechanisms by which TAMs modulate prostate cancer (PCa) growth are poorly understood. Here, we found that expression of Nephroblastoma Overexpressed (NOV/CCN3) is upregulated in PCa cells and correlated with M2 macrophage infiltration. RAW264.7 macrophage migration was induced by conditioned media (CM) from various PCa cells in proportion to the cellular level of CCN3 expression and was inhibited by an anti-CCN3 neutralizing antibody. CCN3 and PCaCM treatment skewed RAW264.7 cell differentiation from an M1 phenotype to an M2 phenotype. PCa-derived CCN3 induced focal adhesion kinase (FAK)/Akt/NF-κB signaling in RAW264.7 cells, which resulted in VEGF expression and subsequently increased tube formation in endothelial progenitor cells. Finally, PCa-secreted CCN3 stimulated RAW264.7 cells and promoted angiogenesis in the chick chorioallantoic membrane assay (CAM), and increased tumor growth and tumor-associated angiogenesis in a PCa xenograft mouse model. Our results indicate that PCa-secreted CCN3 can recruit macrophages and skew their differentiation to an M2 phenotype. In turn, CCN3-stimulated macrophages contribute to VEGF-dependent angiogenesis. This study reveals a novel mechanism by which TAMs enhance PCa angiogenesis and identifies a potential therapeutic target for PCa.
Insights
Prostate cancer (PCa) cells secrete CCN3, which recruits and polarizes macrophages to the M2 phenotype. These CCN3-stimulated macrophages promote PCa growth and angiogenesis via VEGF signaling.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Tumor-associated macrophages (TAMs) are M2-polarized macrophages that infiltrate the tumor microenvironment and promote tumorigenesis.
- The mechanisms by which TAMs modulate prostate cancer (PCa) growth remain poorly understood.
Purpose of the Study:
- To investigate the role of Nephroblastoma Overexpressed (NOV/CCN3) in PCa progression and its interaction with TAMs.
- To elucidate the signaling pathways involved in CCN3-mediated macrophage recruitment and polarization.
- To determine the impact of CCN3 on angiogenesis and tumor growth in PCa.
Main Methods:
- Assessed CCN3 expression in PCa cells and correlated with M2 macrophage infiltration.
- Utilized conditioned media from PCa cells to study macrophage migration and differentiation.
- Investigated CCN3-induced signaling pathways (FAK/Akt/NF-κB) in macrophages.
- Evaluated angiogenesis using endothelial progenitor cell tube formation assays and chick chorioallantoic membrane (CAM) assays.
- Assessed tumor growth and angiogenesis in a PCa xenograft mouse model.
Main Results:
- CCN3 expression is upregulated in PCa and correlates with M2 macrophage infiltration.
- PCa-derived CCN3 induces macrophage migration and skews differentiation towards the M2 phenotype.
- CCN3 activates FAK/Akt/NF-κB signaling, leading to VEGF expression and promoting endothelial cell tube formation.
- PCa-secreted CCN3 promotes angiogenesis in CAM assays and enhances tumor growth and angiogenesis in vivo.
Conclusions:
- PCa-secreted CCN3 recruits and polarizes macrophages to the M2 phenotype.
- CCN3-stimulated M2 macrophages contribute to VEGF-dependent angiogenesis in PCa.
- CCN3 represents a novel mechanism by which TAMs enhance PCa angiogenesis and is a potential therapeutic target.
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