3685

ITGAV

CD51|MSK8|VNRA;integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51);ITGAV;integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)

antigen identified by monoclonal antibody L230|integrin alpha-V|vitronectin receptor subunit alpha

2q31-q32

protein-coding

Count: 1; Generif

The role of the vitronectin receptor (alpha(v)beta(3)-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 alpha(v)beta(3)-integrin is an appropriate target in ovarian cancer treatment. expression of beta(3)-integrin in SKOV3ip1 ovarian cancer cells led to the overexpression of alpha(v)beta(3)-integrin on the cell surface and increased adhesion. However, alpha(v)beta(3)-integrin-overexpressing cells showed impaired invasion, protease expression, and colony formation. These results were recapitulated in xenograft studies: alpha(v)beta(3)-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 alpha(v)beta(3)-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 G(2)M cell cycle arrest. Confirming the above results, inhibition of beta(3)-integrin in cultured or primary OvCa cells decreased adhesion but increased invasion and proliferation. Patients with tumors expressing high beta(3)-integrin had significantly better disease-free and overall survival (52 months versus 27 months, P < 0.05). This study shows that alpha(v)beta(3)-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.

Integrin-mediated cell adhesion and signaling events are essential for the proper development and homeostasis of most epithelial tissues. Dysregulation of integrin expression and function can cause abnormal epithelial cell proliferation and/or differentiation, contributing to the pathogenesis of malignant epithelial cancers. Here we report on the use of a conditional knockout strategy exploiting the Cre/Lox technology to study the in vivo functions of alphav integrins during epithelial cell proliferation and differentiation. We show that genetic ablation of alphav integrin expression in basal epithelial cells of the eyelid skin and conjunctiva causes the formation of tumors that are strikingly similar to the malignant epithelial cancer, squamous cell carcinoma. These data suggest a mechanism whereby alphav integrins normally suppress epithelial cell proliferation, likely via adhesion to ECM ligands, as well as by the modulation of intracellular signaling cascades. We propose that alphav gene deletion eliminates normal integrin-mediated growth suppression, ultimately leading to cellular transformation and tumorigenesis. Hence, these studies reveal a novel tumor suppressor-like function of alphav integrins and provide a genetically tractable mouse model for studying the pathogenesis of squamous cell carcinoma and related cancers of epithelial origin, as well as to test and develop novel therapeutic compounds to treat or prevent squamous cell carcinoma of the skin.