U1003-PHYCEL-Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d'Ascq, 59000 Lille, France.
Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy.
Int J Mol Sci. 2022 Jul 2;23(13):7377. doi: 10.3390/ijms23137377.
Solid tumours are characterised by an altered microenvironment (TME) from the physicochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hypoxia results from uncontrolled proliferation, aberrant vascularization and altered cancer cell metabolism. Tumour cellular apparatus adapts to hypoxia by altering its metabolism and behaviour, increasing its migratory and metastatic abilities by the acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance via the selection of more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca channels represent good target candidates due to their ability to integrate signals from the TME. Ca channels are pH and hypoxia sensors and alterations in Ca homeostasis in cancer progression and vascularization have been extensively reported. In the present review, we present an up-to-date and critical view on Ca permeable ion channels, with a major focus on TRPs, SOCs and PIEZO channels, which are modulated by tumour hypoxia and acidosis, as well as the consequent role of the altered Ca signals on cancer progression hallmarks. We believe that a deeper comprehension of the Ca signalling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutic targets.
实体瘤的微环境（TME）从物理化学角度来看发生了改变，表现出高度缺氧和酸性的细胞间质液。缺氧是由于不受控制的增殖、异常的血管生成和癌细胞代谢改变引起的。肿瘤细胞通过改变其代谢和行为来适应缺氧，通过获得间充质表型和选择侵袭性肿瘤细胞克隆来增加其迁移和转移能力。细胞外酸中毒被认为是癌症的一个标志，通过促进肿瘤转移和化疗耐药性来推动癌症的侵袭性，尽管其潜在机制尚不清楚。在这种情况下，Ca 通道由于能够整合 TME 的信号，因此是很好的靶点候选物。Ca 通道是 pH 值和缺氧的传感器，Ca 稳态在癌症进展和血管生成中的改变已经被广泛报道。在本综述中，我们对 Ca 通透性离子通道进行了最新和批判性的综述，重点介绍了 TRP、SOC 和 PIEZO 通道，这些通道受肿瘤缺氧和酸中毒的调节，以及改变的 Ca 信号对癌症进展标志的相应作用。我们相信，对 Ca 信号和酸性 pH 值/缺氧相互作用的更深入理解将为发现替代和有吸引力的治疗靶点开辟新的道路。
