Fibroblast and prostate tumor cell cross-talk: Fibroblast differentiation, TGF-β, and extracellular matrix down-regulation

Departamento de Bioquímica, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Experimental Cell Research (Impact Factor: 3.37). 11/2010; 316(19):3207-26. DOI: 10.1016/j.yexcr.2010.08.005
Source: PubMed

ABSTRACT Growth and survival of tumors at a site of metastasis involve interactions with stromal cells in the surrounding environment. Stromal cells aid tumor cell growth by producing cytokines as well as by modifying the environment surrounding the tumor through modulation of the extracellular matrix (ECM). Small leucine-rich proteoglycans (SLRPs) are biologically active components of the ECM which can be altered in the stroma surrounding tumors. The influence tumor cells have on stromal cells has been well elucidated. However, little is understood about the effect metastatic cancer cells have on the cell biology and behavior of the local stromal cells. Our data reveal a significant down-regulation in the expression of ECM components such as collagens I, II, III, and IV, and the SLRPs, decorin, biglycan, lumican, and fibromodulin in stromal cells when grown in the presence of two metastatic prostate cancer cell lines PC3 and DU145. Interestingly, TGF-β down-regulation was observed in stromal cells, as well as actin depolymerization and increased vimentin and α5β1 integrin expression. MT1-MMP expression was upregulated and localized in stromal cell protrusions which extended into the ECM. Moreover, enhanced stromal cell migration was observed after cross-talk with metastatic prostate tumor cells. Xenografting metastatic prostate cancer cells together with "activated" stromal cells led to increased tumorigenicity of the prostate cancer cells. Our findings suggest that metastatic prostate cancer cells create a metastatic niche by altering the phenotype of local stromal cells, leading to changes in the ECM.

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    • "Of note, as reported above for other KLKs, we also identified the TGF-␤1 signaling axis as a key KLK4 target (our unpublished data). TGF-␤1 is one of the key growth factors implicated in transforming normal fibroblasts into cancer-associated myofibroblasts , a process integral to cancer progression as the latter phenotype is both permissive and supportive of cancerous outgrowth [94]. Thus, KLK4 and indeed other KLKs that are yet to be screened for fibroblast interactions using similar approaches, may contribute toward cancer progression via modulation of the stromal microenvironment. "
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    • "Initially, Holland et al. (2004) reported that lumican is expressed by prostatic secretory cells but that it is lost in the early stages of malignant transformation. Interestingly, when stromal cells are cultivated in the presence of prostate cancer cells they exhibit a downregulation of ECM molecules they normally express, including that of lumican (Coulson-Thomas et al., 2010). However, Coulson-Thomas et al. (2013) report an overall lumican up-regulation in primary prostate tumors analyzed through both real-time PCR and immunostaining. "
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