Abstract
Dormant breast cancers resurge as metastatic disease after a long dormancy period in the bone marrow, where cancer cells interact with mesenchymal stem cells (MSC). However, the nature of early interactions between breast cancer cells and MSCs in the bone marrow microenvironment that facilitate adaptation to a quiescent state remains poorly understood. Here, we report that breast cancer cells prime MSC to release exosomes containing distinct miRNA contents, such as miR-222/223, which in turn promotes quiescence in a subset of cancer cells and confers drug resistance. Building on these results, we developed a novel, nontoxic therapeutic strategy to target dormant breast cancer cells based on systemic administration of MSC loaded with antagomiR-222/223. In an immunodeficient mouse model of dormant breast cancer, this therapy sensitized breast cancer cells to carboplatin-based therapy and increased host survival. Overall, our findings illuminate the nature of the regulatory interactions between breast cancer cells and MSCs in the evolution of tumor dormancy and resurgence in the micrometastatic microenvironment of the bone marrow. Cancer Res; 76(19); 5832-44. ©2016 AACR.
Highlights
Breast cancer recurrence continues to pose a major clinical problem, despite significant advancement in early diagnosis and an aggressive mode of treatment
We validated the transfer of exosomes between mesenchymal stem cells (MSC) and breast cancer cells (BCC) in a Transwell system separated by 0.4-mm membranes (Fig. 1C)
Findings presented here reveal how MSCs initiate a quiescent phenotype in BCCs and opened up a new avenue to target miRNA within stem cells for therapeutic gains
Summary
Breast cancer recurrence continues to pose a major clinical problem, despite significant advancement in early diagnosis and an aggressive mode of treatment. It is widely accepted that breast cancer recurrence is linked to a prolonged dormancy and successful survival of breast cancer cells (BCC) in the bone marrow. In such state, the BCCs are in mitotic arrest and resist anticycling treatments [1,2,3,4,5,6,7,8]. To prevent the recurrence of breast cancer, one potential novel approach includes targeting the dormant BCCs and/or restraining BCCs from establishing dormancy. Because the region of dormancy is the home of the endogenous hematopoietic stem cells in the bone marrow, this approach poses a major challenge for successful targeting of the.
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