Changes in gap junctional intercellular communication in mouse skin carcinogenesis

Gap junction intercellular communication (GJIC) has been measured in celllines that represent different stages of chemically induced mouse skincarcinogenesis. No significant difference in GJIC, as measured by dyespread, was found in cultures of normal keratinocyte, papilloma or squamouscarcinoma cell lines. There was no correlation, in this system, between thepresence of a mutant Ha-ras gene and down- regulation of communication.There was, however, a marked decrease in GJIC (80-90%) on progression fromsquamous to spindle carcinoma cells. Measurement of GJIC in somatic cellhybrids shows that the genetic defect responsible for this down-regulationis recessive and is common to two independently isolated spindle celllines. No abnormalities were found in the spindle cells in expression ofconnexin 43, a cell component involved in gap junction formation andpermeability. However, expression of E-cadherin, a cell-cell adhesionmolecule implicated in the process of gap junction formation, was missingin the spindle carcinoma cells. Introduction of an E-cadherin cDNA into thespindle cells partially restored junctional communication without causingany noticeable alterations in cell morphology. During the study a non-tumourigenic keratinocyte line, a sub-clone of a normal keratinocyte line,was also found to have a low level of GJIC. However, the defect in thisline was shown, by genetic complementation in somatic cell hybrids, to bedifferent from that in the spindle carcinoma cell lines. Consistent withthese data, analysis by immunofluorescence shows an abnormal distributionof connexin 43 in these cells.