Matrix Metalloproteinase (MMP)-9 in Cancer-Associated Fibroblasts (CAFs) Is Suppressed by Omega-3 Polyunsaturated Fatty Acids In Vitro and In Vivo
Open Access
- 27 February 2014
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 9 (2), e89605
- https://doi.org/10.1371/journal.pone.0089605
Abstract
Cancer associated fibroblasts (CAFs) are responsible for tumor growth, angiogenesis, invasion, and metastasis. Matrix metalloproteinase (MMP)-9 secreted from cancer stroma populated by CAFs is a prerequisite for cancer angiogenesis and metastasis. Omega-3 polyunsaturated fatty acids (omega-3 PUFA) have been reported to have anti-tumor effects on diverse types of malignancies. Fat-1 mice, which can convert omega-6 to omega-3 PUFA independent of diet, are useful to investigate the functions of endogenous omega-3 PUFA. To examine the effect of omega-3 PUFA on tumorigenesis, TC-1 cells, a murine epithelial cell line immortalized by human papillomavirus (HPV) oncogenes, were injected subcutaneously into fat-1 or wild type mice. Tumor growth and angiogenesis of the TC-1 tumor were significantly suppressed in fat-1 compared to wild type mice. cDNA microarray of the tumors derived from fat-1 and wild type mice revealed that MMP-9 is downregulated in fat-1 mice. Immunohistochemical study demonstrated immunoreactivity for MMP-9 in the tumor stromal fibroblasts was diffusely positive in wild type whereas focal in fat-1 mice. MMP-9 was expressed in primary cultured fibroblasts isolated from fat-1 and wild type mice but was not expressed in TC-1 cells. Co-culture of fibroblasts with TC-1 cells enhanced the expression and the proteinase activity of MMP-9, although the protease activity of MMP-9 in fat-1-derived fibroblasts was lower than that in wild type fibroblasts. Our data suggests that omega-3 PUFAs suppress MMP-9 induction and tumor angiogenesis. These findings may provide insight into mechanisms by which omega-3 PUFAs exert anti-tumor effects by modulating tumor microenvironment.This publication has 48 references indexed in Scilit:
- Tumor Metastasis: Molecular Insights and Evolving ParadigmsCell, 2011
- Cancer associated fibroblasts in cancer pathogenesisSeminars in Cell & Developmental Biology, 2010
- Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent MannerCancer Cell, 2010
- Papillomaviruses in the causation of human cancers — a brief historical accountVirology, 2009
- Microenvironmental regulation of metastasisNature Reviews Cancer, 2008
- Fat-1 transgenic mice: A new model for omega-3 researchProstaglandins, Leukotrienes & Essential Fatty Acids, 2007
- Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acidsProceedings of the National Academy of Sciences of the United States of America, 2006
- Fibroblasts in cancerNature Reviews Cancer, 2006
- Resolution of inflammation: the beginning programs the endNature Immunology, 2005
- Stromal fibroblasts in cancer initiation and progressionNature, 2004