Stem cells have the ability to regenerate themselves (i.e., self-renew) and also give rise to more mature progeny (i.e., differentiate). Stem cells normally reside in a relatively protective microenvironment (i.e., niche) to keep their quiescence but maintain their proliferative potential. The best understood mammalian adult stem cells are those in the rapidly renewing organs, such as the blood (hematopoietic stem cells or HSCs), skin (epidermal or keratinocyte stem cells; KSCs), and gut (intestinal stem cells; ISCs). Significant knowledge has also been gained in the past decade on stem cells in tissues once considered ‘post-mitotic,’ such as the brain (neural stem cells or NSCs), heart (cardiac stem cells), and skeletal muscle. It is now appreciated that perhaps all adult tissues/organs harbor resident stem cells, which gradually deteriorate with aging, probably associated with accumulation of oxidative damages and p16. One of the most exciting recent developments in stem cell research is derivation of induced pluripotent stem cells (iPS cells) from differentiated cells reprogrammed by various genetic and chemical factors. See Stem Cells 101 (Aug, 2011) for more background information.
Somatic tumors share one characteristic with adult organs, i.e., they are heterogeneous, harboring many phenotypically and functionally distinct cell subpopulations. Tumor cell heterogeneity likely underlies differential tumor response to clinical therapeutics and has been explained, mainly, by two non-mutually exclusive hypotheses, clonal evolution driven by genetic instability, and phenotypic diversification from CSCs or tumor-initiating cells. At present, CSCs are operationally defined as a subset of tumorigenic cells that can be phenotypically isolated and are functionally endowed with extensive clonogenic, self-renewal and differentiation potentials in vitro and enhanced tumor-initiating ability in immune-deficient (e.g., NOD/SCID) mice. One of the most widely used criteria for defining CSCs is their ability, at low cell numbers, to regenerate serially transplantable tumors that histologically recapitulate the phenotypic heterogeneity of the parental tumor. CSCs were first identified in leukemia and, since 2003, have been reported for most human solid tumors. Of clinical relevance, CSCs have recently been reported to mediate therapy resistance, tumor recurrence and metastasis. Hence, curative treatment of cancer patients and prevention of disease recurrence may entail eradication of CSCs. For a current review on CSCs, please see Tang, Cell Res (2012).
Not all tumors may follow the CSC model. Also, CSCs are defined by functional rather than marker (phenotypic) assays. Moreover, CSCs may not necessarily be derived from normal stem cells. More mature cells such as progenitor and even differentiated cells may acquire genetic mutations and/or epigenetic alterations that confer them stem cell properties. Furthermore, CSCs may not necessarily be rare in all tumors that do follow the CSC model. Some tumors such as melanomas seem to harbor a significant fraction of tumor-initiating cells. It is also conceivable that the relative abundance of CSCs may fluctuate dramatically in response to treatment. For example, it has become evident that many treated human tumors such as breast cancer show a significant enrichment in CSCs. Finally, it should be emphasized that CSCs represent a dynamic state rather than a fixed and static population. For more discussions on CSCs, please also refer to Stem Cells & Cancer (2010 Sept).
Our lab has been studying the following aspects of prostate CSCs (PCSCs):
- Normal prostate stem/progenitor cells and tumorigenesis
- PCSCs in xenograft & patient tumors
- PCSCs & metastasis
- PCSC response to androgen deprivation & other therapeutics
- PCSC self-renewal: Role of Nanog
- PCSC epigenetic landscape
- PCSC regulation by miRNAs
- PCSC asymmetric cell division
- PCSC-targeting novel therapeutics