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"TLR-4 activation of Mesenchymal Stem Cell reverses Breast Cancer Dormancy via Macrophage Polarization"

Nykia D. Walker
Cell Biology, Neuroscience and Physiology Program
B.A. 1999, University of Pennsylvania, Philadelphia, PA
M.S. 2004, Thomas Jefferson University, Philadelphia, PA

Thesis Advisor: Pranela Rameshar, PhD
Department of Medicine
Rutgers New Jersey Medical School

Friday, February 16, 2018
10:00 A.M., MSB C600


Clinical evidence indicates that breast cancer (BC) cells (BCC) can exist in a dormant phase, within the bone marrow (BM) for decades. Dormancy arises when cancer cells undergo quiescence, which can occur at the level of cell cycle or proliferative balance. Quiescent BCCs can remain undetected until they are triggered by a cellular stimulus to enter cell cycle; resulting in metastasis. A small subset of breast cancer stem cells (B-CSCs) is responsible for BC dormancy and chemotherapy resistance. The mechanisms involved in the promoting B-CSCs towards dormancy and subsequent resurgence is under extensive investigation. Previous studies reported on BC quiescence by intercellular communication between bone marrow (BM) stroma and B-CSCs through gap junction (GJIC) and exosomes. This thesis examined the interactions between specific components of BM stroma, macrophages (MÍ) and mesenchymal stem cells (MSCs), in BC dormancy. MÍs are classified as M1 phenotype, which has pro-inflammatory functions and M2 phenotype with anti-inflammatory properties. The stromal MÍs were found to be M2 phenotype, which was shown to maintain cycling quiescence of B-CSCs through GJIC. The conversion of M2 MÍs into M1 phenotype reversed the dormant phase and this enhanced chemosensitivity both in vitro and in vivo. Activation of the toll-like receptor 4 (TLR4) on M2 MÍs and MSCs indicated that the conversion to M1 MÍs can occur directly and indirectly through the exosome secretome of MSCs. In summary, we report on a novel mechanism that disrupts GJIC between B-CSCs and BM-stroma-derived M2a MÍ, through direct stimulation of the M2 MÍ and indirectly, through the release of exosomes from MSCs.

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