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

Jinhan Xie, Christina Mølck, Sophie Paquet-Fifield, Lisa Butler, Australian Prostate Cancer BioResource, Erica Sloan, Sabatino Ventura, Frédéric Hollande

Research output: Contribution to journalArticleResearchpeer-review

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 androgenindependent prostate tumors and that it may be a predictive biomarker for prostate cancer treatment response in androgen-sensitive tumors.

Original languageEnglish
Pages (from-to)44492-44504
Number of pages13
JournalOncotarget
Volume7
Issue number28
DOIs
Publication statusPublished - 7 Jun 2016

Keywords

  • Prostate cancer
  • Self-renewal
  • Treatment resistance
  • TROP2

Cite this

Xie, J., Mølck, C., Paquet-Fifield, S., Butler, L., Australian Prostate Cancer BioResource, Sloan, E., ... Hollande, F. (2016). High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgenindependent prostate cancer cells. Oncotarget, 7(28), 44492-44504. https://doi.org/10.18632/oncotarget.9876
Xie, Jinhan ; Mølck, Christina ; Paquet-Fifield, Sophie ; Butler, Lisa ; Australian Prostate Cancer BioResource ; Sloan, Erica ; Ventura, Sabatino ; Hollande, Frédéric. / High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgenindependent prostate cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 28. pp. 44492-44504.
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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 androgenindependent prostate tumors and that it may be a predictive biomarker for prostate cancer treatment response in androgen-sensitive tumors.",
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Xie, J, Mølck, C, Paquet-Fifield, S, Butler, L, Australian Prostate Cancer BioResource, Sloan, E, Ventura, S & Hollande, F 2016, 'High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgenindependent prostate cancer cells' Oncotarget, vol. 7, no. 28, pp. 44492-44504. https://doi.org/10.18632/oncotarget.9876

High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgenindependent prostate cancer cells. / Xie, Jinhan; Mølck, Christina; Paquet-Fifield, Sophie; Butler, Lisa; Australian Prostate Cancer BioResource ; Sloan, Erica; Ventura, Sabatino; Hollande, Frédéric.

In: Oncotarget, Vol. 7, No. 28, 07.06.2016, p. 44492-44504.

Research output: Contribution to journalArticleResearchpeer-review

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