Mesenchymal Stem Cell–Derived Exosomes Stimulate Cycling Quiescence and Early Breast Cancer Dormancy in Bone Marrow
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 01, 2016
- Source ID
- 10.1158/0008-5472.can-16-1092
Entities
People
- Daniel J. Engelberth
- Garima Sinha
- Khadidiatou Guiro
- Leidy L. Isenalumhe
- Lisa M. Williams
- Margarette Bryan
- Nicholas M. Ponzio
- Oleta A. Sandiford
- Pranela Rameshwar
- Rakesh Kumar
- Sarah A. Bliss
- Seda Ayer
- Steven J. Greco
Organizations
- George Washington University
- New Jersey Medical School
- Rutgers University
- United States Department of Defense