Brief Report: A Bioassay to Identify Primary Human Prostate Cancer Repopulating Cells

Author:

Toivanen Roxanne1,Berman David M.2,Wang Hong1,Pedersen John13,Frydenberg Mark14,Meeker Alan K.2,Ellem Stuart J.1,Risbridger Gail P.1,Taylor Renea A.1

Affiliation:

1. Prostate and Breast Cancer Research Group, Department of Anatomy and Developmental Biology; andFaculty of Medicine, Monash University, Clayton, Victoria, Australia

2. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

3. TissuPath Laboratories, Hawthorn, Victoria, Australia

4. Department of Surgery, Faculty of Medicine, Monash University, Clayton, Victoria, Australia

Abstract

Abstract Cancer cells are heterogeneous in both their phenotypes and ability to promote tumor growth and spread. Xenografting is used to identify the most highly capable cells of regenerating tumors, referred to as cancer repopulating cells. Because prostate cancers (PCa's) rarely grow as xenografts, indentifying PCa repopulating cells has not been possible. Here, we report improved methods to xenograft localized primary PCa tissues using chimeric grafts with neonatal mouse mesenchyme. Xenograft survival of tumor tissue was significantly increased by neonatal mesenchyme (six of six patients, 66% of grafts, versus four of six patients, 41% of grafts) and doubled the proliferation index of xenografted cancer cells. When applied to isolated PCa cells, neonatal mesenchyme effectively reconstituted PCa's and increased xenograft survival (four of nine patients; 32% of grafts with mesenchyme and 0% without), and supported active cancer cell proliferation. Using this assay, we showed that unfractionated α2β1integrinhi and α2β1integrinlo cells from primary localized PCa's demonstrated tumor formation at comparable rates, similar to previous reports using metastatic specimens. Thus, this new protocol efficiently established tumors and enabled proliferative expansion of both intact tumor tissue and fractionated cancer cells, providing a bioassay to identify and therapeutically target PCa repopulating cells.

Funder

National Health and Medical Research Council of Australia

Prostate Cancer Foundation of Australia

Victorian Prostate Cancer Research Consortium

US Department of Defense

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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