Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer microenvironment.
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.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Po-Chun
PC
Chen
Hsu-Chen
HC
Cheng
John
J
Wang
Shin-Wei
SW
Wang
Huai-Ching
HC
Tai
Chiao-Wen
CW
Lin
Chih-Hsin
CH
Tang
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D055514:Nephroblastoma Overexpressed Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C526319:CCN3 protein, human; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D055514:Nephroblastoma Overexpressed Protein; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt