A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors

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Abstract

A lack of clinically relevant experimental models of human prostate cancer hampers evaluation of potential therapeutic agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably, a subpopulation of cancer cells survives and repopulates the tumor. Tumor cells that survive androgen withdrawal are critical therapeutic targets for more effective treatments, but current model systems cannot determine when they arise in disease progression and are unable to recapitulate variable patient response to treatment. A model system was developed in which stromal-supported xenografts from multiple patients with early-stage localized disease can be tested for response to castration. The histopathology of these xenografts mimicked the original tumors, and short-term host castration resulted in reduced proliferation and increased apoptosis in tumor cells. After 4 weeks of castration, residual populations of quiescent, stem-like tumor cells remained. Without subsequent treatment, these residual cells displayed regenerative potential, because testosterone readministration resulted in emergence of rapidly proliferating tumors. Therefore, this model may be useful for revealing potential cellular targets in prostate cancer, which exist before the onset of aggressive incurable disease. Specific eradication of these regenerative tumor cells that survive castration could then confer survival benefits for patients.
Original languageEnglish
Pages (from-to)1 - 7
Number of pages7
JournalScience Translational Medicine
Volume5
Issue number187 (Art. No.:187ra71)
DOIs
Publication statusPublished - 2013

Cite this

@article{e5330824f49e4670be6b1e13414a904e,
title = "A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors",
abstract = "A lack of clinically relevant experimental models of human prostate cancer hampers evaluation of potential therapeutic agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably, a subpopulation of cancer cells survives and repopulates the tumor. Tumor cells that survive androgen withdrawal are critical therapeutic targets for more effective treatments, but current model systems cannot determine when they arise in disease progression and are unable to recapitulate variable patient response to treatment. A model system was developed in which stromal-supported xenografts from multiple patients with early-stage localized disease can be tested for response to castration. The histopathology of these xenografts mimicked the original tumors, and short-term host castration resulted in reduced proliferation and increased apoptosis in tumor cells. After 4 weeks of castration, residual populations of quiescent, stem-like tumor cells remained. Without subsequent treatment, these residual cells displayed regenerative potential, because testosterone readministration resulted in emergence of rapidly proliferating tumors. Therefore, this model may be useful for revealing potential cellular targets in prostate cancer, which exist before the onset of aggressive incurable disease. Specific eradication of these regenerative tumor cells that survive castration could then confer survival benefits for patients.",
author = "Roxanne Toivanen and Mark Frydenberg and Declan Murphy and Pedersen, {John S} and Andrew Ryan and Pook, {David William} and Berman, {David M} and Taylor, {Renea Anne} and Risbridger, {Gail Petuna}",
year = "2013",
doi = "10.1126/scitranslmed.3005688",
language = "English",
volume = "5",
pages = "1 -- 7",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "187 (Art. No.:187ra71)",

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TY - JOUR

T1 - A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors

AU - Toivanen, Roxanne

AU - Frydenberg, Mark

AU - Murphy, Declan

AU - Pedersen, John S

AU - Ryan, Andrew

AU - Pook, David William

AU - Berman, David M

AU - Taylor, Renea Anne

AU - Risbridger, Gail Petuna

PY - 2013

Y1 - 2013

N2 - A lack of clinically relevant experimental models of human prostate cancer hampers evaluation of potential therapeutic agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably, a subpopulation of cancer cells survives and repopulates the tumor. Tumor cells that survive androgen withdrawal are critical therapeutic targets for more effective treatments, but current model systems cannot determine when they arise in disease progression and are unable to recapitulate variable patient response to treatment. A model system was developed in which stromal-supported xenografts from multiple patients with early-stage localized disease can be tested for response to castration. The histopathology of these xenografts mimicked the original tumors, and short-term host castration resulted in reduced proliferation and increased apoptosis in tumor cells. After 4 weeks of castration, residual populations of quiescent, stem-like tumor cells remained. Without subsequent treatment, these residual cells displayed regenerative potential, because testosterone readministration resulted in emergence of rapidly proliferating tumors. Therefore, this model may be useful for revealing potential cellular targets in prostate cancer, which exist before the onset of aggressive incurable disease. Specific eradication of these regenerative tumor cells that survive castration could then confer survival benefits for patients.

AB - A lack of clinically relevant experimental models of human prostate cancer hampers evaluation of potential therapeutic agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably, a subpopulation of cancer cells survives and repopulates the tumor. Tumor cells that survive androgen withdrawal are critical therapeutic targets for more effective treatments, but current model systems cannot determine when they arise in disease progression and are unable to recapitulate variable patient response to treatment. A model system was developed in which stromal-supported xenografts from multiple patients with early-stage localized disease can be tested for response to castration. The histopathology of these xenografts mimicked the original tumors, and short-term host castration resulted in reduced proliferation and increased apoptosis in tumor cells. After 4 weeks of castration, residual populations of quiescent, stem-like tumor cells remained. Without subsequent treatment, these residual cells displayed regenerative potential, because testosterone readministration resulted in emergence of rapidly proliferating tumors. Therefore, this model may be useful for revealing potential cellular targets in prostate cancer, which exist before the onset of aggressive incurable disease. Specific eradication of these regenerative tumor cells that survive castration could then confer survival benefits for patients.

UR - http://stm.sciencemag.org/content/5/187/187ra71.full.pdf

U2 - 10.1126/scitranslmed.3005688

DO - 10.1126/scitranslmed.3005688

M3 - Article

VL - 5

SP - 1

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JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 187 (Art. No.:187ra71)

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