Roles of the alpha2beta1 Integrin in Cancer Progression and Metastasis

Abstract

In this dissertation, I examined the function of the alpha2beta1 integrin in epithelial tumor cells as well as in the tumor microenvironment. The alpha2beta1 integrin is a surface heterodimeric receptor found on epithelial, endothelial, fibroblasts, platelets, and several immune system cell subsets where it is responsible for cell-cell and cell-matrix interactions. Using the K14-HPV16 mouse model of inflammation-driven skin carcinogenesis on wild-type or alpha2beta1 integrin-null backgrounds, as well as an orthotopic murine breast cancer model, I elucidated the roles of this integrin during the multi-step progression towards cancer and eventual metastasis. My studies have implicated a role of the alpha2beta1 integrin in determining the growth and invasive behavior of tumor cells that is independent of the tumor microenvironment, yet influenced by the malignant cell type involved. My findings demonstrate an important function of the alpha2beta1 integrin on maintaining lymphatic vasculature integrity, thus providing novel insights into the function of this integrin in normal physiology as well as in tumor-associated lymphatics and metastasis. Through my examination of the multiple compartments known to drive cancer, it has been possible to ascertain this integrin’s contribution on the tumor cells, inflammatory cells, and additional cells of the tumor microenvironment towards mediating neoplastic progression and hematogenous as well as lymphatic metastasis.