From Stem Cells to Cancer: Balancing Immortality and Neoplasia

Home , Adult stem cell, Cancer stem cell

W Nicol Keith*,1

1Centre for Oncology & Applied Pharmacology, Cancer Research UK Beatson Laboratories, University of Glasgow, Garscube Estate, Switchback Rd., Glasgow G61 1BD, UK

In this issue of Oncogene,Serakinci et al show that adult the hMSC in more detail, a number of groups have stem cells can be targets for neoplastic transformation. therefore used the forced expression of telomerase to After transducing human adult mesenchymal stem cells extend the replicative capacity of hMSC with consider- (hMSC) with the telomerase hTERT gene,and growing able success (Shi et al., 2002; Simonsen et al., 2002). In them for many population doublings in culture,Serakinci this latter study, hMSC, rendered replicatively immortal et al observed that the transduced cells developed by the ectopic expression of telomerase, were shown to characteristics consistent with transformation including retain the functional characteristics and differentiation loss of contact inhibition,anchorage independence and potential of the hMSC from which they were derived, tumour formation in mice. Underlying these changes were and on transplantation into immunodeficient mice they alterations to genes involved in cell cycle regulation and formed bone tissue more effectively than their normal senescence as well as oncogene activation. The importance counterparts, but no tumours (Simonsen et al, 2002). In of these observations is twofold. Firstly,showing that stem terms of stem cell therapeutics these results were very cells can become tumours raises a note of caution for stem encouraging, however, with a commendable lack of cell therapeutics. Secondly,the findings lend support to complacency, this same group has investigated the the stem cell hypothesis of cancer development,and neoplastic potential of the hMSC more exhaustively. provide an experimental system in which the tantalizing As a result, it is now clear that telomerase-modified hint of new diagnostic,prognostic,and therapeutic hMSC can accumulate premalignant changes on con- opportunities offered by this concept can be explored tinued division in culture, in some cases to the extent of further. acquiring the ability to form tumours in immunodefi- Oncogene (2004) 23, 5092–5094. doi:10.1038/sj.onc.1207762 cient mice (Figure 3, Serakinci et al., 2004). Published online 26April 2004 While the role that stem cells play in tissue home- ostasis is clear, their contribution to the development of Keywords: mesenchyme; stem cell; cancer stem cell; cancer is still an issue of much debate (Table 1) (Marx, telomerase; neoplasia; mesenchymal stem cell 2003; Preston et al., 2003). However, for a tumour to grow, metastasise and recur after therapeutic interven- tion, the presence of a subpopulation of cells with extensive self-renewal capacity and thus stem cell Stem cells can be defined as having extensive self- properties would make biological sense. The stem cell renewal capacity and also the ability to differentiate into hypothesis of cancer development further proposes that a wide variety of cell types. Stem cells can be found both stem cells are particularly susceptible targets of carci- in the embryo (ES cells) and in adult tissues (Preston nogenesis and consequently the origin of many cancers. et al., 2003). While the embryonic stem cells are able to Although stem cells are rare and so have a low target give rise to all cell types required for mammalian number for carcinogenesis, their potential to continue to development, the less well characterized adult stem cells divide over a long period of time may make them more appear to have a more restricted lineage potential but likely to accumulate the requisite number of molecular may be essential for tissue repair and renewal (Figure 1). alterations to cause cancer. A high replicative potential An example of an adult stem cell is the mesenchymal therefore confers a high malignant potential on the stem stem cell (hMSC) which is present in a variety of tissues cell. This malignant potential may be held in check by but prevalent in the bone marrow. As shown in Figure 2, suppressing telomerase expression, as by supplying telo- the hMSC can differentiate into a variety of adult merase to the hMSC, Serakinci et al are able to uncover mesenchymal tissues such as bone, cartilage, adipose the latent neoplastic potential of the adult stem cell. and muscle (Simonsen et al., 2002). Interestingly, despite Whereas the neoplastic potential of the stem cell having stem cell qualities, the hMSC has limited has been obvious to haematologists for many years, replicative capacity in tissue culture and lacks expression data to support a cancer stem cell basis for solid of the immortalizing enzyme, telomerase (Simonsen tumours has been sparse (Passegue et al., 2003). et al., 2002; Zimmermann et al., 2003). In order to study Recently however, a number of groups have demon- strated the presence of subpopulations of cells within *Correspondence: WN Keith; E-mail: [email protected] tumour biopsies from brain and breast cancers to Published online 26April 2004 have stem cell characteristics (Al-Hajj et al., 2003; Commentary WN Keith 5093

Figure 1 Maintaining the stem cell phenotype. Through a process of asymmetric division, the stem cell produces one daughter cell identical to stem cell and therefore capable of self-renewal and a second progenitor cell that becomes committed to differentiation. The self-renewal capacity of a cancer stem cell parallels that of a stem cell and so the stem cell may be protected by a block to Figure 3 Neoplastic development of the hMSC. In order to transformation that can be overcome during carcinogenesis become transformed, the hMSC may have to subvert normal proliferative, cell fate and differentiation signals

Hemmati et al., 2003; Singh et al., 2003). These findings together with those of Serakinci et al. (2004) lend tremendous support to the cancer stem cell hypothesis (Table 1). However, they do not exclude the possibility that cancers can arise from non-stem cell populations. If malignant potential is linked to the replicative potential of the target cell for carcinogenesis, less aggressive tumours would be predicted to arise from non-stem cells. Alternatively, a non-stem cell could acquire a stem cell phenotype during carcinogenesis. The identification of cancer stem cells strongly suggests that these cells are the key targets for future therapeutic development as they fuel the replicative capacity of the cancer. However, in order to develop such therapies, relevant, representative tissue culture models will be necessary. In this respect, the work described by Serakinci makes a significant contribution, and their choice of the hMSC is a fortuitous one. As illustrated in Figure 2, the hMSC has the potential to give rise to a wide variety of differentiated tissues, and the stem cell hypothesis of cancer development postulates that it may also be the origin of a clinically interesting range of cancers. Thus the hMSC seems an ideal system in which to study the adult stem cell as a target for transformation, and the molecular basis Figure 2 Relationship between the hMSC and cancer. The underlying this process. Serakinci et al. have already mesenchymal stem cell gives rise to a variety of differentiated cells provided some valuable information on the molecular types. In turn, many of these tissues can give rise to cancers of mesenchymal origin. This raises the interesting question as to what changes that accompany the neoplastic transformation is the target cell for neoplastic transformation within the normal of the hMSC. It will be important to see whether cancer mesenchymal tissue stem cells can be identified in human mesenchymal

Oncogene Commentary WN Keith 5094 Table 1 The stem cell hypothesis of cancer development Basic postulates Stem cells are present in adult tissues and can be targets for carcinogenesis and transformation Although stem cells are rare, they have a high malignant potential because they continue to divide over a long period of time and are therefore more likely to accumulate the requisite number of molecular alterations to cause cancer Mutations in pathways disturbing proliferative lifespan, cell cycle and differentiation may be required to reveal the full malignant potential of the cancer stem cell The self-renewing capacity of cancer stem cells parallels that of normal stem cells A small number of cancer stem cells can fuel the growth of a large tumour mass

Empirical support A number of haematological malignancies have stem cell characteristics, for example CML Recent studies on solid tumours have shown that the capacity for self-renewal is limited to a subpopulation of tumour cells, and that these can be distinguished from cells without this capacity by markers typical of stem cells The experiments of Serakinci et al. show that mesenchymal adult stem cells can form tumours after being transduced by telomerase. By contrast, numerous studies have transduced non-stem cells with telomerase without observing neoplastic transformation

Outstanding questions Are all adult tissue stem cells targets for neoplastic transformation? Do all cancers arise from normal stem cells? Is a cancer stem cell necessary for long-term tumour growth? Is malignant potential related to the replicative potential of the target cell for carcinogenesis? How do cancer stem cells differ from normal stem cells? Are the pathways regulating self-renewal the same for both normal stem cells and the cancer stem cell? Can the biology of the cancer stem cell be used for patient beneﬁt? Diagnostics: detection of cancer stem cell markers Prognostics: does the cancer stem cell determine clinical outcome? Therapeutics: can therapeutics be developed that speciﬁcally target the cancer stem cell?

tumours and to what extent the experimental system produce replicatively immortal cultures of adult stem recapitulates the natural development of these tumours cells for transplantation may need to proceed with in vivo. Any differences between normal stem cells and caution in the light of this new data (Serakinci et al., cancer stem cells provide valuable targets for drug 2004). I would argue, however, that while caution is of discovery. Model systems such as the one described by course warranted, the field should not be put off. Very Serakinci will help both in the identification of such little is ever straightforward in translating science to differences and in screening for successful drugs, as this health care. Stem cell therapeutics continues to hold will need to be done using both of these stem cell types. great promise and the more we understand about stem Not only will this approach uncover new therapeutic cells the greater are our chances of successfully and targets but also more relevant and specific markers for safely realizing their clinical potential for tissue regen- the detection of cancer and residual disease after eration and repair. therapy. Indeed, markers of the cancer stem cell may Overall, the new data from Serakinci et al. are be useful in prediction of response to treatment and in valuable in several respects. On the one hand, they prognostics (Table 1). carry a warning that should help guide the safe While the latest results of Serakinci et al. should have development of stem cell therapeutics, on the other they a positive impact on the nascent field of cancer stem cell offer a new experimental model of human tumour biology, they will be a cause for some concern to those development, which can be used to further explore the hoping to use adult stem cells in cell replacement potentially far-reaching concept of cancer stem cells, strategies and in tissue engineering (Tuan et al., 2003). and the exciting new possibilities of therapy directed In particular, the approach of using telomerase to against them.

References

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ Shi S, Gronthos S, Chen S, Reddi A, Counter CM, and Clarke MF. (2003). Proc. Natl. Acad. Sci. USA, 100, Robey PG and Wang CY. (2002). Nat. Biotechnol., 20, 3983–3988. 587–591. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Geschwind DH, Bronner-Fraser M and Kornblum HI. Rattan SI, Jensen TG and Kassem M. (2002). Nat. (2003). Proc. Natl. Acad. Sci. USA, 100, 15178–15183. Biotechnol., 20, 592–596. Marx J. (2003). Science, 301, 1308–1310. Singh SK, Clarke ID, Terasaki M, Bonn VE, Passegue E, Jamieson CH, Ailles LE and Weissman IL. (2003). Hawkins C, Squire J and Dirks PB. (2003). Cancer Res., Proc. Natl. Acad. Sci. USA, 100 (Suppl 1), 11842–11849. 63, 5821–5828. Preston SL, Alison MR, Forbes SJ, Direkze NC, Poulsom R Tuan RS, Boland G and Tuli R. (2003). Arthritis Res. Ther., 5, and Wright NA. (2003). Mol. Pathol., 56, 86–96. 32–45. Serakinci N, Guldberg P, Burns J, Abdallah B, Schrdder H, Zimmermann S, Voss M, Kaiser S, Kapp U, Waller CF and Jensen T and Kassem M. (2004). Oncogene, in press. Martens UM. (2003). Leukemia, 17, 1146–1149.

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