PCSC Self-renewal: Role of Nanog
Most advanced and recurrent PCa patients die from metastasis, especially metastasis to the bone. The nature of PCa cells that are endowed with the enhanced metastatic propensity remains unclear. In pancreatic cancer, CD133+ cancer cells are enriched in tumor-initiating cells whereas CD133+CXCR4+ cells represent the metastatic pancreatic CSCs, suggesting that only a subset of CSCs may be able metastasize. We have generated evidence that purified CD44+ PCa cells, i.e., LAPC9, Du145, and LAPC4, are highly enriched in not only tumor-initiating but also metastatic cells (Patrawala et al., 2006), suggesting that the metastatic PCSCs, or mPCSCs, may also be harbored in the CD44+ cell population. There is emerging evidence that mCSCs exist in many human tumors (reviewed in Li & Tang, 2009; Li & Tang, 2011).
CD44 is an adhesion molecule with many ligands including, hyaluronic acid, osteopontin and integrins and is intimately involved in development and metastasis of human cancers, including PCa (reviewed in Patrawala & Tang, 2008). Even the tumor-suppressive functions of p53 depend on repression of CD44. Recent evidence indicates that CD44+ cancer cells in many human tumors, including breast, pancreatic, colon and small intestine, liver, gastric, bladder, head & neck, and ovarian cancers, are enriched in stem-like cancer cells. These CSCs are identified using either CD44 alone or CD44 in combination with other surface marker(s). CD44 possesses versatile signaling functions, with some recently implicated in regulating stem cell and CSC properties. For instance, CD44, upon ligand binding, translocates to the nucleus, promotes acetylation and activation of STAT3 and forms complexes with dimerized STAT3, which then bind to the promoters of many genes such as cyclin D1 leading to cell fate ‘reprogramming’. CD44 has also been proposed to directly interact with Nanog, a homeodomain transcription factor essential for the self-renewal of ES cells. The importance of CD44 in cancer metastasis is evidenced by early observations of the impressive ‘therapeutic’ efficacy of anti-CD44 antibodies in preventing tumor cell dissemination. Recent studies not only validate the efficacy of blocking CD44 signaling or CD44-ligand (e.g., HA) interactions in inhibiting tumor development/metastasis but also reveal novel findings that such therapeutic potential is likely mediated via interfering with CSCs. These new studies indicate that unlike some CSC markers, such as CD133, CD44 has a clear functional role in conferring CSC properties.
Consistent with the idea that the CD44+ PCa cell population is enriched in both tumor-initiating cells and mCSCs, we have recently observed that knocking down of CD44 in Du145, PC3, and LAPC9 cells dramatically inhibits tumor regeneration and/or metastasis (Liu et al., 2011). An anti-CD44 mAb also partially inhibits the sphere formation of CD44+ PCa cells. Using isogenic GFP/RFP-tagged human PCa cells implanted in the orthotopic (prostate) and ectopic (s.c) sites in NOD/SCID mice, we have obtained a mPCSC signature and we are currently investigating whether this signature can be applied to human PCa metastasis. In the meantime, we are also exploring PCSC response to androgen deprivation and other therapeutics.