Membrane Type 1 Matrix Metalloproteinase–Mediated Stromal Syndecan-1 Shedding Stimulates Breast Carcinoma Cell Proliferation

Abstract

Mounting evidence implicates stromal fibroblasts in breast carcinoma progression. We have recently shown in threedimensional coculture experiments that human mammary fibroblasts stimulate the proliferation of T47D breast carcinoma cells and that this activity requires the shedding of the heparan sulfate proteoglycan syndecan-1 (Sdc1) from the fibroblast surface. The goal of this project was to determine the mechanism of Sdc1 ectodomain shedding. The broad spectrum matrix metalloproteinase (MMP) inhibitor GM6001 specifically blocked Sdc1-mediated carcinoma cell growth stimulation, pointing toward MMPs as critical enzymes involved in Sdc1 shedding. MMP-2 and membrane type 1 MMP (MT1-MMP) were the predominant MMPs expressed by the mammary fibroblasts. Fibroblast-dependent carcinoma cell growth stimulation in three-dimensional coculture was abolished by MT1-MMP expression silencing with small interfering RNA and restored either by adding recombinant MT1-MMP catalytic domain or by expressing a secreted form of Sdc1 in the fibroblasts. These findings are consistent with a model where fibroblast-derived MT1-MMP cleaves Sdc1 at the fibroblast surface, leading to paracrine growth stimulation of carcinoma cells by Sdc1 ectodomain. The relevance of MT1-MMP in paracrine interactions was further supported by coculture experiments with T47D cells and primary fibroblasts isolated from human breast carcinomas or matched normal breast tissue. Carcinoma-associated fibroblasts stimulated T47D cell proliferation significantly more than normal fibroblasts in three-dimensional coculture. Function-blocking anti-MT1-MMP antibody significantly inhibited the T47D cell growth stimulation in coculture with primary fibroblasts. In summary, these results ascribe a novel role to fibroblastderived MT1-MMP in stromal-epithelial signaling in breast carcinomas. [Cancer Res 2008;68(22):9558-65]

TIMP2 Deficiency Accelerates Adverse Post–Myocardial Infarction Remodeling Because of Enhanced MT1-MMP Activity Despite Lack of MMP2 Activation

“…MT1-MMP is a potent collagenase, 45,46 which also targets other ECM components, such as fibronectin, 47,48 laminin, 47,49 and proteoglycans. 50,51 In addition, MT1-MMP can mediate activation of other pro-MMPs, such as MMP13 (collagenase-3), 52 which is also a potent collagenase with broad substrate specificity, thereby amplifying the collagen-degradation process. Recently, it has been reported that MT1-MMP overexpression results in a severe dilated cardiomyopathy.…”

Shedding; towards a new paradigm of syndecan function in cancer

“…The most important and well-studied function of shed syndecans are their role(s) in tumorigenesis. MT1-MMP promotes syndecan-1 shedding, and shed syndecan-1 stimulates HEK293T cell migration (33), T47D breast carcinoma cell proliferation (49), and breast carcinoma cell growth in three-dimensional co-culture (33). Overexpression of shed syndecan-1 also promotes an invasive phenotype in MCF-7 breast cancer cells (50).…”

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

“…For example, in comparison to normal fibroblasts, CAFs have been shown to have greater stimulatory effects on triple-positive BCCs in three-dimensional cultures [41]. CAFs and BCCs have a reciprocal relationship and are in constant interaction [41].…”

“…For example, in comparison to normal fibroblasts, CAFs have been shown to have greater stimulatory effects on triple-positive BCCs in three-dimensional cultures [41]. CAFs and BCCs have a reciprocal relationship and are in constant interaction [41]. For example, the exposure of MSCs to conditioned media from BCCs can lead to MSC conversion into CAF-like cells expressing stromal cell-derived factor-1 (SDF-1), which has implications in BCC chemotaxis and metastasis to the bone marrow [37] (Fig.…”