Abstract
CD44 is a multifunctional protein involved in cell adhesion and signaling. The role of CD44 in prostate cancer (PCa) development and progression is controversial with studies showing both tumor-promoting and tumor-inhibiting effects. Most of these studies have used bulk-cultured PCa cells or PCa tissues to carry out correlative or overexpression experiments. The key experiment using prospectively purified cells has not been carried out. Here we use FACS to obtain homogeneous CD44+ and CD44− tumor cell populations from multiple PCa cell cultures as well as four xenograft tumors to compare their in vitro and in vivo tumor-associated properties. Our results reveal that the CD44+ PCa cells are more proliferative, clonogenic, tumorigenic, and metastatic than the isogenic CD44− PCa cells. Subsequent molecular studies demonstrate that the CD44+ PCa cells possess certain intrinsic properties of progenitor cells. First, BrdU pulse-chase experiments reveal that CD44+ cells colocalize with a population of intermediate label-retaining cells. Second, CD44+ PCa cells express higher mRNA levels of several ‘stemness’ genes including Oct-3/4, Bmi, β-catenin, and SMO. Third, CD44+ PCa cells can generate CD44− cells in vitro and in vivo. Fourth, CD44+ PCa cells, which are AR−, can differentiate into AR+ tumor cells. Finally, a very small percentage of CD44+ PCa cells appear to undergo asymmetric cell division in clonal analyses. Altogether, our results suggest that the CD44+ PCa cell population is enriched in tumorigenic and metastatic progenitor cells.
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Acknowledgements
We thank C Conti, T-J Liu, and C Sawyers for providing cells; E Richie for her insights; N Navone for guidance in prostate tumor experiments; the Histology Core for excellent assistance in tissue processing and IHC; the Animal Facility Core for help in tumor experiments; and members of the Tang lab for support and helpful discussion. This work was supported in part by grants from NIH (CA90297, AG023374, and CCSG-5 P30 CA166672), NIEHS (ES07784), American Cancer Society (RSG MGO-105961), Department of Defense (DAMD17-03-1-0137), Prostate Cancer Foundation, and MD Anderson Cancer Center (PCRP and IRG).
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Patrawala, L., Calhoun, T., Schneider-Broussard, R. et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25, 1696–1708 (2006). https://doi.org/10.1038/sj.onc.1209327
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DOI: https://doi.org/10.1038/sj.onc.1209327
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