Intercellular Communication and Cancer

  • Roobik Azarnia
  • William J. Larsen


Among the several different forms of cell interactions known to exist in multicellular organisms intercellular communication provides the most direct form of communication by allowing free exchange of ions and small molecules between neighboring cells via permeable membrane junctions. This type of communication has been implicated in various biological functions such as cell differentiation, embryonic development, and tissue growth regulation. In this chapter we will review highlights of functional and structural evidence of junctional communication in normal and cancerous tissues and discuss the existing hypotheses concerning the possible significance of cell junctions in cancer.


Granulosa Cell Intercellular Communication Septate Junction Ionic Coupling Membrane Junction 
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  1. Albertini, D. F., and Anderson, E., 1974, The appearance and structure of intercellular connections during the ontogeny of the rabbit ovarian follicle with particular reference to gap junctions, J. Cell Biol. 63:234.PubMedGoogle Scholar
  2. Albertini, D. F., Fawcett, D. W., and Olds, D. J., 1975, Morphological variations in gap junctions of ovarian granulosa cells, Tissue Cell 7:389.PubMedGoogle Scholar
  3. Anderson, W. B., Johnson, G. S., and Pastan, I., 1973a, Transformation of chick-embryo fibroblast by wild type and temperature sensitive Rous sarcoma virus alters adenylate cyclase activity, Proc. Nat. Acad. Sci. U.S.A. 70:1055.Google Scholar
  4. Anderson, W. B., Russell, T. R., Carchnan, R. A., and Pastan, I., 1973b, Interrelationship between adenylate cyclase activity, adenosine 3′,5′-cyclic monophosphate phosphodiesterase activity, adenosine 3′,5′-cyclic monophosphate levels, and growth of cells in culture, Proc. Nat. Acad. Sci. U.S.A. 70:3802.Google Scholar
  5. Azarnia, R., and Loewenstein, W. R., 1971, Intercellular communication and tissue growth. V. A cancer cell strain that fails to make permeable membrane junctions with normal cells, J. Membrane Biol. 6:368.Google Scholar
  6. Azarnia, R., and Loewenstein, W. R., 1973, Parallel correction of cancerous growth and of a genetic defect of cell-to-cell communication, Nature 241:455.PubMedGoogle Scholar
  7. Azarnia, R., Michalke, W., and Loewenstein, W. R., 1972, Intercellular communication and tissue growth. VI. Failure of exchange of endogenous molecules between cancer cells with defective junctions and non-cancerous cells, J. Membrane Biol. 10:247.Google Scholar
  8. Azarnia, R., Larsen, W. J., and Loewenstein, W. R., 1974, The membrane junctions in communicating and non-communicating cells, their hybrids, and segregants, Proc. NatAcad. Sci U.S.A. 71:880.Google Scholar
  9. Bannai, S., and Shepard, J. R., 1974, Cyclic AMP, ATP, and cell contact, Nature (London) 250:62.Google Scholar
  10. Bennett, M. V. L., 1973, Function of electrotonic junctions in embryonic and adult tissues,Fed. Proc. 32:65.PubMedGoogle Scholar
  11. Bennett, M. V. L., and Trinkaus, J. P., 1970, Electrical coupling between embryonic cells by way of extracellular space and specialized junctions, J. Cell Biol. 44:592.PubMedGoogle Scholar
  12. Bennett, M. V. L., Aljure, E., Nakajima, Y., and Pappas, G. D., 1963, Electrotonic junctions between teleost spinal neurons: Electrophysiology and ultrastructure, Science 141:262.PubMedGoogle Scholar
  13. Bennett, M. V. L., Pappas, G. D., Giminez, M., and Nakajima, Y., 1967, Physiology and ultrastructure of electrotonic junctions. IV. Medullary electromotor nuclei in Gymnotid fish, J. Neurophysiol. 30:209.PubMedGoogle Scholar
  14. Bennett, M. V. L., Spira, M., and Pappas, G. D., 1972, Properties of electrotonic junctions between embryonic cells of Fundulus, Dev. Biol. 29:419.Google Scholar
  15. Bergman, R. A., 1968, Uterine smooth muscle fibers in castrate and estrogen-treated rats, J. Cell Biol. 36:639.PubMedGoogle Scholar
  16. Bjersing, L., and Cajander, S., 1974, Ovulation and the mechanism of follicle rupture. IV. Ultrastructure of membrana granulosa of rabbit Graafian follicles prior to induced ovulation, Cell Tissue Res. 153:1.PubMedGoogle Scholar
  17. Borek, C., Higashino, S., and Loewenstein, W. R., 1969, Intercellular communication and tissue growth. IV. Conductance of membrane junctions of normal and cancerous cells in culture, J. Membrane Biol. 1:274.Google Scholar
  18. Bürk, R. R., 1968, Reduced adenylate cyclase activity in a polyoma virus transformed cell line, Nature (London) 219:1272.Google Scholar
  19. Caveney, S., and Podgorski, C., 1975, Intercellular communication in a positional field. Ultrastructural correlates and tracer analysis of communication between insect epidermal cells, Tissue Cell 7:559.PubMedGoogle Scholar
  20. Chalcroft, J. P., and Bullivant, S., 1970, An interpretation of liver cell membrane and junction structure based on observation of freeze fracture replicas of both sides of the structure, J. Cell Biol. 47:49.PubMedGoogle Scholar
  21. Cho-Chung, Y. S., and Gullino, P. M., 1974, In vivo inhibition of growth of two hormone-dependent mammary tumors by dibutyryl cyclic AMP, Science 183:87.PubMedGoogle Scholar
  22. Claude, P., and Goodenough, D. A., 1973, Fracture faces of zonulae occludentes from “tight” and “leaky” epithelia, J. Cell Biol. 58:390.PubMedGoogle Scholar
  23. Connell, C. J., 1976, Personal communication. Connell, C. J., and Christensen, A. K., 1975, The ultrastructure of the canine testicular interstitial tissue, Biol. Reprod. 12:368.PubMedGoogle Scholar
  24. D’Armiento, M., Johnson, G. S., and Pastan, I., 1973, Cyclic AMP and growth of fibroblasts: Effect of environmental pH, Nature New Biol. 242:78.PubMedGoogle Scholar
  25. Decker, R. S., and Friend, D., 1974, Assembly of gap junctions during amphibian neurulation, J. Cell Biol. 62:32.PubMedGoogle Scholar
  26. Dewey, M. M., and Barr, L., 1964, A study of the structure and distribution of the nexus, J. Cell Biol. 23:553.Google Scholar
  27. Enders, A. C., 1973, Cytology of the corpus luteum, Biol. Reprod. 8:158.PubMedGoogle Scholar
  28. Espey, L. L., and Stutts, R. H., 1972, Exchange of cytoplasm between cells of the membrane granulosa in rabbit ovarian follicles, Biol. Reprod. 6:168.PubMedGoogle Scholar
  29. Felix, E. L., Loyd, B., and Cohen, M. H., 1975, Inhibition of the growth and development of a transplantable murine melanoma by vitamin A, Science 189:886.PubMedGoogle Scholar
  30. Fisher, S. K., and Linberg, K. A., 1975, Intercellular junctions in the early human embryonic retina, J. Ultrastruct. Res. 51:69.PubMedGoogle Scholar
  31. Flaxman, B. A., and Cavoto, F. V., 1973, Low-resistance junctions in epithelial outgrowths from normal and cancerous epidermis in vitro, J. Cell Biol. 58:219.Google Scholar
  32. Furshpan, E. J., and Potter, D. D., 1959, Transmission at the giant motor synapses of the crayfish, J. Physiol. (London) 145:289.Google Scholar
  33. Furshpan, E. J., and Potter, D. D., 1968, Low resistance junctions between cells in embryos and tissue culture, in: Current Topics in Developmental Biology (A. A. Moscona and A. Monroy, eds.), Vol. 3, p. 95, Academic Press, New York.Google Scholar
  34. Garant, P. R., 1972, The demonstration of complex gap junctions between the cells of the enamel organ with lanthanum nitrate, J. Ultrastruct. Res. 40:333.PubMedGoogle Scholar
  35. Gilula, N. B., 1974, Junctions between cells, in: Cell Communication (R. P. Cox, ed.), pp. 1–29, Wiley, New York.Google Scholar
  36. Gilula, N. B., and Satir, P., 1971, Septate and gap junctions in molluscan gill epithelium, J. Cell Biol. 51:869.PubMedGoogle Scholar
  37. Gilula, N. B., Branton, D., and Satir, P., 1970, The septate junction: A structural basis for intercellular coupling, Proc. Nat. Acad. Sci. U.S.A. 67:213.Google Scholar
  38. Gilula, N. B., Reeves, O. R., and Steinbach, A., 1972, Metabolic coupling, ionic coupling and cell contacts, Nature (London) 235:262.Google Scholar
  39. Heidrick, M. L., and Ryan, W. L., 1971, Adenosine-3′,5′-cyclic monophosphate and contact inhibition, Cancer Res. 31:1313.PubMedGoogle Scholar
  40. Hsie, A. W., and Puck, T. T., 1971, Morphological transformation of Chinese hamster cells by dibutyryl adenosine cyclic 3′,5′-monophosphate and testosterone, Proc. Nat. Acad. Sci. U.S.A. 68:358.Google Scholar
  41. Hudspeth, A. J., and Revel, J. P., 1971, Coexistence of gap and septate junctions in an invertebrate epithelium, J. Cell Biol. 50:92.PubMedGoogle Scholar
  42. Hülser, D. F., and Webb, D. J., 1973, Relation between ionic coupling and morphology of established cells in culture, Exp. Cell Res. 80:210.PubMedGoogle Scholar
  43. Hyde, A., Blondel, B., Matter, A., Cheneval, J. P., Filions, B., and Girardier, L., 1969, Homo-and heterocellular junctions in cell cultures: An electrophysiological study, Prog. BrainRes. 31:282.Google Scholar
  44. Ito, S., and Hori, N., 1966, Electrical characteristics of triturus egg cells during cleavage, J. Gen. Physiol. 49:1019.PubMedGoogle Scholar
  45. Ito, S., and Loewenstein, W. R., 1969, Ionic communication between early embryonic cells,Dev. Biol. 19:228.PubMedGoogle Scholar
  46. Ito, S., Sato, E., and Loewenstein, W. R., 1974, Studies on the formation of a permeable cell membrane junction, J. Membrane Biol. 19:305.Google Scholar
  47. Jamakosmanovic, A., and Loewenstein, W. R., 1968, Intercellular communication and tissue growth. III. Thyroid cancer, J. Cell Biol. 38:556.PubMedGoogle Scholar
  48. Johnson, G. S., and Pastan, I., 1972, Role of 3′,5′-adenosine monophosphate in regulation of morphology and growth of transformed and normal fibroblasts, J. Nat. Cancer Inst. 48:1377.PubMedGoogle Scholar
  49. Johnson, R., and Sheridan, J. D., 1971, Junctions between cancer cells in culture: Ultrastructure and permeability, Science 174:717.PubMedGoogle Scholar
  50. Johnson, R. G., Hammer, M., Sheridan J. D., and Revel, J. P., 1974, Gap junction formation between reaggregated Novikoff hepatoma cells, Proc. Nat. Acad. Sci. U.S.A. 71:4536.Google Scholar
  51. Kanno, Y., and Loewenstein, W. R., 1966, Cell-to-cell passage of large molecules, Nature (London) 212:629.Google Scholar
  52. Kanno, Y., and Matsui, Y., 1968, Cellular uncoupling in cancerous stomach epithelium, Nature (London) 218:755.Google Scholar
  53. Kogon, M., and Pappas, G. D., 1975, Atypical gap junctions of the ciliary epithelium of the albino rabbit eye. J. Cell Biol. 66:671.PubMedGoogle Scholar
  54. Kolodney, G. M., 1971, Evidence for transfer of macromolecular RNA between mammalian cells in culture, Exp. Cell Res. 65:313.Google Scholar
  55. Larsen, W. J. 1973, Tracing cell-to-cell pathway with the electron microscope, 17th Annual Meeting of the Biophysical Society, Abstract.Google Scholar
  56. Larsen, W. J., 1975, Opaque deposits on gap junction membranes after glutaraldehydecalcium fixation, J. Cell Biol. 67:801.PubMedGoogle Scholar
  57. Larsen, W. J., and Azarnia, R., 1974, Unpublished observations.Google Scholar
  58. Letourneau, R. J., Li, J. J., Rosen, S., and Villee, C., 1975, Junctional specialization in estrogen-induced renal adenocarcinoma of the golden hamster, Cancer Res. 35:6.PubMedGoogle Scholar
  59. Lincoln, T. M., and Vaughan, G. L., 1974, A lesion in membrane adenylate cyclase affecting transformation in mouse melanoma cells, J. Cell Biol. 63:194 (Abstract).Google Scholar
  60. Locke, M., 1969, The ultrastructure of the oenocytes in the molt/intermolt cycle of an insect, Tissue Cell 1:103.PubMedGoogle Scholar
  61. Loewenstein, W. R., 1968, Communication through cell junctions. Implications in growth control and differentiation, Dev. Biol. 2 (Suppl.) 151.Google Scholar
  62. Loewenstein, W. R. 1974a, Intercellular communication through membrane junctions and cancer etiology, in: Membrane Transformations in Neoplasia (J. Schultz and R. E. Block, eds.), pp. 1–18, Academic Press, New York.Google Scholar
  63. Loewenstein, W. R., 1974b, Permeable junctions between cells, in: Cell Membranes (G. Weissmann and R. Claiborne, eds.), pp. 113–122, H. P. Publ. Co., New York.Google Scholar
  64. Loewenstein, W. R., and Kanno, Y., 1964, Studies on epithelial (gland) cell junction. I. Modifications of surface membrane permeability, J. Cell Biol. 22:565.PubMedGoogle Scholar
  65. Loewenstein, W. R., and Kanno, Y., 1966, Intercellular communication and the control of tissue growth. Lack of communication between cancer cells, Nature (London) 209:1248.Google Scholar
  66. Loewenstein, W. R., and Kanno, Y., 1967, Intercellular communication and tissue growth. I. Cancerous growth, J. Cell Biol. 33:225.PubMedGoogle Scholar
  67. Machen, T. E., Erlij, D., and Wooding, F. B. P., 1972, Permeable junctional complexes: The movement of lanthanum across rabbit gall bladder and intestine, J. Cell Biol. 54:302.PubMedGoogle Scholar
  68. Marsh, J. M., Mills, T. M., and Lemaire, W. J., 1973, Preovulatory changes in the synthesis of cyclic AMP by rabbit Graafian follicles, Biochim. Biophys. Acta 304:197.PubMedGoogle Scholar
  69. Martinez-Palomo, A., Braislovsky, C., and Bernhard, W., 1969, Ultrastructural modifications of the cell surface and intercellular contacts of some transformed cell strains, Cancer Res. 29:925.PubMedGoogle Scholar
  70. McNutt, N. S., and Weinstein, R. S., 1973, Membrane ultrastructure at mammalian intercellular junctions, in: Progress in Biophysics and Molecular Biology (J. A. Butler and D. Noble, eds.), Vol. 26, pp. 45–101, Pergamon Press, Oxford.Google Scholar
  71. McNutt, N. S., Hershberg, R. A., and Weinstein, R. S., 1971, Further observations on the occurence of nexuses in benign and malignant human cervical epithelium, J. Cell Biol. 51:805.PubMedGoogle Scholar
  72. Merk, F. B., Botticelli, C. R., and Albright, J. T., 1972, An intercellular response to estrogen by granulosa cells in the rat ovary: An electron microscopic study, Endocrinology 90:992.PubMedGoogle Scholar
  73. Merk, F. B., Albright, J. T., and Botticelli, C. R., 1973, The fine structure of granulosa cell nexuses in rat ovarian follicles, Anat. Rec. 175:107.PubMedGoogle Scholar
  74. Michalke, W., and Loewenstein, W. R., 1971, Communication between cells of different type, Nature (London) 232:121.Google Scholar
  75. Mukerjee, H., and Goldfeder, A., 1974, Adenylate cyclase activity in mouse tumors of diverse growth rates, J. Cell Biol. 63:235 (Abstract).Google Scholar
  76. O’Lague, P. O., and Dalen, H., 1974, Low resistance junctions between normal and between virus transformed fibroblasts in tissue culture, Exp. Cell Res. 86:374.PubMedGoogle Scholar
  77. Orwin, D. F. G., Thomson, R. W., and Flower, N. E., 1973, Plasma membrane differentiations of keratinizing cells of the wool follicle. I. Gap junctions, J. Ultrastruct. Res. 45:1.PubMedGoogle Scholar
  78. Otten, J., Johnson, G. S., and Pastan, I., 1971, Cyclic AMP levels in fibroblasts: Relationship to growth rate and contact inhibition of cell growth, Biochem. Biophys. Res. Commun. 44:1192.PubMedGoogle Scholar
  79. Pappas, G. D., 1975, Junctions between cells, in: Cell Membranes (G. Weissmann and R. Claiborne, eds.), pp. 87–94, H. P. Publ. Co., New York.Google Scholar
  80. Pappas, G. D, Asada, Y., and Bennett, M. V. L., 1971, Morphological correlates of increased coupling resistance at an electrotonic synapse, J. Cell Biol. 49:173.PubMedGoogle Scholar
  81. Payton, B. W., Bennett, M. V. L., and Pappas, G. D., 1969, Permeability and structure of junctional membranes at an electrotonic synapse, Science 166:1641.PubMedGoogle Scholar
  82. Penn, R. D., 1966, Ionic communication between liver cells, J. Cell Biol. 29:171.PubMedGoogle Scholar
  83. Peracchia, C., 1973, Low resistance junctions in the crayfish. II. Structural details and further evidence for intercellular channels by freeze fracture and negative staining, J. Cell Biol. 57:66.PubMedGoogle Scholar
  84. Peracchia, C., 1974, Excitable membrane ultrastructure. I. Freeze fracture of crayfish axons,J. Cell Biol. 61:107.PubMedGoogle Scholar
  85. Pickett, P. B., Pitelka, D. R., Hamamoto, S. T., and Misfelt, D. S., 1975, Occluding junctions and cell behavior in primary cultures of normal and neoplastic mammary gland cells, J. Cell Biol. 66:316.PubMedGoogle Scholar
  86. Pinto da Silva, P., and Gilula, N. B., 1972, Gap junctions in normal and transformed fibroblasts in culture, Exp. Cell Res. 71:393.Google Scholar
  87. Pinto da Silva, P., and Martinez-Palomo, A., 1975, Distribution of membrane particles and gap junctions in normal and transformed 3T3 cells studied in situ, in suspension, and treated with concanavalin A, Proc. Nat. Acad. Sci. U.S.A. 72:572.Google Scholar
  88. Potter, D. D., Furshpan, E. J., and Lennox, E. S., 1966, Connections between cells of the developing squid as revealed by electrophysiological methods, Proc. Nat. Acad. Sci. U.S.A. 55:328.Google Scholar
  89. Prutkin, L., 1975, Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, keratoacanthoma, Cancer Res. 35:364.PubMedGoogle Scholar
  90. Ramachandran, J., and Suyama, A. T., 1975, Inhibition of replication of normal adrenocortical cells in culture by adrenocorticotropin, Proc. Nat. Acad. Sci. U.S.A. 72:113.Google Scholar
  91. Revel, J. P., and Karnovsky, M. J., 1967, Hexagonal array of subunits in intercellular junctions of the mouse heart and liver, J. Cell Biol. 33:C7.PubMedGoogle Scholar
  92. Revel, J. P., Yee, A. G., and Hudspeth, A. J., 1971, Gap junctions between electrotonically coupled cells in tissue culture and brown fat, Proc. Nat. Acad. Sci. U.S.A. 68:2924.Google Scholar
  93. Robertson, J. D., 1963, The occurrence of a subunit pattern in the unit membranes of club endings in Mauthner cell synapses in goldfish brains, J. Cell Biol. 19:201.PubMedGoogle Scholar
  94. Robison, G. A., Butcher, R. W., and Sutherland, E. W., 1971, Cyclic AMP, Academic Press, New York.Google Scholar
  95. Rose, B., 1971, Intercellular communication and some structural aspects of membrane junctions in a simple cell system, J. Membrane Biol. 5:1.Google Scholar
  96. Satir, P., and Gilula, N. B., 1970, The cell junction in a Lamellibranch gill ciliated epithelium,J. Cell Biol. 47:468.PubMedGoogle Scholar
  97. Satir, P., and Gilula, N. B., 1973, The fine structure of membranes and intercellular communication in insects, Annu. Rev. Entomol. 18:143.PubMedGoogle Scholar
  98. Schwann, T., 1839, Mikroskopishe Untersuchugen über die Übereinstimmung, in der Strukturund dem Wachstum der Tiere und Pflanzen, G. E. Reimer, Berlin.Google Scholar
  99. Shepard, J. R., 1972, Difference in the cyclic adenosine 3′,5′-monophosphate levels in normal and transformed cells, Nature New Biol. 236:14.Google Scholar
  100. Sheridan, J. D., 1968, Electrophysiological evidence for low resistance intercellular junctions in the early chick embryo, J. Cell Biol. 37:650.PubMedGoogle Scholar
  101. Sheridan, J. D., 1970, Low resistance junctions between cancer cells in various solid tumors,J. Cell Biol. 45:91.PubMedGoogle Scholar
  102. Sheridan, J. D., 1971, Electrical coupling between fat cells in newt fat body and mouse brown fat,J. Cell Biol. 50:795.PubMedGoogle Scholar
  103. Simpson, I., 1975, Personal communication. Slack, C., and Palmer, J. P., 1969, The permeability of intercellular junctions in the early embryo of Xenopus laevis, studied with a fluorescent tracer, Exp. Cell Res. 55:416.Google Scholar
  104. Subak-Sharp, H., Bürk, R. R., and Pitts, J. D., 1969, Metabolic cooperation between biochemically marked mammalian cells in culture, J. Cell Biol. 4:353.Google Scholar
  105. Wade, J. B., and Karnovsky, M. J., 1974, Fracture faces of osmotically disrupted zonulae occludentes, J. Cell Biol. 62:344.PubMedGoogle Scholar
  106. Weidmann, S., 1952, The electrical constants of Purkinje fibers, J. Physiol. (London) 118:348.Google Scholar
  107. Weinstein, R. S., Merk, F. B., and Alroy, J., 1976, The structure and function of intercellular junctions in cancer, in: Advances in Cancer Research (G. Klein and S. Weinhouse, eds.), Vol. 23, pp. 23–89, Academic Press, New York.Google Scholar
  108. Wiener, J., Spiro, D., and Loewenstein, W. R., 1964, Studies on an epithelial (gland) cell junction. II. Surface structure, J. Cell Biol. 22:587.PubMedGoogle Scholar
  109. Wood, R. L., 1959, Intercellular attachment in the epithelium of Hydra as revealed by electron microscopy, J. Biophys. Biochem. Cytol. 6:343.PubMedGoogle Scholar
  110. Woodbury, J. W., and Crill, W. E., 1961, In:Nervous Inhibition (E. Florey, ed.), p. 124, Pergamon Press, Oxford.Google Scholar
  111. Yee, A. G., 1972, Gap junctions between hepatocytes in regenerating rat liver, J. Cell Biol. 55:294a (Abstract).Google Scholar
  112. Zamboni, L., 1974, Fine morphology of the follicle wall and follicle cell-oocyte association,Biol. Reprod. 10:125.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Roobik Azarnia
    • 1
  • William J. Larsen
    • 2
  1. 1.Department of Physiology and BiophysicsUniversity of Miami, School of MedicineMiamiUSA
  2. 2.Department of AnatomyThe University of Iowa, College of MedicineIowa CityUSA

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