In this study, we show that the transmembrane glycoprotein Trop-2 is up-regulated in human prostate cancer (PCa) with extracapsular extension (stages pT3/pT4) as compared to organ-confined (stage pT2) PCa.
Consistent with this evidence, Trop-2 expression is found to be increased in metastatic prostate tumors of Transgenic Adenocarcinoma of Mouse Prostate mice and to strongly correlate with α5β1 integrin levels. Using PCa cells, we show that Trop-2 specifically associates with the α5 integrin subunit, as binding to α3 is not observed, and that Trop-2 displaces focal adhesion kinase from focal contacts. In support of the role of Trop-2 as a promoter of PCa metastatic phenotype, we observe high expression of this molecule in exosomes purified from Trop-2-positive PCa cells. These vesicles are then found to promote migration of Trop-2-negative PCa cells on fibronectin, an α5β1 integrin/focal adhesion kinase substrate, thus suggesting that the biological function of Trop-2 may be propagated to recipient cells. In summary, our findings show that Trop-2 promotes an α5β1 integrin-dependent pro-metastatic signaling pathway in PCa cells and that the altered expression of Trop-2 may be utilized for early identification of capsule-invading PCa.
Oncotarget. 2015 Jun 10;6(16):14318-28.
Trerotola M1,2,3, Ganguly KK1,2, Fazli L4, Fedele C1,2, Lu H1,2, Dutta A1,2, Liu Q1,5, De Angelis T1,2, Riddell LW1,2, Riobo NA6, Gleave ME4, Zoubeidi A4, Pestell RG2, Altieri DC1,5, Languino LR1,2.
1 Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA.
2 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
3 Current address: Ce.S.I. - University of Chieti-Pescara, Chieti Scalo, Italy.
4 The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
5 Tumor Microenvironment and Metastasis Program, The Wistar Institute Cancer Center, Philadelphia, PA, USA.
6 Department of Biochemistry, Thomas Jefferson University, Philadelphia, PA, U