Chapter 5 │ Page 168 carcinomas (SCC), which facilitated invasion and metastasis [76]. The authors found that Cx26-positive lung SCC cells were specifically located facing the tumor stroma or fibrous capsule, and the ratio of Cx26-positive over Cx26-negative cancer cells was significantly higher in metastatic lesions, compared to the corresponding primary tumor. Moreover, in these cancer cells, Cx26 proteins were preferentially localized on the plasma membrane, and could form Cx26-GJs between lung SCC cells and normal lung cells [76]. This heterologous communication between malignant and normal cells via GJs was also reported by others; Zhang et al. demonstrated dye transfer between lung cancer cells and normal lung fibroblasts via GJs formation. GJs formation allowed the sharing of metabolites to initiate metastasis, although coupling levels may need to exceed a certain threshold to allow propagation of signals over a su icient distance to a ect the behavior of a cell population [77]. Likewise, more in-depth studies detected coupling between melanoma and endothelial cells via homologous [78] and heterologous [79] Cx26-GJs, which contributed to the intravasation and extravasation of melanoma cells during the metastatic process [78,79]. Conversely, inhibition of Cx26 proteins rendered the tumor cells deficient in Cx26-GJs formation and reduced their metastatic potential [79]. Overexpression of Cx32 proteins in normal and metastatic breast cancer cells led to a more mesenchymal-like phenotype [80]. Adak and co-workers reported an increased migratory capacity of healthy breast cells, while mesenchymal markers, including vimentin, were further upregulated in the metastatic counterpart, thus presenting, for the first time, the metastasis-stimulating properties of the Cx32 protein in breast cancer [80]. Heterologous Cx43 protein-composed GJs (Cx43-GJs) have also been linked to the initiation of brain metastatic lesions from both melanoma and breast cancer. Depletion of Cx43 proteins or pharmacological blocking of the Cx43-GJ coupling inhibited brain colonization via blocking of tumor cell extravasation and blood vessel co-option, a non-angiogenic mechanism of
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