Adhesion-mediated signalling in cancer: Recent advances and mathematical modelling

Cancer can be viewed as a "tissue", where neoplastic cells are immersed into a peculiar microenvironment (the "tumor microenvironment", TME) which modulates tumor cell behaviour during multistep tumorigenesis. Based on this concept, antineoplastic therapy should be tuned to target not only tumor cells but also the cellular constituents of the TME. Such necessity is well exemplified by considering tumor angiogenesis, a major aspect of cancer biology. Ion channels and transporters are increasingly recognized as relevant players in the tumor cell-TME cross-talk. For example, during tumor neo-angiogenesis, soluble factors as well as fixed components of the extracellular matrix (ECM) and membrane proteins determine signal exchange between the TME and the implicated cell types. The signalling network is coordinated by functional "hubs", which may be constituted by integrin receptors associated with other proteins to form macromolecular signalling platforms at the adhesive sites. These complexes often include ion channels. The K+ channels encoded by the human ether-à-go-go related gene (Kv11.1, or hERG1) are frequently overexpressed in human cancers and regulate intracellular signalling by physically associating with integrin subunits and growth factor/chemokine receptors. In colorectal cancer (CRC) we recently identified a novel signalling pathway centered on hERG1 channels and integrins. This pathway involves the p53 protein, which is encoded by a tumor suppressor gene often mutated in human cancers. p53 controls angiogenesis, through a mechanism regulated by hERG1 K+ channels. The central role played by hERG1 in CRC angiogenesis suggests that targeting hERG1 may be an effective therapeutic option in patients with advanced CRC. To better understand the above process, it is necessary to study the interlaced dynamics of the key microscopic actors by using dedicated mathematical models. We here review a simple model, of reductionist inspiration, that explores the intimate connections between apoptosis and hypoxia, passing through angiogenesis. We show that a dynamical switch takes place between the normoxia and cellular death conditions. When oxygen lacks, cells can cross the transition line and so gain their way towards the normoxia regime, by implementing point mutations that affect the p53 production and activation rate, with the involvement of K+ ion homeostasis, in agreement with the experimental observations.