Résumés
Résumé
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.
Abstract
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.
Parties annexes
Références
- 1. Abarcrombie M, HeaysmanEM. Social behavior of cells in monolayering of fibroblasts. Exp Cell Res 1954 ; 6 : 293.
- 2. Makowski L, Caspar DL, Phillips WC, Goodenough DA. Gap junction structures. II. Analysis of the X-ray diffraction data. J Cell Biol 1977 ; 74 : 629-45.
- 3. Meda P. Connexines, canaux jonctionnels et communications cellulaires. Med Sci (Paris) 1996 ; 12 : 909-20.
- 4. Willecke K, Eiberger J, Degen J, et al. Structural and functional diversity of connexin genes in the mouse and human genome. J Biol Chem 2002 ; 383 : 725-37.
- 5. Mesnil M. Connexins and cancer. Biol Cell 2002 ; 94 : 493-500.
- 6. Loewenstein WR. Junctional intercellular communication and the control of growth. Biochim Biophys Acta 1979 ; 560 : 1-65.
- 7. Murray AW, Fitzgerald DJ. Tumor promoters inhibit metabolic cooperation in cocultures of epidermal and 3T3 cells. Biochem Biophys Res Comm 1979 ; 91 : 395-401.
- 8. Yotti LP, Chang CC, Trosko JE. Elimination of metabolic cooperation in Chinese hamster cells by a tumor promoter. Science 1979 ; 206 : 1089-91.
- 9. Yamasaki H, Naus CCG. Role of connexin genes in growth control. Carcinogenesis 1996 ; 17 : 1199-213.
- 10. Budunova IV, Williams GM. Cell culture assays for chemicals with tumor-promoting or tumor-inhibiting activity based on the modulation of intercellular communication. Cell Biol Toxicol 1994 ; 10: 71-116.
- 11. Paul DL. Molecular cloning of cDNA for rat liver gap junction protein. J Cell Biol 1986 ; 103: 123-34.
- 12. Beyer EC, Paul DL, Goodenough DA. Connexin 43 : a protein from rat heart homologous to a gap junction protein from liver. J Cell Biol 1987 ; 105 : 2621-9.
- 13. Zhang JT, Nicholson BJ. Sequence and tissue distribution of a second protein of hepatic gap junctions, Cx26, as deduced from its cDNA. J Cell Biol 1989 ; 109 : 3391-401.
- 14. Mesnil M, Krutovskikh V, Piccoli C, et al. Negative growth control of HeLa cells by connexin genes : connexin species specificity. Cancer Res 1995 ; 55 : 629-39.
- 15. Bond SL, Bechberger JF, Khoo NK, Naus CCG. Transfection of C6 glioma cells with connexin 32: the effects of expression of a nonendogenous gap junction protein. Cell Growth Differ 1994 ; 5 : 179-86.
- 16. Princen F, Robe P, Gros D, et al. Rat gap junction connexin-30 inhibits proliferation of glioma cell lines. Carcinogenesis 2001 ; 22 : 507-13.
- 17. Mesnil M, Yamasaki H. Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res 2000 ; 60 : 3989-99.
- 18. Goldberg GS, Lampe PD, Sheedy D, Stewart CC, Nicholson BJ, Naus CCG. Direct isolation and analysis of endogenous transjunctional ADP from Cx43-transfected C6 glioma cells. Exp Cell Res 1998 ; 239 : 82-92.
- 19. Saez JC, Connor JA, Spray DC, Bennett MVL. Hepatocyte gap junctions are permeable to the second messenger, inositol 1, 4, 5-triphosphate, and to calcium ions. Proc Natl Acad Sci USA 1989 ; 86 : 2708-12.
- 20. Elfgang C, Eckert R, Lichtenberg-Fraté H, et al. Specific permeability and selective formation of gap junction channels in connexin-transfected HeLa cells. J Cell Biol 1995 ; 129 : 805-17.
- 21. Kumar NM, Gilula NB. The gap junction communication channel. Cell 1996 ; 84 : 381-8.
- 22. Duflot-Dancer A, Mesnil M, Yamasaki H. Dominant-negative abrogation of connexin-mediated cell growth control by mutant connexin genes. Oncogene 1997 ; 15 : 2151-8.
- 23. De Feijter AW, Matesic DF, Ruch RJ, Guan X, Chang CC, Trosko JE. Localization and function of the connexin 43 gap-junction protein in normal and various oncogene-expressing rat liver epithelial cells. Mol Carcinogen 1996 ; 16 : 203-12.
- 24. Huang RP, Fan Y, Hossain MZ, Peng A, Zeng ZL, Boynton AL. Reversion of the neoplastic phenotype of human glioblastoma cells by connexin 43 (Cx43). Cancer Res 1998 ; 58 : 5089-96.
- 25. Hervé JC, Duthé F, Plaisance I, Bahbouhi B, Sarrouilhe D. The partner proteins of connexins on the track. Recent Res Dev Physiol 2003 ; 1: 103-17.
- 26. Trosko JE, Goodman JI. Intercellular communication may facilitate apoptosis: implications for tumor promotion. Mol Carcinogen 1994 ; 11 : 8-12.
- 27. Chen SC, Pelletier DB, Ao P, Boynton AL. Connexin 43 reverses the phenotype of transformed cells and alters their expression of cyclin/cyclin-dependent kinases. Cell Growth Differ 1995 ; 6 : 681-90.
- 28. Mesnil M, Piccoli C, Tiraby G, Willecke K, Yamasaki H. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc Natl Acad Sci USA 1996 ; 93 : 1831-5.
- 29. Klatzmann D, Valery CA, Bensimon G, et al. A phase I/II study of herpes simplex virus type1 thymidine kinase «suicide» gene therapy for recurrent glioblastoma. Study group on gene therapy for glioblastoma. Hum Gene Ther 1998 ; 9 : 2595-604.
- 30. Ram Z, Culver KW, Oshiro EM, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med 1997 ; 3 : 1354-61.
- 31. Mesnil M, Yamasaki H. La possibilité d’une thérapie génique antitumorale amplifiée par l’induction de la communication jonctionnelle intercellulaire. Med Sci(Paris) 1996 ; 12 : 1435-8.
- 32. Huang RP, Hossain MZ, Huang R, Gano J, Fan Y, Boynton AL. Connexin 43 (cx43) enhances chemotherapy-induced apoptosis in human glioblastoma cells. Int J Cancer 2001 ; 92 : 130-8.
- 33. King TJ, Fukushima LH, Hieber AD, Shimabukuro KA, Sakr WA, Bertram JS. Reduced levels of connexin 43 in cervical dysplasia: Inducible expression in a cervical carcinoma cell line decreases neoplastic potential with implications for tumor progression. Carcinogenesis 2000 ; 21 : 1097-109.
- 34. Dubina MV, Iatckii NA, Popov DE, Vasiliev SV, Krutovskikh VA. Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer. Oncogene 2002 ; 21 : 4992-6.
- 35. Krutovskikh V, Mazzoleni G, Mironov N, et al. Altered homologous and heterologous gap-junctional intercellular communication in primary human liver tumors associated with aberrant protein localization but not gene mutation of connexin 32. Int J Cancer 1994 ; 56 : 87-94.
- 36. Schneider B, Teschner M, Sudermann T, Pikula B, Lautermann J. Expression of gap junction proteins (connexin 26, 30, 32, 43) in normal mucosa, hyperkeratosis and carcinoma of the human larynx. J Otorhinolaryngol Relat Spec 2002 ; 64 : 324-9.
- 37. Mehta PP, Perez-Stable C, Nadji M, Mian M, Asotra K, Roos BA. Suppression of human prostate cancer cell growth by forced expression of connexin genes. Dev Genet 1999 ; 24 : 91-110.
- 38. Habermann H, Ray V, Habermann W, Prins GS. Alterations in gap junction protein expression in human benign prostatic hyperplasia and prostate cancer. J Urol 2002 ; 167 : 655-60.
- 39. Laird DW, Fistouris P, Batist G, et al. Deficiency of connexin 43 gap junctions is an independent marker for breast tumors. Cancer Res 1999; 59: 4104-10.
- 40. Al Moustafa AE, Alaoui-Jamali MA, Batist G, et al. Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells. Oncogene 2002 ; 21 : 2634-40.
- 41. Krutovskikh VA, Piccoli C, Yamasaki H. Gap junction intercellular communication propagates cell death in cancerous cells. Oncogene 2002 ; 27 : 1989-99.
- 42. Park JY, Elshami AA, Amin K, Rizk N, Kaiser LR, Albelda SM. Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy. Gene Ther 1997 ; 4 : 909-17.
- 43. Touraine RL, Ishii-Morita H, Ramsey WJ, Blaese RM. The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication. Gene Ther 1998 ; 5 : 1705-11.