Molecular and Cellular Pathobiology Integrin-Free Tetraspanin CD 151 Can Inhibit Tumor Cell Motility uponClustering and Is aClinical Indicator of Prostate Cancer Progression

Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins a3b1 anda6b1.However, this interaction cannot explain the ability ofCD151 to controlmigration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151) correlates clinically with tumor progression and metastasis. Clustering CD151 through its integrin-binding domain promotes accumulation in areas of cell–cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151 clustering is a strong regulator ofmotility even in the absence ofa3 expression but requires PKCa, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151 in prostate cancer correlates with poor patient outcome. When CD151 is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151 as an independent predictor of survival.Moreover, thedetectionof CD151 can stratify survival amongpatientswith elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151 with prostate cancer progression suggests that itmay contribute to the disease and predict cancer progression. Cancer Res; 74(1); 173–87. 2013 AACR.