Oncotarget

Research Papers:

Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer microenvironment

Po-Chun Chen, Hsu-Chen Cheng, John Wang, Shin-Wei Wang, Huai-Ching Tai, Chiao-Wen Lin and Chih-Hsin Tang _

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Oncotarget. 2014; 5:1595-1608. https://doi.org/10.18632/oncotarget.1570

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Abstract

Po-Chun Chen1,2, Hsu-Chen Cheng3, John Wang4, Shin-Wei Wang5, Huai-Ching Tai6,7, Chiao-Wen Lin8,9, and Chih-Hsin Tang1,10,11

1 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan

2 Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan

3 Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan

4 Department of Pathology, Taichung Veterans General Hospital, Taichung, Taiwan

5 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

6 Department of Urology, National Taiwan University Hospital, Taipei, Taiwan

7 Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan

8 Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan

9 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan

10 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan

11 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan

Correspondence:

Chih-Hsin Tang, email:

Chiao-Wen Lin, email:

Keywords: CCN3; VEGF; Prostate cancer; M2 macrophage; angiogenesis

Received: November 4, 2013 Accepted: February 2, 2014 Published: February 4, 2014

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.


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