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 þ and CD44 À 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 þ PCa cells are more proliferative, clonogenic, tumorigenic, and metastatic than the isogenic CD44 À PCa cells. Subsequent molecular studies demonstrate that the CD44 þ PCa cells possess certain intrinsic properties of progenitor cells. First, BrdU pulse-chase experiments reveal that CD44 þ cells colocalize with a population of intermediate label-retaining cells. Second, CD44 þ PCa cells express higher mRNA levels of several 'stemness' genes including Oct-3/4, Bmi, b-catenin, and SMO. Third, CD44 þ PCa cells can generate CD44 À cells in vitro and in vivo. Fourth, CD44 þ PCa cells, which are AR À , can differentiate into AR þ tumor cells. Finally, a very small percentage of CD44 þ PCa cells appear to undergo asymmetric cell division in clonal analyses. Altogether, our results suggest that the CD44 þ PCa cell population is enriched in tumorigenic and metastatic progenitor cells.

CD44+CD24− prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis

“…CD44 þ from immortalised prostate cancer cell lines formed colonies in soft agar and tumours in NOD/SCID mice (Patrawala et al, 2006). However, it was concluded in this study that the CD44 þ prostate cells were a heterogenous population containing both primitive stem cells as well as later progenitor cells.…”

“…It is thought that the cancer stem cells survive conventional treatment to later re-emerge more resistant to therapy (Reya et al, 2001). To date, putative cancer stem cells have been identified in blood (Bonnet and Dick, 1997), brain (Singh et al, 2004), breast (Al-Hajj et al, 2003), lung (Kim et al, 2005), skin (Fang et al, 2005), pancreas (Li et al, 2007), colon (O'Brien et al, 2007;Ricci-Vitiani et al, 2007), and prostate (Collins et al, 2005;Patrawala et al, 2006).…”

“…Previously, CD44 þ prostate cancer cells were shown to have the stem-like properties of increased tumorigenic, clonogenic, and metastatic potential (Patrawala et al, 2006). CD44 þ from immortalised prostate cancer cell lines formed colonies in soft agar and tumours in NOD/SCID mice (Patrawala et al, 2006).…”

“…We also sought to determine the global molecular signatures and the differentiation potential of these prostate cancer stem cells, as these were issues not previously studied (Collins et al, 2005;Patrawala et al, 2006). Here, we identify a rare subpopulation of CD44 þ CD24 À prostate cancer cells with stem-like characteristics such as increased clonogenic and tumorigenic properties, and the ability to grow as nonadherent spheres in serum-replacement medium.…”

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

“…To date, the existence of CSCs has been proven in the context of many cancers, including those of leukemia, breast cancer, glioblastoma, prostate cancer, pancreatic cancer and colon cancer (Lapidot et al, 1994;Bonnet and Dick, 1997;Al-Hajj et al, 2003;Hemmati et al, 2003;Singh et al, 2003Singh et al, , 2004Collins et al, 2005;Ponti et al, 2005;Haraguchi et al, 2006;Patrawala et al, 2006;Li et al, 2007;O'Brien et al, 2007;Ricci-Vitiani et al, 2007). Recently, we have determined that HCC is hierarchically organized and originates from a primitive stem/progenitor group of cells for which CD133 þ precursors constitute one of the most immature stage (Ma et al, 2007).…”