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B.S., Montclair State University - 2006
Thesis Advisors: Ramsey Foty, Ph.D.
Graduate Program in Cell & Developmental Biology
Clinical Academic Building
Thursday, July 10, 2014
Dispersal of neoplastic cells from the primary tumor involves processes that regulate their detachment, invasion, and migration to local and more distant sites. Dispersal facilitates metastasis, and in turn metastasis complicates treatment and significantly worsens prognosis of several cancers. Ultimately the dispersal of neoplastic cells is based, in part, on the balance between two key forces; those that mediate cell-cell cohesion and those that mediate cell-substratum adhesion. Intratumoral cohesion acts to restrict tumor cell detachment, and is usually lost in aggressive cancers. Optimal cell-ECM adhesion promotes tumor cell detachment, invasion, and motility of neoplastic cells, while excessive cell-ECM adhesion acts to restrict locomotion. The prognosis of neoplasms such as carcinoma of the prostate (CaP) and glioblastoma multiforme (GBM) are closely linked with their ability to disperse. In CaP, dispersal facilitates the metastatic process that accounts for bone lesions, pathological fractures, and ultimately death. In GBM, dispersal facilitates recurrence, which complicates further treatment and contributes significantly to patient death. Although these neoplasms are disparate in nature, dysregulation of cohesion and adhesion likely promotes their dispersal. Increasing either force, intratumoral cohesion or cell-ECM adhesion, can in principle reduce dispersal in prostate cancer (CaP) and glioblastoma multiforme (GBM). We previously identified a novel invasion suppressive role for -integrin, the main receptor for Fn. Specifically, we demonstrated a role for -integrin as a mediator of fibronectin matrix assembly (FNMA), a process that, in 3D tissues, was shown to increase aggregate cohesion and restrain dispersal of rat CaP and human GBM cells. Our studies were some of the first to identify cell-ECM interactions as a source of intercellular cohesion. In the first part of this thesis we investigated pharmacological means of reactivating FNMA, and demonstrated that it increased cohesion and adhesion sufficient to reduce the dispersive nature of rat CaP cells. In the second part of this thesis we extended these studies to human prostate cancer cell lines and demonstrated that deficiency in FNMA exists in both the human and rat model of CaP, and that treatment with cationic manganese is capable of restoring function to human -integrin. In the third part of this thesis we explored the role FNMA plays in reducing dispersal of primary GBM cells. In the final part of this thesis we demonstrate that FNMA-mediated cohesion effectively increases contact inhibition of growth in 3D. Our results indicate that deficiency in FNMA is common to rat and human CaP as well as GBM. We also demonstrate that reactivation of FNMA increases aggregate cohesion and reduces tumor cell detachment in rat CaP and GBM. Our results indicate that reactivating FNMA also increases the ability of -integrin to promote cell-ECM adhesion to Fn, effectively reducing the dispersal of neoplastic cells. These results support the concept that an imbalance between the forces of cohesion and adhesion contributes to the dispersal of neoplastic cells. Moreover, our findings indicate that reactivation of FNMA is a means to increase both forces simultaneously, and reduce the dispersal of neoplastic cells.