Fibroblast and prostate tumor cell cross-talk: fibroblast differentiation, TGF-β, and extracellular matrix down-regulation.
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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ABSTRACT: BACKGROUND: The extracellular matrix (ECM) influences the structure, viability and functions of cells and tissues. Recent evidence indicates that tumor cells and stromal cells interact through direct cell-cell contact, the production of ECM components and the secretion of growth factors. Syndecans are a family of transmembrane heparan sulfate proteoglycans that are involved in cell adhesion, motility, proliferation and differentiation. Syndecan-2 has been found to be highly expressed in colorectal cancer cell lines and appears to be critical for cancer cell behavior. We have examined the effect of stromal fibroblast-produced ECM on the production of proteoglycans by colorectal cancer cell lines. RESULTS: Our results showed that in a highly metastatic colorectal cancer cell line, HCT-116, syndecan-2 expression is enhanced by fibroblast ECM, while the expression of other syndecans decreased. Of the various components of the stromal ECM, fibronectin was the most important in stimulating the increase in syndecan-2 expression. The co-localization of syndecan-2 and fibronectin suggests that these two molecules are involved in the adhesion of HCT-116 cells to the ECM. Additionally, we demonstrated an increase in the expression of integrins alpha-2 and beta-1, in addition to an increase in the expression of phospho-FAK in the presence of fibroblast ECM. Furthermore, blocking syndecan-2 with a specific antibody resulted in a decrease in cell adhesion, migration, and organization of actin filaments. CONCLUSIONS: Overall, these results show that interactions between cancer cells and stromal ECM proteins induce significant changes in the behavior of cancer cells. In particular, a shift from the expression of anti-tumorigenic syndecans to the tumorigenic syndecan-2 may have implications in the migratory behavior of highly metastatic tumor cells.BMC Cell Biology 05/2013; 14(1):25. · 2.81 Impact Factor
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ABSTRACT: After many years of limited treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), multiple systemic therapies are now available, providing patients with significant improvements in survival, symptom control and bone health. Most of the recent advances in this area have been based on better understanding of mCRPC biology, particularly with respect to the key role of androgen receptor signalling. However, most therapies are targeted towards the malignant epithelial cell component of the cancer and it should not be forgotten that cancer cells exist in close and symbiotic relationships with other components of the tumour. Paracrine and stromal signals are often critical to the growth of the cancer and represent new potential therapeutic targets that are separate from the malignant epithelial cells. The stroma produces numerous growth factors, including vascular endothelial growth factor family members, platelet-derived growth factors and fibroblast growth factors, which are all critical for tumour growth. Targeting prostate-cancer-associated fibroblasts in order to destroy the physical and functional scaffold of a cancer is also a logical approach. The interaction between prostate cancer and the immune system remains an active topic of basic and clinical research, with cytokines, chemokines and growth factors being potential targets for therapy. The biology of epithelial-mesenchymal transition and of circulating tumour cells might also provide insight into new therapeutic targets.Nature Reviews Urology 07/2013; · 4.79 Impact Factor
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ABSTRACT: The consecutive steps of tumor growth, local invasion, intravasation, extravasation and invasion of anatomically distant sites are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Lumican, a class II small leucine-rich proteoglycans (SLRP) has been designated key roles both in extracellular matrix (ECM) organisation and as an important modulator of biological functions. This review will critically discuss lumicans' roles in tumor development and progression. We will especially focus on correlating lumicans' expression and distribution in tumor tissues with: (1) the organization of the tumor matrices; (2) tumor cell signaling and functions; (3) tumor cell-matrix interface; (4) tumor angiogenesis; and (5) lumicans potential roles in tumor-associated inflammatory response. Present knowledge of lumicans' biology provides a fundamental platform upon which to build and deepen our understanding of lumican function in tumorigenesis in order to be able to design credible anti-tumor approaches.Matrix biology: journal of the International Society for Matrix Biology 09/2013; · 3.56 Impact Factor