Overcoming Bone Marrow-Stroma-Mediated Chemoresistance in Metastatic Breast Cancer Cells

摘要

Mammary ductal integrity is lost during dedifferentiation to cancer. Ductal morphogenesis has been reported to depend on expression of FGF-2 and laminin 5. We demonstrate that the two proteins are coordinately lost during the progression to cancer and that FGF-2 may contribute to the deposition of Laminin 5. Breast cancer cells metastasize to the bone marrow early during cancer formation where they can remain dormant for years and are resistant to chemotherapy. We developed an in vitro model where FGF-2, a growth factor abundant in the marrow microenvironment, induces partial re-differentiation and integrin re-expression that permits ligation of bone marrow fibronectin in estrogen-dependent cells. Dormant cells require survival signaling through Pl3K/Akt and Rho and combined disruption of Pl3K and Rho can result in near complete elimination of dormant cells. Broad transcription inhibitors such as Flavopiridol have pleiotropic effects on key targets involved with survival of dormant breast cancer cells and may represent a useful approach to eliminating cells dependent on multiple signal pathways for survival that are resistant to taxanes. We developed a flow retardation device that represents the first application of a technology for assessing cell surface protein expression in single cancer cells without prior manipulation.