Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer microenvironment
Resource
Oncotarget, 5(6), 1595-1608
Journal
Oncotarget
Pages
1595-1608
Date Issued
2014
Date
2014
Author(s)
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-kappa B 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.
Subjects
CCN3
VEGF
Prostate cancer
M2 macrophage
angiogenesis
SDGs
Other Subjects
focal adhesion kinase; immunoglobulin enhancer binding protein; nephroblastoma overexpressed protein; neutralizing antibody; protein kinase B; vasculotropin; culture medium; focal adhesion kinase 1; immunoglobulin enhancer binding protein; nephroblastoma overexpressed protein; NOV protein, human; protein kinase B; PTK2 protein, human; small interfering RNA; vasculotropin A; VEGFA protein, human; animal cell; animal experiment; animal model; animal tissue; article; cancer growth; carcinogenesis; cell differentiation; cell infiltration; cell migration; controlled study; endothelial progenitor cell; human; human cell; human tissue; in vivo study; macrophage; mouse; nonhuman; phenotype; prostate cancer; prostate cancer cell line; protein expression; protein targeting; signal transduction; tumor associated leukocyte; tumor microenvironment; upregulation; animal; antagonists and inhibitors; cell culture; cell motion; cell proliferation; culture medium; cytology; drug screening; enzyme immunoassay; genetics; macrophage; male; metabolism; neovascularization (pathology); pathology; pharmacology; prostate tumor; SCID mouse; tumor microenvironment; vascularization; Western blotting; Animals; Blotting, Western; Cell Differentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Culture Media, Conditioned; Endothelial Progenitor Cells; Focal Adhesion Kinase 1; Humans; Immunoenzyme Techniques; Macrophages; Male; Mice; Mice, SCID; Neovascularization, Pathologic; Nephroblastoma Overexpressed Protein; NF-kappa B; Phenotype; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; Tumor Microenvironment; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays