Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1991 Jun;93:191–197. doi: 10.1289/ehp.9193191

Aberrant expression and function of gap junctions during carcinogenesis.

H Yamasaki 1
PMCID: PMC1568039  PMID: 1663449

Abstract

Gap junctional intercellular communication plays a key role in the maintenance of homeostasis in multicellular organisms. Reflecting deranged homeostasis in cancer cells, most transformed or cancerous cells show aberrant gap junctional intercellular communication; they have decreased junctional communication between each other and/or with surrounding normal cells. Studies with in vitro cell transformation and animal carcinogenesis models suggest an involvement of blocked intercellular communication in later stages of carcinogenesis. Analysis of expression of gap junction proteins (connexins) and corresponding mRNA indicates that a number of regulation sites are involved in aberrant function of gap junctions during carcinogenesis. Suppression of transformed phenotypes is often seen when transformed cells are physically in contact with their normal counterparts. Some studies suggest that gap junctional intercellular communication is involved in such tumor suppression.

Full text

PDF
191

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atkinson M. M., Menko A. S., Johnson R. G., Sheppard J. R., Sheridan J. D. Rapid and reversible reduction of junctional permeability in cells infected with a temperature-sensitive mutant of avian sarcoma virus. J Cell Biol. 1981 Nov;91(2 Pt 1):573–578. doi: 10.1083/jcb.91.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Azarnia R., Loewenstein W. R. Intercellular communication and the control of growth: X. Alteration of junctional permeability by the src gene. A study with temperature-sensitive mutant Rous sarcoma virus. J Membr Biol. 1984;82(3):191–205. doi: 10.1007/BF01871629. [DOI] [PubMed] [Google Scholar]
  3. Azarnia R., Loewenstein W. R. Polyomavirus middle T antigen downregulates junctional cell-to-cell communication. Mol Cell Biol. 1987 Feb;7(2):946–950. doi: 10.1128/mcb.7.2.946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Azarnia R., Reddy S., Kmiecik T. E., Shalloway D., Loewenstein W. R. The cellular src gene product regulates junctional cell-to-cell communication. Science. 1988 Jan 22;239(4838):398–401. doi: 10.1126/science.2447651. [DOI] [PubMed] [Google Scholar]
  5. Beer D. G., Neveu M. J., Paul D. L., Rapp U. R., Pitot H. C. Expression of the c-raf protooncogene, gamma-glutamyltranspeptidase, and gap junction protein in rat liver neoplasms. Cancer Res. 1988 Mar 15;48(6):1610–1617. [PubMed] [Google Scholar]
  6. Bertram J. S., Faletto M. B. Requirements for and kinetics of growth arrest of neoplastic cells by confluent 10T1/2 fibroblasts induced by a specific inhibitor of cyclic adenosine 3':5'-phosphodiesterase. Cancer Res. 1985 May;45(5):1946–1952. [PubMed] [Google Scholar]
  7. Beyer E. C., Paul D. L., Goodenough D. A. Connexin43: a protein from rat heart homologous to a gap junction protein from liver. J Cell Biol. 1987 Dec;105(6 Pt 1):2621–2629. doi: 10.1083/jcb.105.6.2621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bignami M., Rosa S., Falcone G., Tató F., Katoh F., Yamasaki H. Specific viral oncogenes cause differential effects on cell-to-cell communication, relevant to the suppression of the transformed phenotype by normal cells. Mol Carcinog. 1988;1(1):67–75. doi: 10.1002/mc.2940010113. [DOI] [PubMed] [Google Scholar]
  9. Boreiko C. J., Abernethy D. J., Sanchez J. H., Dorman B. H. Effect of mouse skin tumor promoters upon [3H]uridine exchange and focus formation in cultures of C3H/10T1/2 mouse fibroblasts. Carcinogenesis. 1986 Jul;7(7):1095–1099. doi: 10.1093/carcin/7.7.1095. [DOI] [PubMed] [Google Scholar]
  10. Boreiko C. J., Abernethy D. J., Sanchez J. H., Dorman B. H. Effect of mouse skin tumor promoters upon [3H]uridine exchange and focus formation in cultures of C3H/10T1/2 mouse fibroblasts. Carcinogenesis. 1986 Jul;7(7):1095–1099. doi: 10.1093/carcin/7.7.1095. [DOI] [PubMed] [Google Scholar]
  11. Chang C. C., Trosko J. E., Kung H. J., Bombick D., Matsumura F. Potential role of the src gene product in inhibition of gap-junctional communication in NIH/3T3 cells. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5360–5364. doi: 10.1073/pnas.82.16.5360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dotto G. P., Weinberg R. A., Ariza A. Malignant transformation of mouse primary keratinocytes by Harvey sarcoma virus and its modulation by surrounding normal cells. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6389–6393. doi: 10.1073/pnas.85.17.6389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Enomoto T., Yamasaki H. Lack of intercellular communication between chemically transformed and surrounding nontransformed BALB/c 3T3 cells. Cancer Res. 1984 Nov;44(11):5200–5203. [PubMed] [Google Scholar]
  14. Enomoto T., Yamasaki H. Phorbol ester-mediated inhibition of intercellular communication in BALB/c 3T3 cells: relationship to enhancement of cell transformation. Cancer Res. 1985 Jun;45(6):2681–2688. [PubMed] [Google Scholar]
  15. Falcone G., Summerhayes I. C., Paterson H., Marshall C. J., Hall A. Partial transformation of mouse fibroblastic and epithelial cell lines with the v-myc oncogene. Exp Cell Res. 1987 Jan;168(1):273–284. doi: 10.1016/0014-4827(87)90435-6. [DOI] [PubMed] [Google Scholar]
  16. Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  17. Fentiman I. S., Hurst J., Ceriani R. L., Taylor-Papadimitriou J. Junctional intercellular communication pattern of cultured human breast cancer cells. Cancer Res. 1979 Nov;39(11):4739–4743. [PubMed] [Google Scholar]
  18. Fitzgerald D. J., Mesnil M., Oyamada M., Tsuda H., Ito N., Yamasaki H. Changes in gap junction protein (connexin 32) gene expression during rat liver carcinogenesis. J Cell Biochem. 1989 Oct;41(2):97–102. doi: 10.1002/jcb.240410206. [DOI] [PubMed] [Google Scholar]
  19. Frixen U., Yamasaki H. Enhancement of transformation and continuous inhibition of intercellular communication by 1-oleoyl-2-acetyl glycerol in BALB/c 3T3 cells. Carcinogenesis. 1987 Aug;8(8):1101–1104. doi: 10.1093/carcin/8.8.1101. [DOI] [PubMed] [Google Scholar]
  20. Gainer H. S., Murray A. W. Diacylglycerol inhibits gap junctional communication in cultured epidermal cells: evidence for a role of protein kinase C. Biochem Biophys Res Commun. 1985 Feb 15;126(3):1109–1113. doi: 10.1016/0006-291x(85)90300-6. [DOI] [PubMed] [Google Scholar]
  21. Goodenough D. A., Paul D. L., Jesaitis L. Topological distribution of two connexin32 antigenic sites in intact and split rodent hepatocyte gap junctions. J Cell Biol. 1988 Nov;107(5):1817–1824. doi: 10.1083/jcb.107.5.1817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hamel E., Katoh F., Mueller G., Birchmeier W., Yamasaki H. Transforming growth factor beta as a potent promoter in two-stage BALB/c 3T3 cell transformation. Cancer Res. 1988 May 15;48(10):2832–2836. [PubMed] [Google Scholar]
  23. Herschman H. R., Brankow D. W. Ultraviolet irradiation transforms C3H10T1/2 cells to a unique, suppressible phenotype. Science. 1986 Dec 12;234(4782):1385–1388. doi: 10.1126/science.3787250. [DOI] [PubMed] [Google Scholar]
  24. Janssen-Timmen U., Traub O., Dermietzel R., Rabes H. M., Willecke K. Reduced number of gap junctions in rat hepatocarcinomas detected by monoclonal antibody. Carcinogenesis. 1986 Sep;7(9):1475–1482. doi: 10.1093/carcin/7.9.1475. [DOI] [PubMed] [Google Scholar]
  25. Kanno Y., Matsui Y. Cellular uncoupling in cancerous stomach epithelium. Nature. 1968 May 25;218(5143):775–776. doi: 10.1038/218775b0. [DOI] [PubMed] [Google Scholar]
  26. Katoh F., Fitzgerald D. J., Giroldi L., Fujiki H., Sugimura T., Yamasaki H. Okadaic acid and phorbol esters: comparative effects of these tumor promoters on cell transformation, intercellular communication and differentiation in vitro. Jpn J Cancer Res. 1990 Jun-Jul;81(6-7):590–597. doi: 10.1111/j.1349-7006.1990.tb02614.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Klann R. C., Fitzgerald D. J., Piccoli C., Slaga T. J., Yamasaki H. Gap-junctional intercellular communication in epidermal cell lines from selected stages of SENCAR mouse skin carcinogenesis. Cancer Res. 1989 Feb 1;49(3):699–705. [PubMed] [Google Scholar]
  28. Kumar N. M., Gilula N. B. Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein. J Cell Biol. 1986 Sep;103(3):767–776. doi: 10.1083/jcb.103.3.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lawrence T. S., Beers W. H., Gilula N. B. Transmission of hormonal stimulation by cell-to-cell communication. Nature. 1978 Apr 6;272(5653):501–506. doi: 10.1038/272501a0. [DOI] [PubMed] [Google Scholar]
  30. Loewenstein W. R. Junctional intercellular communication and the control of growth. Biochim Biophys Acta. 1979 Feb 4;560(1):1–65. doi: 10.1016/0304-419x(79)90002-7. [DOI] [PubMed] [Google Scholar]
  31. Loewenstein W. R., Kanno Y. Intercellular communication and the control of tissue growth: lack of communication between cancer cells. Nature. 1966 Mar 19;209(5029):1248–1249. doi: 10.1038/2091248a0. [DOI] [PubMed] [Google Scholar]
  32. Loewenstein W. R., Kanno Y. Intercellular communication and tissue growth. I. Cancerous growth. J Cell Biol. 1967 May;33(2):225–234. doi: 10.1083/jcb.33.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mege R. M., Matsuzaki F., Gallin W. J., Goldberg J. I., Cunningham B. A., Edelman G. M. Construction of epithelioid sheets by transfection of mouse sarcoma cells with cDNAs for chicken cell adhesion molecules. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7274–7278. doi: 10.1073/pnas.85.19.7274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mehta P. P., Bertram J. S., Loewenstein W. R. Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell. 1986 Jan 17;44(1):187–196. doi: 10.1016/0092-8674(86)90497-6. [DOI] [PubMed] [Google Scholar]
  35. Mehta P. P., Bertram J. S., Loewenstein W. R. The actions of retinoids on cellular growth correlate with their actions on gap junctional communication. J Cell Biol. 1989 Mar;108(3):1053–1065. doi: 10.1083/jcb.108.3.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mesnil M., Montesano R., Yamasaki H. Intercellular communication of transformed and non-transformed rat liver epithelial cells. Modulation by TPA. Exp Cell Res. 1986 Aug;165(2):391–402. doi: 10.1016/0014-4827(86)90593-8. [DOI] [PubMed] [Google Scholar]
  37. Mesnil M., Yamasaki H. Selective gap-junctional communication capacity of transformed and non-transformed rat liver epithelial cell lines. Carcinogenesis. 1988 Aug;9(8):1499–1502. doi: 10.1093/carcin/9.8.1499. [DOI] [PubMed] [Google Scholar]
  38. Milks L. C., Kumar N. M., Houghten R., Unwin N., Gilula N. B. Topology of the 32-kd liver gap junction protein determined by site-directed antibody localizations. EMBO J. 1988 Oct;7(10):2967–2975. doi: 10.1002/j.1460-2075.1988.tb03159.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Murray A. W., Fitzgerald D. J. Tumor promoters inhibit metabolic cooperation in cocultures of epidermal and 3T3 cells. Biochem Biophys Res Commun. 1979 Nov 28;91(2):395–401. doi: 10.1016/0006-291x(79)91535-3. [DOI] [PubMed] [Google Scholar]
  40. Oyamada M., Krutovskikh V. A., Mesnil M., Partensky C., Berger F., Yamasaki H. Aberrant expression of gap junction gene in primary human hepatocellular carcinomas: increased expression of cardiac-type gap junction gene connexin 43. Mol Carcinog. 1990;3(5):273–278. doi: 10.1002/mc.2940030507. [DOI] [PubMed] [Google Scholar]
  41. Paul D. L. Molecular cloning of cDNA for rat liver gap junction protein. J Cell Biol. 1986 Jul;103(1):123–134. doi: 10.1083/jcb.103.1.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pitts J. D., Finbow M. E. The gap junction. J Cell Sci Suppl. 1986;4:239–266. doi: 10.1242/jcs.1986.supplement_4.15. [DOI] [PubMed] [Google Scholar]
  43. Rosen A., van der Merwe P. A., Davidson J. S. Effects of SV40 transformation on intercellular gap junctional communication in human fibroblasts. Cancer Res. 1988 Jun 15;48(12):3485–3489. [PubMed] [Google Scholar]
  44. Sivak A., Van Duuren B. L. Phenotypic expression of transformation: induction in cell culture by a phorbol ester. Science. 1967 Sep 22;157(3795):1443–1444. doi: 10.1126/science.157.3795.1443. [DOI] [PubMed] [Google Scholar]
  45. Small M. B., Hay N., Schwab M., Bishop J. M. Neoplastic transformation by the human gene N-myc. Mol Cell Biol. 1987 May;7(5):1638–1645. doi: 10.1128/mcb.7.5.1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Stoker M. G. Transfer of growth inhibition between normal and virus-transformed cells: autoradiographic studies using marked cells. J Cell Sci. 1967 Sep;2(3):293–304. doi: 10.1242/jcs.2.3.293. [DOI] [PubMed] [Google Scholar]
  47. Streuli M., Krueger N. X., Tsai A. Y., Saito H. A family of receptor-linked protein tyrosine phosphatases in humans and Drosophila. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8698–8702. doi: 10.1073/pnas.86.22.8698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Swenson K. I., Jordan J. R., Beyer E. C., Paul D. L. Formation of gap junctions by expression of connexins in Xenopus oocyte pairs. Cell. 1989 Apr 7;57(1):145–155. doi: 10.1016/0092-8674(89)90180-3. [DOI] [PubMed] [Google Scholar]
  49. Sáez J. C., Connor J. A., Spray D. C., Bennett M. V. Hepatocyte gap junctions are permeable to the second messenger, inositol 1,4,5-trisphosphate, and to calcium ions. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2708–2712. doi: 10.1073/pnas.86.8.2708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Takeda A., Hashimoto E., Yamamura H., Shimazu T. Phosphorylation of liver gap junction protein by protein kinase C. FEBS Lett. 1987 Jan 5;210(2):169–172. doi: 10.1016/0014-5793(87)81330-3. [DOI] [PubMed] [Google Scholar]
  51. Terzaghi-Howe M. Inhibition of carcinogen-altered rat tracheal epithelial cell proliferation by normal epithelial cells in vivo. Carcinogenesis. 1987 Jan;8(1):145–150. doi: 10.1093/carcin/8.1.145. [DOI] [PubMed] [Google Scholar]
  52. Vanhamme L., Rolin S., Szpirer C. Inhibition of gap-junctional intercellular communication between epithelial cells transformed by the activated H-ras-1 oncogene. Exp Cell Res. 1989 Jan;180(1):297–301. doi: 10.1016/0014-4827(89)90234-6. [DOI] [PubMed] [Google Scholar]
  53. Yamasaki H., Enomoto T., Martel N., Shiba Y., Kanno Y. Tumour promoter-mediated reversible inhibition of cell-cell communication (electrical coupling). Relationship with phorbol ester binding and de novo macromolecule synthesis. Exp Cell Res. 1983 Jul;146(2):297–308. doi: 10.1016/0014-4827(83)90132-5. [DOI] [PubMed] [Google Scholar]
  54. Yamasaki H., Enomoto T., Shiba Y., Kanno Y., Kakunaga T. Intercellular communication capacity as a possible determinant of transformation sensitivity of BALB/c 3T3 clonal cells. Cancer Res. 1985 Feb;45(2):637–641. [PubMed] [Google Scholar]
  55. Yamasaki H., Hollstein M., Mesnil M., Martel N., Aguelon A. M. Selective lack of intercellular communication between transformed and nontransformed cells as a common property of chemical and oncogene transformation of BALB/c 3T3 cells. Cancer Res. 1987 Nov 1;47(21):5658–5664. [PubMed] [Google Scholar]
  56. Yamasaki H., Katoh F. Further evidence for the involvement of gap-junctional intercellular communication in induction and maintenance of transformed foci in BALB/c 3T3 cells. Cancer Res. 1988 Jun 15;48(12):3490–3495. [PubMed] [Google Scholar]
  57. Yotti L. P., Chang C. C., Trosko J. E. Elimination of metabolic cooperation in Chinese hamster cells by a tumor promoter. Science. 1979 Nov 30;206(4422):1089–1091. doi: 10.1126/science.493994. [DOI] [PubMed] [Google Scholar]
  58. Zampighi G., Unwin P. N. Two forms of isolated gap junctions. J Mol Biol. 1979 Dec 5;135(2):451–464. doi: 10.1016/0022-2836(79)90446-7. [DOI] [PubMed] [Google Scholar]
  59. Zhang J. T., Nicholson B. J. Sequence and tissue distribution of a second protein of hepatic gap junctions, Cx26, as deduced from its cDNA. J Cell Biol. 1989 Dec;109(6 Pt 2):3391–3401. doi: 10.1083/jcb.109.6.3391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. el Aoumari A., Fromaget C., Dupont E., Reggio H., Durbec P., Briand J. P., Böller K., Kreitman B., Gros D. Conservation of a cytoplasmic carboxy-terminal domain of connexin 43, a gap junctional protein, in mammal heart and brain. J Membr Biol. 1990 May;115(3):229–240. doi: 10.1007/BF01868638. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES