High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells

// Jinhan Xie 1, 6 , Christina Mølck 2 , Sophie Paquet-Fifield 2 , Lisa Butler 3 , Australian Prostate Cancer Bioresource, Erica Sloan 1, 4, 5 , Sabatino Ventura 1 , Frédéric Hollande 1, 2 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia 2 Department of Pathology, The University of Melbourne, Parkville, Australia 3 School of Medicine, South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, South Australia, Australia 4 Cousins Center for PNI, UCLA Semel Institute, Jonsson Comprehensive Cancer Center, and UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA, USA 5 Peter MacCallum Cancer Centre, Division of Cancer Surgery, East Melbourne, Victoria, Australia 6 Current address: Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Kensington, Australia Correspondence to: Frédéric Hollande, email: frederic.hollande@unimelb.edu.au Keywords: prostate cancer, TROP2, self-renewal, treatment resistance Received: January 05, 2016     Accepted: May 19, 2016     Published: June 7, 2016 ABSTRACT Progression of castration-resistant tumors is frequent in prostate cancer. Current systemic treatments for castration-resistant prostate cancer only produce modest increases in survival time and self-renewing Tumor-Initiating Cells (TICs) are suspected to play an important role in resistance to these treatments. However it remains unclear whether the same TICs display both chemo-resistance and self-renewing abilities throughout progression from early stage lesions to late, castration resistant tumors. Here, we found that treatment of mice bearing LNCaP-derived xenograft tumors with cytotoxic (docetaxel) and anti-androgen (flutamide) compounds enriched for cells that express TROP2, a putative TIC marker. Consistent with a tumor-initiating role, TROP2 high cells from androgen-sensitive prostate cancer cell lines displayed an enhanced ability to re-grow in culture following treatment with taxane-based chemotherapy with or without androgen blockade. TROP2 down-regulation in these cells reduced their ability to recur after treatment with docetaxel, in the presence or absence of flutamide. Accordingly, in silico analysis of published clinical data revealed that prostate cancer patients with poor prognosis exhibit significantly elevated TROP2 expression level compared to low-risk patients, particularly in the case of patients diagnosed with early stage tumors. In contrast, in androgen-independent prostate cancer cell lines, TROP2 high cells did not exhibit a differential treatment response but were characterized by their high self-renewal ability. Based on these findings we propose that high TROP2 expression identifies distinct cell sub-populations in androgen-sensitive and androgen-independent prostate tumors and that it may be a predictive biomarker for prostate cancer treatment response in androgen-sensitive tumors.