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.
Highlights
The tumor microenvironment is comprised of microvascular endothelial cells, adjacent normal epithelial cells and cancerassociated fibroblasts (CAFs), and is reported to be an important regulator of tumorigenesis [1,2]
As the most common cellular population found in the tumor microenvironment, CAFs are responsible for the synthesis of proteins involved in the remodeling of the extracellular matrix (ECM), and for the secretion of growth factors and cytokines that regulate tumor cell proliferation and invasion [3,4]
We examined the expression of Matrix metalloproteinase (MMP) in these TC-1 tumors to further address stroma-related angiogenesis in the tumor microenvironments (Table 1). cDNA microarray demonstrated that the expression of MMP-2 and -9 were suppressed in fat-1 micederived TC-1 tumor while those of other MMPs were tended to be upregulated when compared to controls
Summary
The tumor microenvironment is comprised of microvascular endothelial cells, adjacent normal epithelial cells and cancerassociated fibroblasts (CAFs), and is reported to be an important regulator of tumorigenesis [1,2]. As the most common cellular population found in the tumor microenvironment, CAFs are responsible for the synthesis of proteins involved in the remodeling of the extracellular matrix (ECM), and for the secretion of growth factors and cytokines that regulate tumor cell proliferation and invasion [3,4]. MMPs are reported to influence tumor progression by facilitating events pivotal for neovascularization and establishment of distant metastasis including proliferation, survival and migration of endothelial, tumor and stromal cells [8,9]. MMP-9 is well-known to be secreted from cancer stromal fibroblasts and endothelial cells [11,12]. MMP-9 is a member of a family of zinc containing endoproteinases that is involved in degradation of extracellular matrix (ECM) and in vascular remodeling [13]
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