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"A MODEL FOR REAWAKENING OF DORMANT
BREAST CANCER MICROMETASTASES"

by
Samir Tivari
Interdisciplinary Biomedical Sciences Program
B.A. 2006, Bard College, Annandale on Hudson, NY


Thesis Advisor: Robert Wieder, M.D., Ph.D.
Professor
Department of Medicine

Tuesday, December 20, 2016
12:00 PM,Cancer Center, G Level Conference Room 1196


Abstract

Estrogen-dependent breast cancer cells can remain dormant in the bone marrow microenvironment for more than a decade and continue to recur in a stochastic pattern at continuous, low rates. Mechanisms of dormancy in the bone marrow are mostly uncharacterized but data suggest that the establishment and maintenance of dormancy depend on close interactions of micrometastases with stromal elements and on effects by structural and soluble proteins.
To better understand these signaling pathways, we developed a well-characterized in vitro model of dormancy incorporating relevant key elements of the bone marrow niche. With it, we have demonstrated that FGF-2, which is abundantly deposited on bone marrow stroma, induces the dormancy of well-differentiated breast cancer cells on fibronectin or on human or murine stromal co-cultures. We have also shown that stromal cells (i) export growth factors, which may induce redifferentiation in metastasized cancer cells, and (ii) allow them to bind to structural proteins which initiate signaling that supports tumor dormancy.
Mechanisms of breast cancer recurrence are also not understood, but data in other systems suggest that inflammatory cytokines can stimulate the proliferation of breast cancer cells. We therefore hypothesized that stromal injury induces secretory senescence and cytokines which are able to reawaken co-cultivated breast cancer cells. To this end, we injured human and murine bone marrow stromal monolayers by oxidation and hypoxia through one-hour exposures to variable concentrations of hydrogen peroxide (H2O2) and a cyanide-containing analog (CCCP), respectively. We also studied estrogen deprivation using the antiestrogen agent ICI 182780. These interventions induced the secretion of IL-6 and IL-8, upregulated TNF, activated TGF and stimulated the growth of co-cultivated MCF-7 cells. Subsequently, we found that the addition of exogenous IL-6, IL-8 or TGF-1 to dormant MCF-7 cells on fibronectin-coated plates induced their regrowth. Dormant cells also had decreased expression of E-cadherin and estrogen receptor and increased expression of N-cadherin and SLUG. Cytokine or TGF treatment of dormant clones induced growth of growing clones, a mesenchymal appearance, increased motility and an impaired capacity to re-enter dormancy.
Our data led us to conclude that dormant cells have activated EMT gene expression programs and that stromal inflammation reactivates dormant ER+ breast cancer cells and induces a mesenchymal phenotype. We demonstrated that reactivated dormant cells have an impaired ability to re-enter dormancy.


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