Syndecan-2 is upregulated in colorectal cancer cells through interactions with extracellular matrix produced by stromal fibroblasts

Abstract

BackgroundThe 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.ResultsOur 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.ConclusionsOverall, 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.

Carbohydrate-Containing Molecules as Potential Biomarkers in Colon Cancer

“…Syndecan-1 was observed in all (8 of 8) normal tissue samples and all cancer tissues, with the exception of one (sample 8) that showed enhanced levels of syndecan-1. Interestingly, the expression pattern of syndecan-2, which is normally highly expressed in colon carcinoma (Beauvais and Rapraeger, 2004;Han et al, 2004;Vicente et al, 2013), did not show enhanced levels in the cancer tissues studied. Our data seem to correlate better to a report indicating that colon cancer cell lines HT29 and Caco-2 that show reduced syndecan-2 expression, and the report that decreased levels of syndecan-2 do not influence proliferation and invasion by these cell lines (Han et al, 2004).…”

“…significantly reduced in highly metastatic colon carcinoma cells (Vicente et al, 2013). Oh and co-workers (Han et al, 2004) showed that Caco-2 and HT29 cells endogenously expressed as low levels of syndecan-2, whereas HCT116 cells expressed high levels of syndecan-2, in the same type of human colon adenocarcinomas.…”

Enhanced Tumorigenic Potential of Colorectal Cancer Cells by Extracellular Sulfatases

“…The role of HSPGs on cell adhesion, which is dependent on the interaction of HS chains with ECM proteins such as fibronectin, has already been well established (38). Apparently the decrease of the sulfation status of HS facilitated the adhesion and migration of colorectal cancer cells.…”

“…4A) was observed. Interestingly, this increased adhesion was more significant when cells overexpressing SULFs were plated on fibronectin, which is known to bind HS and participate in the adhesion of colorectal cancer cells (38).…”

“…The effects of SULFs overexpression were more pronounced on the HCT-116 cell line, which is derived from a highly metastatic cancer, than in the Caco-2 cell line, which has low metastatic potential. It is important to mention that, although derived from a colon carcinoma, when cultured under specific conditions, Caco-2 cells become differentiated and polarized, resembling normal enterocytes from small intestine (38).…”