The Marrow Niche Controls The Cancer Stem Cell Phenotype Of Disseminated Prostate Cancer

Dissemination of cancer stem cells (CSCs) serves as the basis of metastasis. Recently, we demonstrated that circulating prostate cancer (PCa) targets the hematopoietic stem cell (HSCs) ‘niche’ in marrow during dissemination. Once in the niche, disseminated tumor cells (DTCs) may remain dormant for extended periods. As the major function of the HSC niche is to maintain stem cell functions, we hypothesized that the niche regulates CSC activities of DTCs. We show that DTCs recovered from marrow were significantly enriched for a CSC phenotype. Critically, the conversion of DTCs to CSCs is regulated by niche. The data demonstrate that the niche plays a significant role in maintaining tumor-initiating PCa in marrow and suggests a functional relationship between CSCs and dormancy. Understanding how the marrow niche regulates the conversion of DTCs to CSCs is critical for the development of therapeutics specifically targeting skeletal bone metastasis and dormancy. We used microarrays to determine the global changes in gene expression underlying the significant roles of the marrow niche in activating cancer stem-like cell programs of prostate caner. The CD133+/CD44+ fraction and CD133-/CD44- fraction were sorted with a FACSAria II Cell Sorter from in vitro cultured prostate cancer cells (PC3, C4-2B) and in vivo disseminated PCa cells obtained from bone marrow of SCID mice innoculated with PCa cells (24 h) by intracadiac injection. Experimental groups were duplicated ((i) PC3, CD133+/CD44+, in vitro; (ii) PC3, CD133-/CD44-, in vitro; (iii) PC3, CD133+/CD44+, in vivo; (iv) PC3, CD133-/CD44-, in vivo; (v) C4-2B, CD133+/CD44+, in vitro; (vi) C4-2B, CD133-/CD44-, in vitro; (vii) C4-2B, CD133+/CD44+, in vivo; (viii) C4-2B, CD133-/CD44-, in vivo). Cells were obtained from 5 animals / group.