Jonctions communicantes et cancer : implications et perspectives

Abstract

Les jonctions communicantes (gap junctions) sont des structures membranaires permettant la diffusion intercellulaire de petites molécules (ions, sucres, acides aminés, nucléotides…). La perte de leur fonction, fréquemment induite par des promoteurs de tumeur et associée au phénotype tumorigénique, a fait supposer que les jonctions communicantes étaient impliquées dans le processus de cancérogenèse. Plus récemment, cette hypothèse a été confortée par le fait que le rétablissement de la communication jonctionnelle intercellulaire s’accompagne d’un effet suppresseur de tumeur spécifique. Malgré ces données, plusieurs zones d’ombre subsistent, parmi lesquelles le mode de régulation de l’effet suppresseur et la véritable implication des jonctions communicantes dans la cancérogenèse humaine. Répondre à ces interrogations est d’importance, puisque les jonctions communicantes pourraient être un paramètre à considérer en terme d’efficacité pour certaines thérapies géniques anticancéreuses, voire même pour certaines chimiothérapies.

Gap junctions are made of intercellular channels which permit the diffusion from cytoplasm to cytoplasm of small hydrophilic molecules (< 1 200 Da) such as ions, sugars, aminoacids, nucleotides, second messengers (calcium, inositol triphosphate, etc.). Since their discovery in the early sixties, several groups have described the loss of their function in cancer cells. The accumulation of such data led to the hypothesis that gap junctions are involved in the carcinogenesis process. This assumption has been confirmed by data establishing that gap junctional intercellular communication is inhibited by most of the tumor promoters and that the restoration of such a communication, by transfection of cDNAs encoding gap junction proteins (connexins), inhibits the aberrant growth rates of tumorigenic cells. Despite these important informations, several fundamental questions remain still open. First, we do not know how gap junctions mediate such a tumor suppressor effect and whether it may depend either on the cell type or on the connexin type. Moreover, most of the data concerning a possible involvement of gap junctions in carcinogenesis have been obtained from in vitro and animal models. The very few results which have been currently collected from human tumors are not sufficient to have a clear idea concerning the real involvement of gap junctions in sporadic human cancers. These points as well as other unresolved questions about the role of gap junctional intercellular communication in carcinogenesis are mentionned. To bring some answers, some prospects are proposed with the objective to use gap junctions for increasing the effect of anticancer therapies.