Neuroendocrine-like cells in prostate cancer express CD44 and may represent the putative cancer stem/progenitor cells
Authors: Guangchun Chen, Christopher Silvers, Chengyu Wu, Linda Salamone, Heather Martin, Karin Williams, Ganesh Palapattu, Jiaoti Huang
Journal: Cancer Research (2008)

4600  Androgen stimulates growth of prostate cancer (PC) via androgen receptor (AR). Androgen ablation therapy is therefore effective for advanced/metastatic PC. Unfortunately, the initial benefit is always followed by progression of the tumor to the hormone-refractory stage in which the tumor cells re-grow in the androgen-deprived environment.  It has been proposed that PC contains cancer stem cells (approximately 1-5% of the total tumor cell population) that renew themselves and give rise to differentiated cancer cells. The cancer stem cells do not express AR and are resistant to androgen ablation therapy and responsible for tumor recurrence. Therefore, identification and targeting of the cancer stem cells is the key to achieve the cure of PC.  Patrawala et al (Oncogene, 2006; 25: 1696) reported convincing evidence that CD44+ cells in PC cell lines and xenograft tumors possess stem/progenitor properties. These cells are more proliferative, clonogenic, tumorigenic, and metastatic than the CD44- cells. They express 9stemness9 genes, are AR- but can generate AR+ CD44- cells in-vitro and in-vivo. Some CD44+ PC cells can undergo asymmetric cell division.  Although there is strong evidence that CD44+ cells may represent PC stem cells, they have not been identified and chracterized in human PC tissue. We and others have shown that in PC tissue from patients, the tumor cells are heterogeneous. The majority of the tumor cells are the secretory type cells that express AR while 1-5% of the tumor cells are the neuroendocrine (NE)-like cells that do not express AR. The NE-like cells increase in high grade/stage PC, particularly after androgen ablation therapy and in hormone-refractory PC. In xenograft and genetic models of PC, castration increases the number of NE-like cells before tumor recurrence.  Since the NE-like PC cells fit the profile of the proposed cancer stem cells, we stained adjacent sections of human PC tissue with antibodies for CD44 and chromogranin A (CgA), a NE cell marker, and showed that in human PC tissue, CD44+ cells are the NE-like cells and vice versa. We performed double staining of human PC tissue microarray containing 200 cores of PC by immunofluorescence and showed that membrane CD44 staining and cytoplasmic CgA staining were always in the same tumor cells (1-5% of total tumor cell population). When PC cell lines LNCaP, DU145 and PC3 were sorted as CD44+ and CD44- cells by flow cytometry, expression of NE marker NSE was exclusively seen in CD44+ cells by western and/or real-time PCR assay.  Thus, our study has firmly established that in PC tissue from patients, the long-recognized NE-like cells are the CD44+ cells which may represent the cancer stem/progenitor cells. We can now explain why every case of human PC contains a small population of NE-like cells that do not express AR and are resistant to hormonal therapy. Targeting NE-like PC cells should be a priority in designing future treatment strategies.