Mechanosensitive Piezo Channels in Cancer: Focus on altered Calcium Signaling in Cancer Cells and in Tumor Progression

Abstract

<jats:p>Mechanotransduction, the translation of mechanical stimuli into biological signals, is a crucial mechanism involved in the function of fundamentally all cell types. In many solid tumors, the malignant transformation is often associated with drastic changes in cell mechanical features. Extracellular matrix stiffness, invasive growth, and cell mobility are just a few hallmarks present in cancer cells that, by inducing mechanical stimuli, create positive feedbacks promoting cancer development. Among the molecular players involved in these pathophysiological processes, the mechanosensitive Ca2+-permeable Piezo channels have emerged as major transducers of mechanical stress into Ca2+ dependent signals. Piezo channels are overexpressed in several cancers, such as in breast, gastric, and bladder, whereas their downregulation has been described in other cancers. Still, the roles of mechanosensitive Piezos in cancer are somewhat puzzling. In this review, we summarize the current knowledge on the pathophysiological roles of these Ca2+-permeable channels, with special emphasis on their functional involvement in different cancer types progression.</jats:p>

Targeting the Calcium Signalling Machinery in Cancer

“… Piezo1 and 2 are bona fide mechanosensitive non-selective Ca 2+ permeable cation channels stimulated by all types of mechanical stimuli to the plasma membrane [ 105 , 106 , 107 , 108 ] Piezo channels are overexpressed in gastric, breast, prostate and glioma where they regulate cell proliferation, migration/invasion and angiogenesis but are oncosuppressors in lung and osteosarcoma [ 106 ] TRPM7 is a bi-functional stretch-activated Ca 2+ and Mg 2+ permeable channel [ 109 , 110 ] TRPV2 is a heat/mechano-sensitive Ca 2+ /Mg 2+ permeable channel expressed in human leukemia cells [ 111 ] Panexins (Panx1) are mechanosensitive channels permeable to ATP which activate P2X7 purinergic ATP-gated Ca 2+ permeable channels both of which are important in cancer [ 112 , 113 ] Polycyctins (TRPP1, TRPP2) are multi-functional mechanosensitive Ca 2+ permeable channels that are over-expressed and facilitate an aggressive phenotype in colorectal cancer [ 114 ] TRPC1, TRPC2, TRPV1, TRPM3, TRPM4, TRPA1 also exhibit mechanosensitivity [ 113 , 115 ] …”

“…Piezo1 and 2 are bona fide mechanosensitive non-selective Ca 2+ permeable cation channels stimulated by all types of mechanical stimuli to the plasma membrane [ 105 , 106 , 107 , 108 ]…”

“…Piezo channels are overexpressed in gastric, breast, prostate and glioma where they regulate cell proliferation, migration/invasion and angiogenesis but are oncosuppressors in lung and osteosarcoma [ 106 ]…”

Trends in Piezo Channel Research Over the Past Decade: A Bibliometric Analysis

“…Increased ECM stiffness, an important clinical tumor feature, activates MS channels to regulate tumor development (Fujii et al, 2020). In addition, Piezo channel activation can deliver local Ca 2+ influx, thereby modulating key Ca 2+− dependent signaling pathways associated with cancer cell migration, proliferation, and angiogenesis (De Felice and Alaimo, 2020). Recent studies have noted the close correlation between the Piezo1 channel and some cancers, including gastric cancer, oral squamous cell carcinoma, prostate cancer, colon cancer, synovial sarcoma, and osteosarcoma (Jiang et al, 2017;Suzuki et al, 2018;Zhang et al, 2018;Han et al, 2019;Sun et al, 2020;Hasegawa et al, 2021;Wang et al, 2021).…”

A New Hope in Spinal Degenerative Diseases: Piezo1

“…This may be a new prognostic indicator for glioma patients. The function of piezo1 ion channels in human osteosarcoma cells is also related to apoptosis, invasion, and cell proliferation [ 196 , 197 ].…”