Ion channels and transporters in cancer. 3. Ion channels in the tumor cell-microenvironment cross talk.

The traditional view of cancer as a collection of proliferating cells must be reconsidered, and cancer must be viewed as a “tissue” constituted by both transformed cells and a heterogeneous microenvironment, that tumor cells construct and remodel during multistep tumorigenesis. The “tumor microenvironment” (TM) is formed by mesenchymal, endothelial, and immune cells immersed in a network of extracellular matrix (ECM) proteins and soluble factors. The TM strongly contributes to tumor progression, through long distance, cell-to-cell or cell-to-matrix signals, which influence different aspects of tumor cell behavior. Understanding the relationships among the different components of the cancer tissue is crucial to design and develop new therapeutic strategies. Ion channels are emerging as relevant players in the cross talk between tumor cells and their TM. Ion channels are expressed on tumor cells, as well as in the different cellular components of the TM. In all these cells, ion channels are in a strategic position to sense and transmit extracellular signals into the intracellular machinery. Often, this transmission is mediated by integrin adhesion receptors, which can be functional partners of ion channels since they form molecular complexes with the channel protein in the context of the plasma membrane. The same relevant role is exerted by ion transporters, which also contribute to determine two facets of the cancer tissue: hypoxia and the acidic extracellular pH. On the whole, it is conceivable to prospect the targeting of ion channels for new therapeutic strategies aimed at better controlling the malignant progression of the cancer tissue.