Abstract
Breast cancer cells (BCCs) can remain quiescent for a long period, before detection and during remission. Mesenchymal stem cells (MSCs) exert both protective and growth support of BCCs. Intercellular interactions between MSCs and BCCs partly occur through membrane-bound CXCL12 (SDF-1α) and its receptor, CXCR4. MSCs can protect BCCs by suppressing immune cytotoxicity and concomitant induction of regulatory T-cells. This study investigated how the cellular interactions between MSCs and BCCs can be targeted to sensitize the BCCs to chemotherapy. Knockdown of CXCR4 and CXCL12 indicated that these molecules are involved in reduced proliferation of MDA-MB-231 and T47D BCCs. We therefore treated co-cultures of MSCs and BCCs with the CXCR4 antagonist, AMD3100, and showed that this treatment led to cycling of BCCs with increased sensitivity to carboplatin, although the effectiveness of carboplatin required the presence of AMD3100. Cytokine array analyses and transwell cultures indicated that AMD3100 caused an increase in BCC proliferation by inducing the production of IL-1α and IL-1β in MSCs after uncoupling from BCCs. The findings with cell lines were validated with primary BCCs from the blood of patients, and in nude BALB/ c mice. MDA-MB-231 was injected in the dorsal flank of mice. The tumors were treated with IL-1 receptor antagonist, AMD3100 and/ or carboplatin. The results verified a critical role for IL-1 in transitioning MSCs from protective to supportive with respect to BCC growth. The clinical significance of these studies was further highlighted in preliminary studies that detected circulating MSCs in obese, but not non-obese patients. Since obese breast cancer patients show poor outcome, these findings underscore that importance of MSCs in consideration for future development of efficient therapy.