Potential role of PCSCs in metastasis

PC is the second leading cause of cancer death in male; but, because of the progress made in the diagnosis and treatment of primary PC, mortality in 70 - 80% of the patients is increasingly linked to its metastatic disease. The bone marrow is the most frequent site for metastasis in PC; and stem cells, besides their role in tumorigenicity, are highly migratory cells that are involved in bone metastasis formation [92].

CSCs contain a subpopulation of cells that are exclusively capable of disseminating and subsequently providing the substrate for tumor metastasis; e.g. CD44+ PC cells are more tumori-genic and metastatic than the corresponding CD44- cells [93]. Stromal cell derived factor and its C-X-C chemokine receptor type 4 (CXCR4) form a critical regulatory axis for SC migration, engraftment and homing, and also function in the metastasis of breast and prostate cancer [94]. Using a mouse/human comparative translational genomics approach an 11-gene signature that consistently displays a stem cell-like expression pattern in metastatic lesions of prostate carcinomas could be recovered from multiple distant target organs [95].

On the other hand, some incidents do not support the CSC involvement in metastasis. For example, CD44+CD24- and CD44+CD24+ breast CSCs have same metastatic potential [96]. Then, in an orthotopic pancreatic cancer model CD133+ cells were not metastatic, whereas CD133+CXCR4+ cells showed strong metastasis [97]. Also, CD133- colon cancer cells were more aggressive and metastatic than their CD133+ counterparts [98]. In conclusion, metastasis and tumor initiation might be processed by distinct cancer cell populations, probably by metastatic CSCs.

Tumor microenvironment facilitates cancer metastasis by several mechanisms. When human PC cells were injected into the dorsal prostate of a nude mouse more metastasis was generated, than when cells were injected subcutaneous [99]. Later, it was shown that dorsal prostate-implanted human PC cells over-express many CSC genes including osteoponin, CXCR4, CD133, ABCG2, CD44 and CD24. Some of these genes clearly have functional roles in PC metastasis [100]. But, the exact molecular mechanisms that account for the microenvironment regulated PC cell metastasis are still not known.

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