Melanoma's connections to the tumour microenvironment.

Melanoma cells interact with and depend on seemingly normal cells in their tumour microenvironment to allow the acquisition of the hallmarks of solid cancer. In general, there are three types of interaction of melanoma cells with their microenvironment. First, there is bilateral communication between melanoma cells and the stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix. Second, while under normal conditions keratinocytes control localisation and proliferative behaviour of melanocytes in the epidermis, once this balance is disturbed and a melanoma has developed, melanoma cells may take over the control of their epidermal tumour microenvironment. Finally, there are subcompartments within tumours with different microenvironmental milieu defined by their access to oxygen and nutrients. Therefore, different melanoma cells within a tumour face different microenvironments. Interactions between melanoma cells among each other and with the cell types in their microenvironment happen through endocrine and paracrine communication and/or through direct contact via cell-cell and cell-matrix adhesion, and gap junctional intercellular communication (GJIC). Connexins have been identified as key molecules for direct cell-cell communication and are also thought to be important for the release of signalling molecules from cells to the microenvironment. In this review we provide an update of the alterations in cell-cell communication in melanoma and the tumour microenvironment associated with melanoma development and progression.