{beta}3-Integrin Expression on Tumor Cells Inhibits Tumor Progression, Reduces Metastasis, and Is Associated with a Favorable Prognosis in Patients with Ovarian Cancer

摘要

The role of the vitronectin receptor (_vβ₃-integrin) as a tumor promoter seems well established, and, consequently, therapies that block this integrin are currently in clinical testing. We undertook the current study to determine whether _vβ₃-integrin is an appropriate target in ovarian cancer treatment. Expression of β₃-integrin in SKOV3ip1 ovarian cancer cells led to the overexpression of _vβ₃-integrin on the cell surface and increased adhesion. However, _vβ₃-integrin-overexpressing cells showed impaired invasion, protease expression, and colony formation. These results were recapitulated in xenograft studies: _vβ₃-integrin-expressing cells showed increased adhesion to mouse peritoneum, but the overall number of metastatic nodules (105 versus 68 tumors) and tumor weight were significantly lower than those in the parental SKOV3ip1 cells. The _vβ₃-integrin-overexpressing cells had a decreased proliferation rate mediated by inhibition of cyclin B1 and induction of phospho-Cdc2 and p53 expression, consistent with a G₂M cell cycle arrest. Confirming the above results, inhibition of β₃-integrin in cultured or primary OvCa cells decreased adhesion but increased invasion and proliferation. Patients with tumors expressing high β₃-integrin had significantly better disease-free and overall survival (52 months versus 27 months, P < 0.05). This study shows that _vβ₃-integrin expression on tumor cells actually slows tumor progression and acts as a tumor suppressor. Therefore, the vitronectin receptor might not be an appropriate therapeutic target in ovarian cancer.