Trop-2 Promotes Prostate Cancer Metastasis By Modulating β1 Integrin Functions

Abstract

The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β(1) integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on fibronectin, a phenomenon dependent on β(1) integrins. Mechanistically, we demonstrate that Trop-2 and the α(5)β(1) integrin associate through their extracellular domains, causing relocalization of α(5)β(1) and the β(1)-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific as this molecule does not modulate migration on vitronectin, does not associate with the major vitronectin receptor, α(v)β(3) integrin, and does not affect localization of α(v)β(3) integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we show that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that β(1) integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2.