Cell Cycle Inhibitors in Normal and Tumor Stem Cells

Oncogene (2004) 23, 7256–7266 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc Cell cycle inhibitors in normal and tumor stem cells Tao Cheng*,1 1Department of Radiation Oncology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA Emerging data suggest that stem cells may be one of the cell types have been or are being defined, the hemato- key elements in normal tissue regeneration and cancer poietic stem cell (HSC) remains one of the best-studied development, although they are not necessarily the same stem cell types and therefore data have been largely entity in both scenarios. As extensively demonstrated in obtained from HSCs partially in comparison with the the hematopoietic system, stem cell repopulation is other stem cell types such as the neural stem cell (NSC). hierarchically organized and is intrinsically limited by The distinct impacts of different CKIs in stem cell the intracellular cell cycle inhibitors. Their inhibitory populations underscore the crucial role that cell cycle effects appear to be highly associated with the differentia- inhibitors play in stem cell regulation and offer new tion stage in stem/progenitor pools. While this negative insights into the mechanisms of cancer development, regulation is important for maintaining homeostasis, especially in light of the concept of ‘tumor stem cell’ especially at the stem cell level under physiological cues (TSC) (or described as ‘cancer stem cell’ in general or or pathological insults, it constrains the therapeutic use of ‘leukemic stem cells’ in leukemias by some other adult stem cells in vitro and restricts endogenous tissue investigators in the field). The biochemical pathways repair after injury. On the other hand, disruption of cell of general cell cycle regulation will not be detailed in the cycle inhibition may contribute to the formation of the so- current review, since they have been extensively called ‘tumor stem cells’ (TSCs) that are currently reviewed elsewhere (Pardee, 1989; Sherr and Roberts, hypothesized to be partially responsible for tumorigenesis 1999; Sherr, 2000). and recurrence of cancer after conventional therapies. Therefore, understanding how cell cycle inhibitors control stem cells may offer new strategies not only for therapeutic manipulations of normal stem cells but also Stem cell proliferation with a limited rate for novel therapies selectively targeting TSCs. Oncogene (2004) 23, 7256–7266. doi:10.1038/sj.onc.1207945 By definition, stem cells have the ability to reproduce themselves indefinitely while possessing the potential to Keywords: adult stem cell; hematopoietic stem cell; differentiate into multiple lineages (or a single lineage in tumor stem cell; tissue regeneration; self-renewal; cell a few tissue types) via transit amplifying cells (progeni- cycle; cyclin-dependent kinase inhibitor; p21; p27; p18; tors). However, the proliferative rate of stem cells in vivo p16; Rb protein under physiological conditions is much slower com- pared to that of intermediate progenies, including the progenitor cells and proliferating precursors. In the hematopoietic system, an increase in stem cell divisions can take place (Pawliuk et al., 1996; Oosten- dorp et al., 2000) under activating conditions, such as Introduction after transplantation or the depletion of cycling cells using the S-phase toxin (5-fluorouracil or hydroxyurea) The therapeutic efficacy of stem cells largely relies on (Harrison and Lerner, 1991; Uchida et al., 1997). their ability to replicate. Therefore, strategies to However, the relative quiescence of the HSC pool manipulate stem cells require an understanding of their appears to be essential to prevent premature depletion cell cycle control. In this review, the distinct cell cycle under conditions of physiologic stress over the lifetime kinetics of adult stem cells will be introduced and briefly of the organism (Cheng et al., 2000a, b). The highly followed by the current understanding of general cell regulated proliferation of HSC occurs at a very limited cycle regulation in mammalian cells. The focus will be rate under homeostatic conditions. It had once been placed on the specific impact of the cell cycle inhibitors, hypothesized that the stem cell quiescence reflects a namely the roles of cyclin-dependent kinase inhibitors complete cell cycle arrest of the majority cells in the stem (CKIs) on adult stem/progenitor cells. While many stem cell compartment, termed the ‘clonal succession model’ (Kay, 1965). While the retrovirus-based clonal marking *Correspondence: T Cheng, Hillman Cancer Center, Research studies revealed few active stem cell clones at a given Pavilion, Office suite 2.42e, 5117 Center Avenue, Pittsburgh, PA time, which supports the clonal succession theory 15213-1863, USA; E-mail: [email protected] (Lemischka et al., 1986), this view has been challenged Cell cycle inhibitors in stem cells T Cheng 7257 by the competitive repopulation model (Harrison et al., to be one of the hurdles in the context of the in vitro 1988) or 5-bromodeoxyuridine (BrdU) incorporation in expansion necessary for stem cell transplantation and the defined stem cell pools with a simulation methodol- gene therapy. Methods for inducing stem cell prolifera- ogy (Cheshier et al., 1999). Using BrdU labeling tion have long been sought as a means to expand the experiments, cell cycle lengths were estimated at population of cells capable of repopulating the bone approximately 30 days in small rodents (Bradford marrow of ablated hosts and to render stem cells et al., 1997) and it was found that only about 8% of transducable with virus-based gene transfer vectors. the cells are in cell cycle daily (Cheshier et al., 1999). Although great effort has been made to directly expand Similar analyses using population kinetics estimated stem cells using different combinations of hematopoietic that stem cells replicate once per 10 weeks in cats growth factors (cytokine cocktails), no culture system (Abkowitz et al., 1996). In non-human primates, the rate has been applied successfully in clinical settings. This is of cell replication in the stem cell pool was estimated to due, in part, to the lack of proof that any of the culture be once per year (Mahmud et al., 2001). In contrast, the conditions support expansion of a long-term repopulat- essential feature of the hematopoietic progenitor cell ing HSC in humans (Verfaillie, 2002). Although data (HPC) population is that it irreversibly develops into suggest that under certain specific conditions murine maturing cells, and in the process undergoes multiple HSCs may divide in vitro, net expansion is achieved in rapid cell divisions. The progenitor cell pool essentially limited fashion and is associated with and often operates as a cellular amplification machine, generating dominated by cellular differentiation (Ema et al., 2000; many differentiated cells from the few cells entering the Uchida et al., 2003). It remains unclear which combina- system (Potten, 1997), and it is therefore directly tion of hematopoietic cytokines is specifically selective responsible for the number of terminally differentiated for stem cell proliferation without differentiation. So cells. For this reason, the progenitor cell pool is also far, there is no cytokine combination that can achieve termed the transit, amplifying cell pool. The differences the effect of stem cell expansion by the HoxB4 protein between the stem and progenitor cell populations have (Antonchuk et al., 2002). A recent promising study been regarded as phenotypic distinctions marking the demonstrated a potent effect of purified Wnt3a protein stage of a cell within the hematopoietic cascade. in the expansion of mouse HSC in vitro. But the effect However, an alternative model was recently put forward appeared to require a strong survival element since the proposing that the specific position in a cell cycle net expansion could be only achieved on the HSCs from determines whether a primitive cell functions as a stem the Bcl2 transgenic mice (Willert et al., 2003). or a progenitor cell (Quesenberry et al., 2002). In this In short, the dichotomy of the relative resistance to hypothetical model, stimuli received at distinct positions proliferative signals by stem cells and the brisk respon- in the cell cycle provoke proliferation/differentiation or siveness by progenitor cells is generally believed to be a not, and thereby yield either HSC or HPC outcomes. central feature of tissue maintenance, although the This seems to contradict the traditional view of phenotypic distinctions between stem and progenitor ‘hierarchy’ within the hematopoietic differentiation. cells in many nonhematopoietic organs have not been Nevertheless, in either model, ‘stemness’ is associated fully defined. Nevertheless, the functional difference in with the limited rate of the cell proliferation. proliferative response between stem cells and progeni- The slow cycling feature seems to be a common tors represents a challenge for the specific manipulations feature in most adult stem cell types if not all (Potten, of the stem cells for therapeutic purposes. While a 1997). In the central nervous system (CNS), evidence complex array of extracellular signals and intracellular suggests that the proliferative pools of adult neural transduction pathways certainly participate in the progenitors are derived from a quiescent multipotent distinct response, the cell cycle machinery, as a final neural precursor

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