Ca2+ channels toolkit in Neuroendocrine tumors

Neuroendocrine tumors (NET) constitute an heterogenous group of malignancies with various clinical presentations and growth rates but all rising from neuroendocrine cells located all over the body. NET present a relatively low frequency disease being mostly represented by gastroenteropancreatic (GEP) and bronchopulmonary tumors (pNET); on the other hand an increasing frequency and prevalence has been associated to NET. Beside the great effort of the latest years, management of NET is still a critical unmet point due to the lack in the knowledge of the biology of the disease, lack of adequate biomarkers, late presentation, the relative insensitivity of imaging modalities and a paucity of predictably effective treatment options. In this context Ca2+ signals, being pivotal molecular devices in sensing and integrating signals from the microenvironment, are emerging to be particularly relevant in cancer, where they mediate interactions between tumor cells and the tumor microenvironment to drive different aspects of neoplastic progression (e.g. cell proliferation and survival, cell invasiveness and pro-angiogenetic programs). Indeed, ion channels represent good potential pharmacological targets due to their location on the plasma membrane, where they can be easily accessed by drugs. The present review aims to provide a critical and up to date overview on NET development integrating Ca2+ signals involvement. In this perspective, we first give an introduction to NET and Ca2+ channels and then describe the different families of Ca2+ channels implicated in NET, namely ionotropic receptors, voltage-dependent Ca2+ channels, Transient Receptor Potential channels as well as intracellular Ca2+ channels and their signaling molecules.