Increased tumor cell dissemination and cellular senescence in the absence of [beta] sub(1)-integrin function

Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization, as well as transduction of signals into cells, to promote various aspects of cellular behavior, such as proliferation or survival. Integrins participate in many aspects of tumor biology. Here, we have employed the Rip1Tag2 transgenic mouse model of pancreatic [beta] cell carcinogenesis to investigate the role of [beta] sub(1)-integrin in tumor progression. Specific ablation of [beta] sub(1)-integrin function in pancreatic [beta] cells resulted in a defect in sorting between insulin-expressing [beta] cells and glucagon-expressing [alpha] cells in islets of Langerhans. Ablation of [beta] sub(1)-integrin in [beta] tumor cells of Rip1Tag2 mice led to the dissemination of tumor cell emboli into lymphatic blood vessels in the absence of ongoing lymphangiogenesis. Yet, disseminating [beta] sub(1)-integrin-deficient [beta] tumor cells did not elicit metastasis. Rather, primary tumor growth was significantly impaired by reduced tumor cell proliferation and the acquisition of cellular senescence by [beta] sub(1)-integrin-deficient [beta] tumor cells. The results indicate a critical role of [beta] sub(1)-integrin function in mediating metastatic dissemination and preventing tumor cell senescence.