The molecular mechanisms underlying metastatic dissemination are still not completely understood.
We have recently shown that β1 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 β1 integrins. Mechanistically, we demonstrate that Trop-2 and the α5β1 integrin associate through their extracellular domains, causing relocalization of α5β1 and the β1-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, αvβ3 integrin, and does not affect localization of αvβ3 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 β1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2.
Written by:
Trerotola M, Jernigan DL, Liu Q, Siddiqui J, Fatatis A, Languino LR. Are you the author?
Prostate Cancer Discovery and Development Program, Department of Cancer Biology; Kimmel Cancer Center, Thomas Jefferson University; Department of Pharmacology and Physiology, Drexel University College of Medicine; Prostate Cancer Discovery and Development Program, and Molecular and Cellular Oncogenesis Program, The Wistar Institute Cancer Center; Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania; and Michigan Center for Translational Pathology, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
Reference: Cancer Res. 2013 May 15;73(10):3155-3167.
doi: 10.1158/0008-5472.CAN-12-3266
PubMed Abstract
PMID: 23536555
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