Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Cell cycle inhibitors in normal and tumor stem cells

Oncogene volume 23, pages 7256–7266 (2004)Cite this article

Abstract

Emerging data suggest that stem cells may be one of the key elements in normal tissue regeneration and cancer development, although they are not necessarily the same entity in both scenarios. As extensively demonstrated in the hematopoietic system, stem cell repopulation is hierarchically organized and is intrinsically limited by the intracellular cell cycle inhibitors. Their inhibitory effects appear to be highly associated with the differentiation stage in stem/progenitor pools. While this negative regulation is important for maintaining homeostasis, especially at the stem cell level under physiological cues or pathological insults, it constrains the therapeutic use of adult stem cells in vitro and restricts endogenous tissue repair after injury. On the other hand, disruption of cell cycle inhibition may contribute to the formation of the so-called ‘tumor stem cells’ (TSCs) that are currently hypothesized to be partially responsible for tumorigenesis 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 for novel therapies selectively targeting TSCs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Abkowitz JL, Catlin SN and Guttorp P . (1996). Nat. Med., 2, 190–197.

  • Aladjem MI, Spike BT, Rodewald LW, Hope TJ, Klemm M, Jaenisch R and Wahl GM . (1998). Curr. Biol., 8, 145–155.

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF . (2003). Proc. Natl. Acad. Sci. USA, 100, 3983–3988.

  • Antonchuk J, Sauvageau G and Humphries RK . (2002). Cell, 109, 39–45.

  • Austin TW, Solar GP, Ziegler FC, Liem L and Matthews W . (1997). Blood, 89, 3624–3635.

  • Bai F, Pei XH, Godfrey VL and Xiong Y . (2003). Mol. Cell. Biol., 23, 1269–1277.

  • Bartek J and Lukas J . (2001). FEBS Lett., 490, 117–122.

  • Becker PS, Nilsson SK, Li Z, Berrios VM, Dooner MS, Cooper CL, Hsieh CC and Quesenberry PJ . (1999). Exp. Hematol., 27, 533–541.

  • Berardi AC, Wang A, Levine JD, Lopez P and Scadden DT . (1995). Science, 267, 104–108.

  • Bloom J and Pagano M . (2003). Semin. Cancer Biol., 13, 41–47.

  • Bonfanti L, G A, Galli R and Vescovi AL . (2001). Stem Cells and CNS Development Rao MS (ed). Humana Press: Totowa, NJ, pp. 31–48.

    Google Scholar 

  • Bonnet D and Dick JE . (1997). Nat. Med., 3, 730–737.

  • Bradford GB, Williams B, Rossi R and Bertoncello GB . (1997). Exp. Hematol., 25, 445–453.

  • Braun SE, Mantel C, Rosenthal M, Cooper S, Liu L, Robertson KA, Hromas R and Broxmeyer HE . (1998). Blood Cells Mol. Dis., 24, 138–148.

  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T and Hannon GJ . (1995). Nature, 377, 552–557.

  • Burdon T, Smith A and Savatier P . (2002). Trends Cell Biol., 12, 432–438.

  • Burton PB, Raff MC, Kerr P, Yacoub MH and Barton PJ . (1999). Dev. Biol., 216, 659–670.

  • Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM and Scadden DT . (2003). Nature, 425, 841–846.

  • Cardoso AA, Li ML, Batard P, Hatzfeld A, Brown EL, Levesque JP, Sookdeo H, Panterne B, Sansilvestri P, Clark SC and Hatzfeld J . (1993). Proc. Natl. Acad. Sci. USA, 90, 8707–8711.

  • Carrano AC, Eytan E, Hershko A and Pagano M . (1999). Nat. Cell Biol., 1, 193–199.

  • Cashman JD, Clark-Lewis I, Eaves AC and Eaves CJ . (1999). Blood, 94, 3722–3729.

  • Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM and Sherr CJ . (1999). EMBO J., 18, 1571–1583.

  • Cheng T, Rodrigues N, Dombkowski D, Stier S and Scadden D . (2000a). Nat. Med., 6, 1235–1240.

  • Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M and Scadden DT . (2000b). Science, 287, 1804–1808.

  • Cheng T, Shen H, Rodrigues N, Stier S and Scadden DT . (2001). Blood, 98, 3643–3649.

  • Cheshier SH, Morrison SJ, Liao X and Weissman IL . (1999). Proc. Natl. Acad. Sci. USA, 96, 3120–3125.

  • Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, Berns A and te Riele H . (1992). Nature, 359, 328–330.

  • Classon M and Harlow E . (2002). Nat. Rev. Cancer, 2, 910–917.

  • Coats S, Flanagan WM, Nourse J and Roberts JM . (1996). Science, 272, 877–880.

  • Conlon I and Raff M . (1999). Cell, 96, 235–244.

  • Cotsarelis G, Cheng SZ, Dong G, Sun TT and Lavker RM . (1989). Cell, 57, 201–209.

  • Cunningham JJ and Roussel MF . (2001). Cell Growth Differ., 12, 387–396.

  • Dao MA, Taylor N and Nolta JA . (1998). Proc. Natl. Acad. Sci. USA, 95, 13006–13011.

  • de Nooij JC and Hariharan IK . (1995). Science, 270, 983–985.

  • de Nooij JC, Letendre MA and Hariharan IK . (1996). Cell, 87, 1237–1247.

  • Deng C, Zhang P, Harper JW, Elledge SJ and Leder P . (1995). Cell, 82, 675–684.

  • Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM and Alvarez-Buylla A . (1999). Cell, 97, 703–716.

  • Doetsch F, Verdugo JM, Caille I, Alvarez-Buylla A, Chao MV and Casaccia-Bonnefil P . (2002). J. Neurosci., 22, 2255–2264.

  • Drexler HG . (1998). Leukemia, 12, 845–859.

  • Ducos K, Panterne B, Fortunel N, Hatzfeld A, Monier MN and Hatzfeld J . (2000). J. Cell Physiol., 184, 80–85.

  • Dunnwald M, Chinnathambi S, Alexandrunas D and Bickenbach JR . (2003). J. Cell Physiol., 195, 194–201.

  • D'Urso G and Datta S . (2001). Stem Cell Biology Daniel R Marshak, Gardner RL and Gottlieb D (eds). Cold Spring Harbor Laboratory Press: New York, pp. 61–94.

    Google Scholar 

  • el-Deiry WS . (1998). Curr. Top Microbiol. Immunol., 227, 121–137.

  • el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW and Vogelstein B . (1992). Nat. Genet., 1, 45–49.

  • Ellisen LW, Carlesso N, Cheng T, Scadden DT and Haber DA . (2001). EMBO J., 20, 1897–1909.

  • Ema H, Takano H, Sudo K and Nakauchi H . (2000). J. Exp. Med., 192, 1281–1288.

  • Fero ML, Randel E, Gurley KE, Roberts JM and Kemp CJ . (1998). Nature, 396, 177–180.

  • Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K and Roberts JM . (1996). Cell, 85, 733–744.

  • Fortunel N, Batard P, Hatzfeld A, Monier MN, Panterne B, Lebkowski J and Hatzfeld J . (1998). J. Cell Sci., 111, 1867–1875.

  • Fortunel NO, Hatzfeld A and Hatzfeld JA . (2000). Blood, 96, 2022–2036.

  • Franklin DS, Godfrey VL, Lee H, Kovalev GI, Schoonhoven R, Chen-Kiang S, Su L and Xiong Y . (1998). Genes Dev., 12, 2899–2911.

  • Franklin DS, Godfrey VL, O'Brien DA, Deng C and Xiong Y . (2000). Mol. Cell. Biol., 20, 6147–6158.

  • Gao FB, Durand B and Raff M . (1997). Curr. Biol., 7, 152–155.

  • Harrison DE and Lerner CP . (1991). Blood, 78, 1237–1240.

  • Harrison DE, Astle CM and Lerner C . (1988). Proc. Natl. Acad. Sci. USA, 85, 822–826.

  • Hartwell LH and Weinert TA . (1989). Science, 246, 629–634.

  • Hatzfeld A, Batard P, Panterne B, Taieb F and Hatzfeld J . (1996). Hum. Gene Ther., 7, 207–213.

  • Hatzfeld J, Li ML, Brown EL, Sookdeo H, Levesque JP, T OT, Gurney C, Clark SC and Hatzfeld A . (1991). J. Exp. Med., 174, 925–929.

  • Hirabayashi Y, Matsuda M, Aizawa S, Kodama Y, Kanno J and Inoue T . (2002). Exp. Biol. Med. (Maywood), 227, 474–479.

  • Horner PJ, Power AE, Kempermann G, Kuhn HG, Palmer TD, Winkler J, Thal LJ and Gage FH . (2000). J. Neurosci., 20, 2218–2228.

  • Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA and Weinberg RA . (1992). Nature, 359, 295–300.

  • Karnezis AN, Dorokhov M, Grompe M and Zhu L . (2001). J. Clin. Invest., 108, 383–390.

  • Kay HE . (1965). Lancet, 15, 418–419.

  • Krosl J, Austin P, Beslu N, Kroon E, Humphries RK and Sauvageau G . (2003). Nat. Med., 9, 428–432.

  • LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A and Harlow E . (1997). Genes Dev., 11, 847–862.

  • Latres E, Malumbres M, Sotillo R, Martin J, Ortega S, Martin-Caballero J, Flores JM, Cordon-Cardo C and Barbacid M . (2000). EMBO J., 19, 3496–3506.

  • Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH and Bradley A . (1992). Nature, 359, 288–294.

  • Legrier ME, Ducray A, Propper A, Chao M and Kastner A . (2001). Cell Growth Differ., 12, 591–601.

  • Lemischka IR, Raulet DH and Mulligan RC . (1986). Cell, 45, 917–927.

  • Lessard J and Sauvageau G . (2003). Nature, 423, 255–260.

  • Liu Y, Martindale JL, Gorospe M and Holbrook NJ . (1996). Cancer Res., 56, 31–35.

  • Mahmud N, Devine SM, Weller KP, Parmar S, Sturgeon C, Nelson MC, Hewett T and Hoffman R . (2001). Blood, 97, 3061–3068.

  • Mal A, Poon RY, Howe PH, Toyoshima H, Hunter T and Harter ML . (1996). Nature, 380, 262–265.

  • Mantel C, Luo Z, Canfield J, Braun S, Deng C and Broxmeyer HE . (1996). Blood, 88, 3710–3719.

  • Marone M, Pierelli L, Mozzetti S, Masciullo V, Bonanno G, Morosetti R, Rutella S, Battaglia A, Rumi C, Mancuso S, Leone G, Giordano A and Scambia G . (2000). Br. J. Haematol., 110, 654–662.

  • Missero C, Di Cunto F, Kiyokawa H, Koff A and Dotto GP . (1996). Genes Dev., 10, 3065–3075.

  • Miyazawa K, Himi T, Garcia V, Yamagishi H, Sato S and Ishizaki Y . (2000). J. Neurosci., 20, 5756–5763.

  • Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF and Morrison SJ . (2003). Nature, 425, 962–967.

  • Morgan DO . (1995). Nature, 374, 131–134.

  • Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, Lin JS, Sawicki JA and Cotsarelis G . (2004). Nat. Biotechnol., 22, 411–417.

  • Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S and van der Kooy D . (1994). Neuron, 13, 1071–1082.

  • Nakanishi M, Adami GR, Robetorye RS, Noda A, Venable SF, Dimitrov D, Pereira-Smith OM and Smith JR . (1995). Proc. Natl. Acad. Sci. USA, 92, 4352–4356.

  • Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY and Nakayama K . (1996). Cell, 85, 707–720.

  • Oostendorp RA, Audet J and Eaves CJ . (2000). Blood, 95, 855–862.

  • Palmer TD, Schwartz PH, Taupin P, Kaspar B, Stein SA and Gage FH . (2001). Nature, 411, 42–43.

  • Pardal R, Clarke MF and Morrison SJ . (2003). Nat. Rev. Cancer, 3, 895–902.

  • Pardee AB . (1989). Science, 246, 603–608.

  • Park IK, Morrison SJ and Clarke MF . (2004). J. Clin. Invest., 113, 175–179.

  • Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ and Clarke MF . (2003). Nature, 423, 302–305.

  • Passegue E, Jamieson CH, Ailles LE and Weissman IL . (2003). Proc. Natl. Acad. Sci. USA, 100 (Suppl 1), 11842–11849.

  • Pawliuk R, Eaves C and Humphries RK . (1996). Blood, 88, 2852–2858.

  • Phelps DE, Hsiao KM, Li Y, Hu N, Franklin DS, Westphal E, Lee EY and Xiong Y . (1998). Mol. Cell. Biol., 18, 2334–2343.

  • Phelps DE and Xiong Y . (1998). Cell Growth Differ., 9, 595–610.

  • Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P and Massague J . (1994). Cell, 78, 59–66.

  • Potten MLAC (ed). (1997). Stem Cells and Cellular Pedigrees – A Conceptual Introduction. Academic Press: London.

    Google Scholar 

  • Prost S, Bellamy CO, Clarke AR, Wyllie AH and Harrison DJ . (1998). FEBS Lett., 425, 499–504.

  • Qiu J, T Y, Harada J, Rodrigues N, Moskowitz MA, Scadden DT and Cheng T . (2004). J. Exp. Med., 199, 937–945.

  • Quesenberry PJ, Colvin GA and Lambert JF . (2002). Blood, 100, 4266–4271.

  • Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R and Weissman IL . (2003). Nature, 423, 409–414.

  • Reya T, Morrison SJ, Clarke MF and Weissman IL . (2001). Nature, 414, 105–111.

  • Rivard N, G LA, Bartek J and Pouyssegur J . (1996). J. Biol. Chem., 271, 18337–18341.

  • Roy V and Verfaillie CM . (1999). Exp. Hematol., 27, 302–312.

  • Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW and DePinho RA . (2001). Nature, 413, 86–91.

  • Sharpless NE, Ramsey MR, Balasubramanian P, Castrillon DH and DePinho RA . (2004). Oncogene, 23, 379–385.

  • Shen H, Cheng T, Preffer FI, Dombkowski D, Tomasson MH, Golan DE, Yang O, Hofmann W, Sodroski JG, Luster AD and Scadden DT . (1999). J. Virol., 73, 728–737.

  • Sherr CJ . (1994). Cell, 79, 551–555.

  • Sherr CJ . (1996). Science, 274, 1672–1677.

  • Sherr CJ . (2000). Cancer Res., 60, 3689–3695.

  • Sherr CJ . (2001). Nat. Rev. Mol. Cell. Biol., 2, 731–737.

  • Sherr CJ and Roberts JM . (1995). Genes Dev., 9, 1149–1163.

  • Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.

  • Sherr CJ and Weber JD . (2000). Curr. Opin. Genet. Dev., 10, 94–99.

  • Steiner P, Philipp A, Lukas J, Godden-Kent D, Pagano M, Mittnacht S, Bartek J and Eilers M . (1995). EMBO J., 14, 4814–4826.

  • Steinman RA, Hoffman B, Iro A, Guillouf C, Liebermann DA and el-Houseini ME . (1994). Oncogene, 9, 3389–3396.

  • Steinman RA, Huang J, Yaroslavskiy B, Goff JP, Ball ED and Nguyen A . (1998). Blood, 91, 4531–4542.

  • Steinman RM and Nussenzweig MC . (2002). Proc. Natl. Acad. Sci. USA, 99, 351–358.

  • Stier S, Cheng T, Dombkowski D, Carlesso N and Scadden DT . (2002). Blood, 99, 2369–2378.

  • Stier S, Cheng T, Forkert R, Lutz C, Dombkowski DM, Zhang JL and Scadden DT . (2003). Blood, 102, 1260–1266.

  • Taniguchi T, Endo H, Chikatsu N, Uchimaru K, Asano S, Fujita T, Nakahata T and Motokura T . (1999). Blood, 93, 4167–4178.

  • Tong X and Srour EF . (1998). Exp. Hematol., 26, 684.

  • Tschan MP, Peters UR, Cajot JF, Betticher DC, Fey MF and Tobler A . (1999). Br. J. Haematol., 106, 644–651.

  • Uchida N, Dykstra B, Lyons KJ, Leung FY and Eaves CJ . (2003). Exp. Hematol., 31, 1338–1347.

  • Uchida N, Friera AM, He D, Reitsma MJ, Tsukamoto AS and Weissman IL . (1997). Blood, 90, 4354–4362.

  • Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S, Pear WS and Bernstein ID . (2000). Nat. Med., 6, 1278–1281.

  • Verfaillie CM . (2002). Nat. Immunol., 3, 314–317.

  • Vogelstein B and Kinzler KW . (1992). Cell, 70, 523–526.

  • Wang J and Walsh K . (1996). Science, 273, 359–361.

  • Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates III JR and Nusse R . (2003). Nature, 423, 448–452.

  • Wlodarski P, Wasik M, Ratajczak MZ, Sevignani C, Hoser G, Kawiak J, Gewirtz AM, Calabretta B and Skorski T . (1998). Blood, 91, 2998–3006.

  • Yaroslavskiy B, Watkins S, Donnenberg AD, Patton TJ and Steinman RA . (1999). Blood, 93, 2907–2917.

  • Yuan Y, Boyer M, Shen H, Cao S, Yu H and Cheng T . (2003). Blood, 102, 3177 (Abstract).

  • Yuan Y, Shen H, Franklin DS, Scadden DT and Cheng T . (2004). Nat. Cell Biol., 6, 436–442.

  • Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y and Li L . (2003). Nature, 425, 836–841.

  • Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA and Elledge SJ . (1997). Nature, 387, 151–158.

  • Zindy F, van Deursen J, Grosveld G, Sherr CJ and Roussel MF . (2000). Mol. Cell. Biol., 20, 372–378.

Download references

Acknowledgements

My research work has been supported by NIH grants DK02761, HL70561. I was a recipient of the Faculty Scholar Award from the American Society of Hematology (2003). Due to the limited space and the targeted topic, many related publications cannot be cited in this review, but I very much appreciate the important contributions from many other investigators in the field. I thank Paulina Huang for the artwork, Jon Kilner for editorial assistance and Jian Yu for critical reading of this manuscript. I specially thank David Scadden for his valuable input, and great inspiration to my research on cell cycle regulation of stem cells.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, 15213, PA, USA

    Tao Cheng

Authors
  1. Tao Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tao Cheng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, T. Cell cycle inhibitors in normal and tumor stem cells. Oncogene 23, 7256–7266 (2004). https://doi.org/10.1038/sj.onc.1207945

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207945

Keywords

This article is cited by

Search

Advanced search

Quick links