Regulatory Roles of the Notch Signaling Pathway in Inflammation-Driven Tumor-MSC Networks in Breast Cancer

Breast tumor cells interact with mesenchymal stem cells (MSC) that are recruited to the tumor and promote processes aggravating disease course. Such tumor-MSC interactions may be mediated by cell-to-cell contacts and may be promoted by inflammatory cytokines that prevail at the tumor microenvironment (TME), leading to elevated angiogenesis, tumor growth and metastasis.

Our recent findings indicate that the release of the inflammatory and metastasis-promoting chemokines CXCL8, CCL2 and CCL5 by breast cancer cells (BCC) and bone-marrow-derived MSC is amplified when the two cell types are grown in co-cultures. The release of the inflammatory chemokines was further potentiated by stimulation by the inflammatory cytokines TNFα and IL-1β, known to be highly prevalent at the TME in breast tumors. This amplified release of chemokines was partly mediated by soluble factors exchanged between the two cell types, but it also required direct tumor-MSC cell-to-cell contacts. Accordingly, confocal studies demonstrated that BCC position themselves in close proximity to MSC and make intimate contacts with them.

Using specific inhibitors and RT-qPCR analyses we identified complex regulatory roles of Notch pathway in the cytokine-induced, contact-dependent processes of chemokine up-regulation. Our results suggest potential roles of Notch-1 and Jagged-2 expressed by BCC and Notch-3 and Delta-like-1 expressed by MSC, in induction of CXCL8 and CCL2 (but not CCL5) in tumor-MSC co-cultures. Direct roles for BCC-expressed Notch-1 were found to play key roles in these events.

Overall, our findings indicate that inflammatory networks regulate the tumor-promoting associations between tumor cells and stroma cells in their vicinity. By further elucidating the impact of such networks on tumor progression, we will provide a better basis for the design of new therapeutic strategies in breast cancer.