La sénescence dans les cellules humaines : un obstacle au développement tumoral ?

Abstract

Le processus de " senescence replicative ", dans de nombreux types cellulaires, est conditionne par l' erosion progressive des extremites specialisees du chromosome - les telomeres -qui constituent une " horloge " mitotique. Une voie de signalisation majeure liant le raccourcissement des telomeres a l' arret de la proliferation s' opererait via l' activation du produit du gene suppresseur de tumeurs, p53, lui-meme inducteur de l' inhibiteur du cycle cellulaire, p21waf-1/cip-1/sdi-1. Au moins une des autres voies implique un gene suppresseur de tumeurs qui code pour l' inhibiteur du cycle cellulaire, p16INK4a. L' inactivation de ces voies par des mutations des genes suppresseurs de tumeurs supprime l' entree en senescence, mais ce gain de proliferation est eventuellement limite par la mort cellulaire (" crise ") a la suite de la perte critique de la fonction telomerique. Pour devenir immortelle, une tumeur doit subir non seulement des mutations des genes suppresseurs de tumeurs, mais aussi echapper a la crise apres stabilisation de la taille des telomeres grace a la reactivation (ou l' augmentation de l' activite) de l' enzyme telomerase.

The proliferative life span of most normal human cells, even in ideal growth conditions, is limited by intrinsic inhibitory signals which induce cell cycle arrest after a pre-set number of cell divisions. There is now good evidence that this process of "replicative senescence" is driven in many cell types by the progressive erosion of the specialised ends of chromosomes - telomeres - which act as a molecular "clock". Although many details are still to be elucidated, one major signal pathway linking telomere shortening to growth arrest operates via activation of the tumour suppressor gene (TSG) product, p53, which in turns induces the cell cycle inhibitor p21WAF1/CIP-1/SDI-1. At least one other pathway involves another TSG-encoded cell cycle inhibitor, p16INK4a, although in this case the link to the senescence clock is still unclear. Loss of these pathways by TSG mutation results in escape from senescence, but proliferative life span is still eventually limited by cell death ("criss") resulting from critical loss of telomere function. To acquire immortality therefore a developing tumour must undergo not only TSG mutation (e.g. p16INK4a and p53) but also evade crisis by stabilization of telomere length, which is most often achieved by reactivation (or upregulation) of the enzyme telomerase. The need to circumvent successive proliferative life span "barriers" fits well with the concept of clonal evolution in tumourigenesis and the existence of multiple genetic abnormalities in nearly all types of human cancer.