Accumulating evidence substantiates a potent pro-malignancy role for the inflammatory microenvironment, comprised of cells, chemokines and cytokines, in breast cancer development and progression. Tumor promotion and progression depend on interactions between tumor cells and other cells in their microenvironment, including human bone marrow-derived mesenchymal stem cells (hMSC). Between others, hMSC recruited to the tumor microenvironment are exposed to the inflammatory cytokines TNFa and IL-1b.
In this study, we investigated the mechanisms by which TNFa and IL-1b induce the release of the pro-angiogenic and tumor-promoting chemokines CCL2 (MCP-1) and CXCL8 (IL-8) from hMSC. We found that exposure to TNFa/IL-1b have led to high levels of CCL2 and CXCL8 secretion by hMSC, and that exposure to both cytokines have cooperatively elevated chemokine secretion. Our findings indicate that TNFa-induced pro-angiogenic switch is mediated primarily via NF-kB activation.
In parallel, we have determined the roles of microRNAs (miRs) in regulating the cytokine-induced pro-angiogenic switch in hMSC. These miRs target, among others, the mRNAs encoding for p65 (NF-kB subunit). We found that over-expression of miR-“A” family members in hMSC, before stimulation with TNFa/IL-1b, caused a significant inhibition of CCL2 and CXCL8 secretion. Our preliminary findings also show that the TNFa-induced pro-angiogenic switch was accompanied by a reduction in the endogenous expression levels of members of this miR family.
These findings emphasize the importance of studying the signaling cascades that promote the pro-angiogenic switch taking place in hMSC, and the miRs regulating these processes. In future studies, we will further investigate the mechanisms that underlie these events, in order to identify potential points for therapeutic intervention.
