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

Roxanne Toivanen, Mark Frydenberg, Declan Murphy, John Pedersen, Andrew Ryan, David Pook, David M. Berman, Renea A. Taylor, Gail P. Risbridger

Research output: Contribution to journalArticle

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 (US)
Article number187ra71
JournalScience Translational Medicine
Volume5
Issue number187
DOIs
StatePublished - May 29 2013
Externally publishedYes

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Castration
Heterografts
Prostate
Neoplasms
Prostatic Neoplasms
Therapeutics
Androgens
Neoplastic Stem Cells
Disease Progression
Testosterone
Theoretical Models
Apoptosis
Survival
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Toivanen, R., Frydenberg, M., Murphy, D., Pedersen, J., Ryan, A., Pook, D., ... Risbridger, G. P. (2013). A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors. Science Translational Medicine, 5(187), [187ra71]. https://doi.org/10.1126/scitranslmed.3005688

A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors. / Toivanen, Roxanne; Frydenberg, Mark; Murphy, Declan; Pedersen, John; Ryan, Andrew; Pook, David; Berman, David M.; Taylor, Renea A.; Risbridger, Gail P.

In: Science Translational Medicine, Vol. 5, No. 187, 187ra71, 29.05.2013.

Research output: Contribution to journalArticle

Toivanen, R, Frydenberg, M, Murphy, D, Pedersen, J, Ryan, A, Pook, D, Berman, DM, Taylor, RA & Risbridger, GP 2013, 'A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors', Science Translational Medicine, vol. 5, no. 187, 187ra71. https://doi.org/10.1126/scitranslmed.3005688
Toivanen, Roxanne ; Frydenberg, Mark ; Murphy, Declan ; Pedersen, John ; Ryan, Andrew ; Pook, David ; Berman, David M. ; Taylor, Renea A. ; Risbridger, Gail P. / A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells in localized prostate tumors. In: Science Translational Medicine. 2013 ; Vol. 5, No. 187.
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