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Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo.

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.

SUBMITTER: Taguchi A

PROVIDER: S-EPMC3937340 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo.

Taguchi Ayumi A Kawana Kei K Tomio Kensuke K Yamashita Aki A Isobe Yosuke Y Nagasaka Kazunori K Koga Kaori K Inoue Tomoko T Nishida Haruka H Kojima Satoko S Adachi Katsuyuki K Matsumoto Yoko Y Arimoto Takahide T Wada-Hiraike Osamu O Oda Katsutoshi K Kang Jing X JX Arai Hiroyuki H Arita Makoto M Osuga Yutaka Y Fujii Tomoyuki T

PloS one 20140227 2

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 end ...[more]

PMID: 24586907

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Project description:Cerebral microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the "single cortical microinfarct model" generated via occluding a penetrating arteriole by femtosecond laser ablation and the "multiple diffuse microinfarcts model" induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the microinfarct size. The protective effects of ω-3 PUFAs against microinfarcts were further verified in a multiple diffuse microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia.

Dataset Information

Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo.

Publications

Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo.

Similar Datasets

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