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Shyam A. Patel
B.S., Drexel University, Philadelphia, PA
Thesis Advisor: Pranela Rameshwar, Ph.D.
Department of Medicine
Friday, May 20, 2011
MSB B-610, 11:00 A.M.
Breast cancer (BC) dormancy continues to be a clinical dilemma, despite education, treatment compliance and widespread research. The residence of dormant BC cells (BCCs) remains a subject of investigation. However, bone marrow (BM) appears to be a major organ, based on cancer resurgence from this organ after years of disease-free survival. Experimental evidence indicates that resident BM cells can facilitate the support the survival and/or growth of BCCs. Supporting BM cells include mesenchymal stem cells (MSCs), stroma, immune cells, osteoblasts and endothelial cells. This thesis tested the hypothesis that a hierarchy of BCCs determines which subset can take advantage of MSCs to evade targeting by the immune system and eventually to form gap junctional intercellular communication (GJIC) with stroma for microRNA (miRNA) exchange, consequently leading to BCC quiescence and chemo-resistance. Through functional and molecular studies, the thesis developed a hierarchy of BCC subsets. The studies indicated that information on breast cancer stem cells regarding CD44/CD24 expression incorporated a heterogeneous subset that can be further subdivided by Octamer 4 (Oct4) expression, stem cell gene expression and formation of GJIC. The most primitive subset within the hierarchy, which is designated BC stem cells, divided asymmetrically, initiated tumor in a xenogeneic model of BC, formed GJIC with stroma in a mouse model and resisted in vivo treatment with carboplatin. Cells that were not designated BC stem cells were collectively referred as BC progenitors. The refractoriness of BC stem cells to chemotherapy is consistent with another section of the thesis that showed GJIC with unsorted BCCs and miRNA exchange via gap junction for BCC quiescence. The studies focused on miRNA specific for the chemokine CXCL12, which is reduced following GJIC. Stroma can also deliver miRNA in BCCs through the release of exosomes. Since quiescent BCCs are found close to the endosteum, the question is how the BCCs can evade immune clearance within the medullary region as they traverse the marrow to the endosteal region. This thesis showed a protective role by MSCs for unsorted BCCs; via expansion and induction of regulatory T-cells (Tregs), decrease in the activities of natural killer and cytotoxic cells. These studies were further `refinedí by comparing the immune responses between BC stem cells and progenitors. The studies showed induction of Tregs by BC stem cells and T-helper 17 (Th17) by BC progenitors. The differences in these immune responses appeared to be partly caused by varied interactions between the particular BCC subset and MSCs. BC stem cells formed GJIC with MSCs and this required interaction between CXCR4 and CXCL12. In contrast, BC progenitors did not form GJIC with MSCs. This led to the MSCs supporting BC growth with sensitivity to carboplatin. Finally, the significance of these studies was determined with primary BCCs from surgical tissues and peripheral blood. In summary, the thesis identified subsets of BCCs that can be demarcated as stem cells and progenitors with the former adapting dormancy and resisting chemotherapy. The thesis has implications for BC treatment, prognosis, diagnosis as well as the development of novel treatments, including modified immune therapy.