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  • Original Article
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Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells

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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References

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . (2003). Proc Natl Acad Sci USA 100: 3983–3988.

  • Beachy PA, Karhadkar SS, Berman DM . (2004). Nature 432: 324–331.

  • Bhatia B, Maldonado C, Tang S-H, Chandra D, Klein RD, Chopra D et al. (2003). J Biol Chem 278: 25091–25100.

  • Bhatia B, Tang S, Yang P, Doll A, Aumüeller G, Newman RA et al. (2005). Oncogene 24: 3583–3595.

  • Bhatt RL, Brown MD, Hart CA, Gilmore P, Ramani VAC, George NJ et al. (2003). Cytometry 54A: 89–99.

  • Bonkhoff H, Stein U, Remberger K . (1994). Prostate 24: 42–46.

  • Chambers I, Smith A . (2004). Oncogene 23: 7150–7160.

  • Collins AT, Habib FK, Maitland NJ, Neal DE . (2001). J Cell Sci 114: 3865–3872.

  • De Marzo AM, Bradshaw C, Sauvageot J, Epstein JI, Miller GJ . (1998). Prostate 34: 162–168.

  • Draffin JE, McFarlane S, Hill A, Johnston PG, Waugh DJ . (2004). Cancer Res 64: 5702–5711.

  • Gao AC, Lou W, Dong JT, Isaacs JT . (1997). Cancer Res 57: 846–849.

  • Gao AC, Lou W, Sleeman JP, Isaacs JT . (1998). Cancer Res 58: 2350–2352.

  • Garraway LA, Lin D, Signoretti S, Waltregny D, Dilks J, Bhattacharya N et al. (2003). Prostate 55: 206–218.

  • Hudson DL, O'Hare M, Watt FM, Masters JRW . (2000). Lab Invest 80: 1243–1250.

  • Kallakury BV, Yang F, Figge J, Smith KE, Kausik SJ, Tacy NJ et al. (1996). Cancer 78: 1461–1469.

  • Latza U, Niedobitek G, Schwarting R, Nekarda H, Stein H . (1990). J Clin Pathol 43: 213–219.

  • Liu AY, True LD, LaTray L, Ellis WJ, Vessella RL, Lange PH et al. (1999). Prostate 40: 192–199.

  • Liu AY, True LD, LaTray L, Nelson PS, Ellis WJ, Vessella RL et al. (1997). Proc Natl Acad Sci USA 94: 10705–10710.

  • Lokeshwar BL, Lokeshwar VB, Block NL . (1995). Anticancer Res 15: 1191–1198.

  • Maitland NJ, Collins AT, Bryce S, Sarah M, Berry P, Hyde K et al. (2005). Proc Am Assoc Cancer Res, A2518.

  • McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT et al. (1992). Cancer Res 52: 6940–6944.

  • Nagabhushan M, Pretlow TG, Guo YJ, Amini SB, Pretlow TP, Sy MS . (1996). Am J Clin Pathol 106: 647–651.

  • Noordzij MA, van Steenbrugge GJ, Schroder FH, van der Kwast TH . (1999). Int J Cancer 84: 478–483.

  • Omara-Opyene AL, Qiu J, Shah GV, Iczkowski KA . (2004). Lab Invest 84: 894–907.

  • Paradis V, Eschwege P, Loric S, Dumas F, Ba N, Benoit G et al. (1998). J Clin Pathol 51: 798–802.

  • Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG . (2005). Cancer Res 65: 6207–6219.

  • Ponta H, Sherman L, Herrlich PA . (2003). Nat Rev Mol Cell Biol 4: 33–45.

  • Reiter RE, Sawyers CL . (2001). In: Chung LWK, Isaacs WB, Simons JW (eds). Prostate Cancer: Biology, Genetics, and the New Therapeutics. Humana Press Inc.: Totowa, NJ, pp 163–174.

    Google Scholar 

  • Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT . (2004). J Cell Sci 117: 3539–3545.

  • Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L et al. (2000). Am J Pathol 157: 1769–1775.

  • Tai MH, Chang CC, Olson LK, Trosko JE . (2005). Carcinogenesis 26: 495–502.

  • Tang S, Bhatia B, Maldonado C, Yang P, Newman RA, Liu J et al. (2002). J Biol Chem 277: 16189–16201.

  • Tran CP, Lin C, Yamashiro J, Reiter RE . (2002). Mol Cancer Res 1: 113–121.

  • Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M et al. (2004). Science 303: 359–363.

  • Valk-Lingbeek ME, Bruggeman SWM, van Lohuizen M . (2004). Cell 118: 409–418.

  • van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL et al. (2003). Prostate 57: 205–225.

  • van Leenders G, Dijkman H, van de Kaa H, Ruiter D, Schalken J . (2000). Lab Invest 80: 1251–1258.

  • Wang Y, Hayward SW, Cao M, Thayer KA, Cunha GR . (2001). Differentiation 68: 270–279.

  • Yardy GW, Brewster SF . (2005). Prostate Cancer Prostatic Dis 8: 119–126.

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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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Correspondence to D G Tang.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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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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