Modulation of the extracellular matrix by Streptococcus gallolyticus subsp. gallolyticus and importance in cell proliferation

Abstract

Streptococcus gallolyticus subspecies gallolyticus (Sgg) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. Previous work showed that this organism stimulated the proliferation of CRC cells. However, the molecular mechanism underlying this ability was unknown. The extracellular matrix (ECM) is an important regulator of cell proliferation. Here, we found that Sgg upregulates the expression of several types of collagens in HT29 and HCT116 cells, with type VI collagen (ColVI) being the highest upregulated collagen. Knockdown of ColVI abolished the ability of Sgg to induce host cell proliferation. Our data further showed the ECM by itself is a direct mediator of Sgg-induced cell proliferation. This is evidenced by the effect of decellularized matrix (dc-matrix), which is free of bacteria or cells. Dc-matrix from Sgg-treated cells showed a significantly higher pro-proliferative activity than that from untreated cells or cells treated with the control bacteria. On the other hand, dc-matrix from Sgg-treated ColVI knockdown cells showed no difference in the capacity to support cell proliferation compared to that from ColVI knockdown cells incubated in media only, suggesting the importance of matrix composition and property in this process. In addition, we showed that ColVI is important for Sgg to promote tumor growth in vivo. Taken together, the results reveal a novel mechanism in which Sgg stimulates CRC proliferation through modulation of the ECM.