Defining a Population of Stem-like Human Prostate Cancer Cells That Can Generate and Propagate Castration-Resistant Prostate Cancer.

Abstract

PURPOSE:

We have shown that the phenotypically undifferentiated (PSA(-/lo)) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA(-/lo) population bearing the ALDH(hi)CD44(+)α2β1(+) phenotype (Triple Marker(+)/TM(+)) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM(+) prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC).

EXPERIMENTAL DESIGN:

The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies.

RESULTS:

By focusing on the LAPC9 model, we show that the TM(+) cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM(+) cells, which possess CSC activities in "castrated" culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM(+) cells preferentially express castration resistance and stem cell-associated molecules that regulate their CSC characteristics; and (iii) the TM(+) cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir.

CONCLUSIONS:

Our results define the TM(+) prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM(+) cell population as a therapeutic target. Clin Cancer Res; 22(17); 4505-16. ©2016 AACR.

• Authors: Xin Chen, Qiuhui Li, Xin Liu, Can Liu, Ruifang Liu, Kiera Rycaj, Dingxiao Zhang, Bigang Liu, Collene Jeter, Tammy Calhoun-Davis, Kevin Lin, Yue Lu, Hsueh-Ping Chao, Jianjun Shen, Dean G Tang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 17 Pg. 4505-16 (Sep 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 27060154 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Androgens
• Biomarkers, Tumor
• MicroRNAs
• SOX9 Transcription Factor
• SOX9 protein, human

Topics

• Androgens (metabolism)
• Animals
• Biomarkers, Tumor
• Castration
• Cell Line, Tumor
• Disease Models, Animal
• Gene Expression Profiling
• Heterografts
• Humans
• Immunophenotyping
• Male
• Mice
• Mice, Knockout
• MicroRNAs (genetics)
• Neoplastic Stem Cells (metabolism, pathology)
• Phenotype
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology)
• SOX9 Transcription Factor (genetics, metabolism)
• Tumor Cells, Cultured