Oncotarget

Research Papers:

Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts

Marco Trerotola, Kirat K. Ganguly, Ladan Fazli, Carmine Fedele, Huimin Lu, Anindita Dutta, Qin Liu, Tiziana De Angelis, Luke W. Riddell, Natalia A. Riobo, Martin E. Gleave, Amina Zoubeidi, Richard G. Pestell, Dario C. Altieri, Lucia R. Languino _

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Oncotarget. 2015; 6:14318-14328. https://doi.org/10.18632/oncotarget.3960

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Abstract

Marco Trerotola1,2,6, Kirat K. Ganguly1,2, Ladan Fazli3, Carmine Fedele1,2, Huimin Lu1,2, Anindita Dutta1,2, Qin Liu1,4, Tiziana De Angelis1,2, Luke W. Riddell1,2, Natalia A. Riobo5, Martin E. Gleave3, Amina Zoubeidi3, Richard G. Pestell2, Dario C. Altieri1,4 and Lucia R. Languino1,2

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 The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada

4 Tumor Microenvironment and Metastasis Program, The Wistar Institute Cancer Center, Philadelphia, PA, USA

5 Department of Biochemistry, Thomas Jefferson University, Philadelphia, PA, USA

6 Current address: Ce.S.I. – University of Chieti-Pescara, Chieti Scalo, Italy

Correspondence to:

Lucia R. Languino, email:

Keywords: pT2/pT3/pT4 prostate cancer, metastasis, gleason grade, TRAMP, exosome

Received: December 30, 2014 Accepted: April 10, 2015 Published: April 29, 2015

Abstract

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.


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