Abstract
Cancer metastasis is one of the leading causes of death worldwide, motivating research into identifying new methods of preventing cancer metastasis. Recently there has been increasing interest in understanding how cancer cells transduce mechanical forces into biochemical signals, as metastasis is a process that consists of a wide range of physical forces. For instance, the circulatory system through which disseminating cancer cells must transit is an environment characterized by variable fluid shear stress due to blood flow. Cancer cells and other cells can transduce physical stimuli into biochemical responses using the mechanosensitive ion channel Piezo1, which is activated by membrane deformations that occur when cells are exposed to physical forces. When active, Piezo1 opens, allowing for calcium flux into the cell. Calcium, as a ubiquitous second-messenger cation, is associated with many signaling pathways involved in cancer metastasis, such as angiogenesis, cell migration, intravasation, and proliferation. In this review, we discuss the roles of Piezo1 in each stage of cancer metastasis in addition to its roles in immune cell activation and cancer cell death.
Highlights
Cancer metastasis accounts for 90% of cancer-related deaths in patients [1]
These findings with other mechanosensitive ion channel (MSC) suggest that the role of Piezo1 in intravasation and extravasation is more complicated than its role in other aspects of metastasis
This study demonstrated that cyclic stretching of the cancer cells caused a Piezo1-mediated calcium influx that resulted in Bax activation and intrinsic apoptosis [129]
Summary
Cancer metastasis accounts for 90% of cancer-related deaths in patients [1]. Metastasis consists of five major steps: (1) invasion and migration, (2) intravasation, (3) dissemination, (4) extravasation, and (5) colonization [2] (Figure 1). The protein Piezo is activated through cell membrane deformations [14] These deformations can be caused by mechanical forces, such as osmotic pressure, fluid shear stress, substrate stiffness, and confinement [15]. Calcium is a ubiquitous second-messenger that is responsible for a diverse host of cellular functions that are necessary for successful cancer metastasis These functions Cells 2021, 10, x FOR PEER REVIEW include survival, metabolism, proliferation, migration, and cytoskeletal remodelin2g o[f171]5. PPiieezzoo sseennsseess llaammiinnaarr sshheeaarr ssttrreessss ffrroomm bblloooodd flflooww rreessuullttiinngg iinn ffooccaall aaddhheessiioonn rreegguullaattiioonn aanndd eennddootthheelliiaall cceellll aalliiggnnmmeenntt vviiaa aaccttiivvaattiioonn ooff tthhee mmeemmbbrraannee--ttyyppee 11 mmaattrriixx mmeettaalllloopprrootteeiinnaassee ((MMTT11--MMMMPP)) eennzzyymmee [[3388]]. While Piezo has not always been explored in the context of cancer, its role in blood vessel growth is evident This role may prompt future studies of Piezo inhibition as a potential angiogenesis-targeting therapy
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