The dysfunction of homologous and/or heterologous gap junctional intercellular communication (GJIC) has been implicated in
tumorigenesis of many kinds of cells. Here we have characterized GJIC and the expression of
connexins in six human lung
carcinoma cell lines and normal lung fibroblasts (HLF). Compared with HLF, all the
carcinoma cells showed reduced or little homologous GJIC. They expressed remarkably reduced
connexin(Cx)43
mRNA and variable levels of Cx45
mRNA, but neither
Cx43 nor Cx45
protein could be detected. However, using a preloading assay, transfer of
calcein was observed between donor HLF cells and first order neighboring recipient
tumor cells (recipient cells in 1000-fold excess). Transfer from
tumor to HLF cells under the same conditions was not seen, although increasing the ratio of donor
tumor cells to recipient HLF cells and plating the cells at low density did reveal weak transfer from
tumor cells to HLF. Transfection of
Cx43 into
giant cell carcinoma PG cells increased homologous communication and eliminated the rectifying behavior of heterologous communication. This indicates that the apparent rectification of
dye transfer between normal and
tumor cells was a product of low rates of heterologous transfer linked to (i) rapid dilution of the
dye to below detectable limits through a very well coupled cell population (
tumor to HLF) and (ii) concentration of
dye in immediate neighbors in a poorly coupled cell population (HLF to
tumor cells). These results suggest that the coupling levels may need to exceed a certain threshold to allow propagation of signals over a sufficient distance to affect behavior of a cell population. We propose that the relative rates of heterologous and homologous coupling of cell populations and the 'pool size' of shared metabolites in
tumor cells and the surrounding normal tissue are likely to be very important in the regulation of their growth.