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A Study of the Molecular Signaling Pathways that Regulate Mesenchymal Stromal Cell Migration to Tumor Cells

by
Sonia C. Picinich
B.A. 2001
Rutgers University
New Brunswick, New Jersey

Thesis Advisor: Debabrata Banerjee, Ph.D.
Graduate Program in Cellular
& Molecular Pharmacology

CINJ, Auditorium A

Wednesday, October 8, 2008
10:00 a.m.


Abstract

Mesenchymal stromal cells (MSCs) are bone marrow-derived cells with pluripotent differentiation potential that are mobilized into the circulation in response to injury and localize to areas of tissue damage including solid tumors. They have the capacity to adopt a phenotype similar to carcinoma-associated fibroblasts (CAFs) in response to long-term exposure to tumor conditioned medium, and like CAFs, support tumor growth. The fundamental signals between MSCs and tumor cells have not been well defined. Therefore, the primary goal of our studies was to elucidate the molecular mechanisms that regulate MSC migration to tumor cells.
We confirmed that MSCs migrate to tumor cells derived from an array of tissues in vivo and in vitro. Additionally, they migrate to tumor conditioned medium with equal alacrity suggesting that the tumor cells secrete soluble chemotactic factors. To identify candidate genes involved in promoting migration, gene expression analysis of MSCs treated with tumor conditioned medium was carried out. Results from the microarray studies revealed that MSCs have increased expression of the chemokine stromal-derived factor 1 (SDF-1) in response to conditioned medium from tumor cells. Furthermore, knockdown of SDF-1 in MSCs inhibits migration in response to tumor conditioned medium suggesting a critical role for SDF-1 production. We then identified tumor-secreted factors that regulate SDF-1 expression by analysis of the tumor conditioned medium. Interleukin-8 (IL-8) is a chemokine secreted by tumor cells, and we demonstrated its function in the activation of MSC migration and SDF-1 expression.
In this study, we further explored the downstream signaling pathways mediated by IL-8. IL-8 induces activation of protein kinase C (PKC). Additionally, PKC inhibitor studies showed that PKC activity is required for regulation and induction of SDF-1 expression and migration of MSCs to tumors through activation of the Sp1 transcription factor. More specifically, functional studies suggested that the PKC zeta isoform is responsible for activation of this signaling pathway. We also investigated the role of p53 activation in SDF-1 expression based on previous studies. We determined that p53 activation may repress SDF-1 expression in a signaling pathway independent of IL-8 and PKC resulting in inhibition of MSC migration. Taken together, these signaling pathways provide insight into possible molecular targets for cancer therapy aimed at disrupting the interaction between components of the tumor microenvironment.


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