title: TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression.
abstract: Treatment options for late stage prostate and colon cancer are limited and there is an urgent need to develop more effective and targeted novel therapies, which starts with identification and validation of novel therapeutic targets. Recent clinical studies have demonstrated that tissue inhibitor matrix metalloproteinase-1 (TIMP-1) levels are elevated in cancer patient plasma and elevated TIMP-1 levels are associated with worse clinical outcomes. However, it is unknown whether TIMP-1 serves merely as a biomarker of cancer progression or has a functional role in promoting cancer progression and can serve as a cancer therapeutic target, which is the main objective of this study. Here, we show that stroma of human prostate and colon cancer express higher levels of TIMP-1 compared to their normal counterparts and increased expression of TIMP-1 promotes in vivo growth of both cancer types. We demonstrate for the first time that increased TIMP-1 expression stimulates accumulation of cancer associated fibroblasts (CAFs) within prostate and colon cancer tissues and that TIMP-1 enhances prostate CAF proliferation and migration in vitro and promotes ERK1/2 kinase activation in these CAF cells. Our results establish the novel promotive effects of TIMP-1 on cancer progression and on accumulation of CAFs that in turn provides a pro-tumor microenvironment. Together, these results establish the potential of TIMP-1 as a novel target for cancer therapy and the mechanism underlying the pro-tumor activity of TIMP-1.
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai, New York, United States of America.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Gong
authors.forename: Evita
authors.initials: E
authors.lastname: Scott
authors.forename: Rong
authors.initials: R
authors.lastname: Lu
authors.forename: Yin
authors.initials: Y
authors.lastname: Xu
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.forename: Qin
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000097:blood / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D004789:Enzyme Activation; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000378:metabolism*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3