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"CHARACTERIZATION OF THE MIGRATORY MECHANISM OF MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) AND ITS CONTRIBUTION TO BREAST CANCER PROGRESSION"

by
Crystal J. DiCosmo-Ponticello
Molecular Pathology and Immunology Program
B.A. 2005, Rutgers University, New Brunswick, NJ



Thesis Advisor: Marion C. Cohen, Ph.D.
Adjunct Associate Professor
Graduate School of Biomedical Sciences

Friday, April 27, 2012
9:30 A.M., MSB C-555


Abstract

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that was initially identified by its ability to inhibit the movement of macrophages. Cell migration is a highly complex process involving changes to the cytoskeleton and cell adhesion molecules, which is essentially regulated by the Rho GTPases, and drives disease progression in cancer through metastasis and invasion. Recent studies implicate a role for MIF in tumor progression; however, little is known about the precise mechanism that contributes to migration of tumor cells.
A simple model using monocytic U-937 cells to elicit the classic MIF response was implemented to establish the role of MIF before studying a more complex system of human breast cancer cell lines of varying malignancy. Our results demonstrate that MIF inhibits migration of U-937 cells through a non-canonical receptor, CXCR4, and through initial activation followed by subsequent inactivation of RhoA, inactivation of Rac1, and cyclic activation of Cdc42. Similar biological activity was also elicited by dimeric SDF-1/CXCL12, the cognate ligand of CXCR4, which suggests an overlapping receptor-mediated signaling response.
Our breast cancer model allowed for the observation of MIF-induced changes in breast epithelial cells during malignant progression. Results from these studies reveal that MIF enhances migration and induces stress fiber formation in MCF-12A, MCF-7, ZR-75-1, and MDA-MB-231 cells through CXCR4. MIF-mediated changes in the activity of the Rho GTPases jointly contributed to motility in this model. Furthermore, each of these responses was inhibited by blocking CXCR4, thus implicating its role in MIF signaling.
Collectively, these data suggest that the migratory response is influenced by the outcome of G-protein signaling and varies by cell type. In less adherent cells such as those of the monocyte/macrophage lineage, RhoA directly affects net translocation through its ability to induce cell body contraction, whereas its role in adherent cells is multifaceted due to its ability to also mediate adhesion, which more heavily contributes to net translocation. Overall, these findings further implicate CXCR4 in MIF signaling and provide insight in uncovering critical signaling mechanisms that contribute to malignant transformation, as well as reveal potential targets for therapeutic intervention.


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