Abstracts
Résumé
La vision que nous avons de la cellule tumorale a considérablement changé depuis la découverte des proto-oncogènes, gènes clés dont le dérèglement faisait du cancer une maladie de la signalisation cellulaire. En effet, l’émergence d’une cellule cancéreuse a progressivement été perçue comme résultant d’une augmentation de la fréquence des mutations, mutations qui sont ensuite sélectionnées par l’apparition d’un avantage sélectif, conduisant ainsi au concept du « phénotype mutateur ». L’instabilité génomique, reconnue comme mécanisme essentiel dans la genèse et l’évolution des processus cancéreux, et dont le rôle avait été entrevu depuis longtemps par les cytogénéticiens, transformait ainsi le cancer en une maladie de la réparation des lésions génotoxiques. Par ailleurs, l’instabilité chromosomique qui est fréquemment observée conduit à un nombre anormal de chromosomes (aneuploïdie) qui, très souvent, ont une structure aberrante. Les coupables, identifiés dans le camp des régulateurs du cycle cellulaire, provoquèrent un nouveau changement dans notre perspective, impliquant ainsi les mécanismes de contrôle de la bonne coordination des deux phases essentielles que sont la phase S et la mitose.
Summary
Our vision of the cancer cell has dramatically changed since the discovery of proto-oncogenes, whose deregulation was proposed to mimic normal growth signalling. This notion, linking cancer to cell signalling pathways, has progressively led the way to the concept of the mutator phenotype, in which genetic instability plays an essential role in the onset of cancer. This then transformed cancer into a DNA repair disease. However, as foreseen decades ago by cytogeneticists, point mutations are not sufficient to give a full picture of the whole process. As a result, aneuploidy, rather than gene mutation, has been proposed as the explanation for the complex changes observed in cancer cells. The culprits were found among genes involved in the control of the cell division cycle, and work aimed at understanding the regulation of S phase and mitosis have yielded new insights into our understanding of cancer.
Appendices
Références
- 1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70
- 2. Fashema SJ, Thomas SM. Signalling by adhesion receptors. Nat Cell Biol 2000; 2: E225-36
- 3. Baron V, Lebrun P. Coopération entre les intégrines et les récepteurs à activité tyrosine kinase. Med Sci 2001; 17: 111-4
- 4. Rassoulzadegan M, Cowie A, Carr A, Glaichenhaus N, Kamen R, Cuzin F. The roles of individual polyoma virus early proteins in oncogenic transformation. Nature 1982; 300: 713-8
- 5. Le Peuch C, Dorée M. Le temps du cycle cellulaire. Med Sci 2000; 16: 461-8
- 6. Sherr CJ, Roberts JM. Cdk inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13: 1501-22.
- 7. Sicinski P, Donaher JL, Parker SB, et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 1995; 82: 621-30.
- 8. Tsutsui T, Heabi B, Moons DS, et al. Targeted disruption of Cdk4 delays cell cycle entry with enhanced p27Kip1 activity. Mol Cell Biol 1999; 19: 7011-9.
- 9. Geng Y, Yu Q, Sicinska E, et al. Deletion of the p27Kip1 gene restores normal development in cyclin D1-deficient mice. Proc Natl Acad Sci USA 2001; 98: 194-9.
- 10. Barnes EA, Kong M, Ollendorff V, Donoghue DJ. Patched 1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J 2001; 20: 2214-23
- 11. Sherr CJ. The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2001; 2: 721-37.
- 12. Motokura T, Bloom T, Goo-Kim H, et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 1991; 350: 512-5.
- 13. Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994; 369: 669-71.
- 14. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Arris AW, Adams JM. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J 1994; 13: 2124-30.
- 15. Lovec H, Grzeschiczk A, Kowalski MB, Moroy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J 1994; 13: 3487-95.
- 16. Blanchard JM. Mécanismes moléculaires de la transformation oncogénique: quoi de neuf? Bull Cancer 2002; 8 : 9-16.
- 17. Fishel R, Wilson T. MutS homologs in mammalian cells. Curr Opin Genet Dev 1997; 7: 105-13.
- 18. Kolodner R. Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev 1996; 10: 1433-42.
- 19. Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a MutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75: 1215-25.
- 20. Fishel R, Lescoe, MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75: 1027-38.
- 21. De Wind N, Dekker M, Berns A, Radman M, Riele H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 1995; 82: 321-30.
- 22. Edelmann WE, Yang K, Umar A, et al. Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell 1997; 91: 467-77.
- 23. De Wind N, Dekker M, Claij N, et al. HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nat Genet 1999; 23: 359-62.
- 24. Wang Y, Cortez D, Yazdi P, et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 2000; 14: 927-39.
- 25. Zhang H, Tombline G, Weber BL. BRCA1, BRCA2, and DNA damage response: collision or collusion? Cell 1998; 92: 433-6.
- 26. Feunteun J. La prédisposition héréditaire au cancer du sein liée à BRCA1 et BRCA2: une maladie de la réponse aux lésions génotoxiques? Med Sci 1999; 15: 38-44.
- 27. Welcsh PL, Owens KN, King MC. Insights into the functions of BRCA1 and BRCA2. Trends Genet 2000; 16: 69-74.
- 28. Wang Q, Zhang H, Fishel R, Greene MI. BRCA1 and cell signaling. Oncogene 2000; 19: 6152-8.
- 29. Zheng L, Li S, Boyer TG, Lee WH. Lessons learned from BRCA1 and BRCA2. Oncogene 2000; 19: 6159-75.
- 30. Bay JO, Uhrhammer N, Hall J, Stoppa-Lyonnet D, Bignon YJ. Fonctions de la protéine ATM et aspects phénotypiques de l’ataxie-télangiectasie. Med Sci 1999; 15: 1086-95.
- 31. Shiloh Y. ATM and ATR: networking cellular responses to DNA damage. Curr Opin Genet Dev 2001; 11: 71-7.
- 32. Gradia S, Acharya S, Fishel R. The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. Cell 1997; 91: 995-1005.
- 33. Fishel R. Mismatch repair, molecular switches, and signal transduction. Genes Dev 1998; 12: 2096-101.
- 34. Fishel R. Signaling mismatch repair in cancer. Nat Med 1999; 5: 1239-41.
- 35. Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res 2001; 61: 818-22.
- 36. Jeanteur P. Le rôle d’APC dans la cancérogenèse colique: en plein dans le Myc! Bull Cancer 1998; 85: 925-8.
- 37. Laurent-Puig P, Blons H. Mutations du gène APC et instabilité génétique. Med Sci 2001; 17: 954.
- 38. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001; 1 : 55-67.
- 39. Samowitz WS, Powers MD, Spirio LN, et al. β-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res 1999; 59: 1442-4.
- 40. Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Näthke IS. A role for the adenomatous polyposis coli in chromosome segregation. Nat Cell Biol 2001; 3: 429-32.
- 41. Fodde R, Kuipers J, Rosenberg C, et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 2001; 3: 433-8.
- 42. Näthke IS, Adams CL, Polakis P, Sellin JH, Nelson WJ. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J Cell Biol 1996; 134: 165-79.
- 43. Mimori-Kiyosue Y, Shiina N, Tsukita S. Adenomatous polyposis coli (APC) protein moves along microtubules and concentrates at their growing ends in epithelial cells. J Cell Biol 2000; 148: 505-17.
- 44. Peter M, Magnaghi-Jaulin L, Castro A, et al. Quand la dynamique chromosomique contrôle la division cellulaire. Pathol Biol 2001; 49: 649-54.
- 45. Abrieu A, Dorée M. La cohésion des chromatides-soeurs et sa régulation au cours du cycle cellulaire. Med Sci 2001; 17: 353-4.
- 46. Nigg E. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2001; 2:21-32.
- 47. Gardner RD, Burke DJ. The spindle checkpoint: two transitions, two pathways. Trends Cell Biol 2000; 10: 154-8.
- 48. Jallepalli PV, Lengauer C. Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer 2001; 1: 109-17.
- 49. Cahill DP, Lengauer C, Yu J, et al. Mutations of mitotic checkpoint genes in human cancers. Nature 1998; 392: 300-3.
- 50. Gemma A, Seike M, Seike Y, et al. Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer. Genes Chrom Cancer 2000; 29: 213-8.
- 51. Michel LS, Liberal V, Chatterjee A, et al. MAD2 haplo-insufficiency causes premature anaphase and chromosomal instability in mammalian cells. Nature 2001; 409: 355-9.
- 52. Kalitsis P, Earle E, Fowler KJ, Choo A. Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev 2000; 14: 2277-82.
- 53. Jallepalli PV, Waizenegger IC, Bunz F, et al. Securin is required for chromosomal stability in human cells. Cell 2001; 105: 445-7.
- 54. Rousseau D. eIF-4E, régulation de la traduction et progression tumorale. Med Sci 2001; 17: 336-43.
- 55. Hunter T. Signaling-2000 and beyond. Cell 2000; 100: 113-27.
- 56. Takisawa H, Mimura S, Kubota Y. Eukaryotic DNA replication: from pre-replication complex to initiation complex. Curr Opin Cell Biol 2000; 12: 690-6.
- 57. Kelly TJ, Brown GW. Regulation of chromosome replication. Annu Rev Biochem 2000; 69: 829-80.
- 58. Bulavin DV, Amundson SA, Fornace Jr AJ. P38 and Chk1 kinases: different conductors for the G2/M checkpoint symphony. Curr Opin Genet Dev 2002; 12: 92-7.
- 59. Scheid MP, Woodgett JR. PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2001; 2: 760-8.
- 60. Howlett NG, Tanigushi T, Olson S, et al. Biallelic inactivation of BRCA-2 in Fanconi anemia. Science 2002; 297: 606-9.
- 61. Jeanteur P. L’anémie de Fanconi et les gènes BRCA: même combat? Bull Cancer 2002; 89: 917-8
- 62. Groisman I, Huang YS, Mendez P, Cao Q, Theurkauf W, Richter JD. CPEB, Maskin, and cyclin B1 mRNA at the mitotic apparatus: implications for local translational control of cell division. Cell 2000; 103: 435-47.
- 63. Fu L, Pelicano H, Liu J, Huang P, Lee CC. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 2002; 111: 41-50.