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, TROP2high 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, TROP2high 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.
Highlights
Prostate cancer is second to lung cancer in incidence worldwide, and is the third most common cause of cancer death in developed countries [1]
Our findings suggest that TROP2expressing cells are detectable across all prostate cancer stages but that differences of TROP2 expression levels among patients may highlight a worse prognosis for prostate cancer patients, for those diagnosed with early stage tumors
In the present study we demonstrate that high expression of cell-surface TROP2 is a marker of, and plays a functional role in the ability of androgen-sensitive prostate cancer cells to recover from docetaxel-based chemotherapy, and that high TROP2 expression is a marker of poor prognosis in patients with low-grade prostate tumors
Summary
Prostate cancer is second to lung cancer in incidence worldwide, and is the third most common cause of cancer death in developed countries [1]. A small population of prostate cancer cells with tumor-initiating www.impactjournals.com/oncotarget cell properties has been shown to harbor intrinsic characteristics that make them resistant to androgen deprivation and chemotherapy [4, 5]. Since they display a robust self-renewing ability and appear to drive tumor progression, their identification, characterization and elimination would provide a significant therapeutic advantage, but little is known on how the chemo-resistance and self-renewing abilities of prostate TICs evolve during progression from early androgen-sensitive lesions to late, castration resistant tumors. It remains unclear whether TROP2 marks tumor-initiating cells in androgen-sensitive and castration resistant prostate tumors and if it plays a role in the resistance of these cells to therapy
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