Abstract
Calcium (Ca2+)-permeable channels are key players in different processes leading to blood vessel formation via sprouting angiogenesis, including endothelial cell (EC) proliferation and migration, as well as in controlling vascular features which are typical of the tumor vasculature.
In this review we present an up-to-date and critical view on the role of Ca2+-permeable channels in tumor vascularization, emphasizing on the dual communication between growth factors (mainly VEGF) and Ca2+ signals. Due to the complexity of the tumor microenvironment (TME) as a source of multiple stimuli acting on the endothelium, we aim to discuss the close interaction between chemical and physical challenges (hypoxia, oxidative stress, mechanical stress) and endothelial Ca2+-permeable channels, focusing on transient receptor potential (TRP), store-operated Ca2+ channels (SOCs), and mechanosensitive Piezo channels. This approach will depict their crucial contribution in regulating key properties of tumor blood vessels, such as recruitment of endothelial progenitors cells (EPCs) in the early steps of tumor vascularization, abnormal EC migration and proliferation, and increased vascular permeability.
Graphical Abstract
Graphical abstract depicting the functional role of Ca2+-permeable TRP, SOCs and Piezo channels in the biological processes regulating tumor angiogenesis in presence of both chemical (oxidative stress and oxygen levels) and mechanical stimuli (ECM stiffness). SOCs store-operated Ca2+ channels, TRPA transient receptor potential ankyrin, TRPV transient receptor potential vanilloid, TRPC transient receptor potential canonical, TRPM transient receptor potential melastatin, TRPM transient receptor potential vanilloid, O2 oxygen, ECM extracellular matrix.
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Acknowledgment
AFP, LM, and GS are supported by grants from the University of Torino and Italian Ministry of Instruction, University and Research (MIUR), PRIN grant “Leveraging basic knowledge of ion channel network in cancer for innovative therapeutic strategies (LIONESS)” (grant number 20174TB8KW); AFP is part of the Marie Curie ITN “pH and Ion Transport in Pancreatic Cancer (pHioniC)”- H2020-MSCA-ITN-2018 (Grant Agreement number: 813834). ARC is supported by European Regional Development Fund (FEDER), La Ligue Contre le Cancer (Pas de Calais), and Agence Nationale de la Recherche, Investissements d’avenir (ANR-16-IDEX-004-ULNE). The authors declare no conflict of interests. All authors read and approved the final version of the manuscript.
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Scarpellino, G., Munaron, L., Cantelmo, A.R., Fiorio Pla, A. (2020). Calcium-Permeable Channels in Tumor Vascularization: Peculiar Sensors of Microenvironmental Chemical and Physical Cues. In: Stock, C., Pardo, L.A. (eds) From Malignant Transformation to Metastasis. Reviews of Physiology, Biochemistry and Pharmacology, vol 182. Springer, Cham. https://doi.org/10.1007/112_2020_32
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