pH sensing in skin tumors: Methods to study the involvement of GPCRs, acid‐sensing ion channels and transient receptor potential vanilloid channels

Abstract

Cancer remains one of the leading causes of death worldwide. Around 1.3 million cases of skin cancer (~7% of all cancer cases) were estimated worldwide for 2018, of which about 1 million were non-melanoma skin cancers (NMSC) and nearly 300 000 were melanoma. [1] pH dysregulation is a hallmark of solid tumors, which further drives tumor growth, metastatic potential and immune escape. [2,3] The extracellular pH (pH e) of solid tumor cells is more acidic (pH e 6.2-7.0) as compared to normal cells (pH e 7.2-7.4), while the intracellular pH (pH i) of tumor cells (pH i 7.2-7.7) is slightly increased compared to normal (pH i 6.9-7.2). [4,5] This reversed/inside-out pH gradient is

Expression of pH-Sensitive TRPC4 in Common Skin Tumors

“…Cell lines with knockout and overexpression of pH-sensitive TRPC4 could be subjected to varying pH e in order to examine the role of this protein in proliferation, migration and cell survival. After identifying individual protein levels in different cell types (qPCR, Western blot), the next step is to use knockdown (siRNA)/knockout (CRISPR/Cas9) and overexpression strategies in combination with functional cellular assays to answer these questions, as we proposed before [ 16 ].…”

“…Furthermore, decreased extracellular pH activates proton-sensitive receptors, such as certain G protein-coupled receptors (GPCRs), acid-sensitive ion channels (ASICs), transient receptor potential vanilloid channels (TRPVs), TWIK-related acid-sensitive potassium channels (TASKs) and transient receptor-gated channels (TRPCs). We recently published first data on the expression profiles of pH-GPCRs, TASKs/TRPVs and ASICs in various skin tumors [ 5 , 15 , 16 , 17 ].…”

Matriptase generates a tissue damage response via promoting Gq signalling, leading to RSK and DUOX activation

“…How it might act as a sensor is not clear; however, Matriptase activity is highly sensitive to reduced pH and has been linked to response to acidosis (Tseng et al, 2010). Altered pH has recently been proposed to regulate wound progression (Stolwijk et al, 2020). In the mammalian epidermis, Matriptase becomes active at the transition to the stratum corneum where the matrix becomes acidic (Miller & List, 2013), and the acid sensing ion channel, ASIC1, is also a target of Matriptase further supporting a link between Matriptase and environmental pH (Clark, Jovov, Rooj, Fuller, & Benos, 2010).…”

Focus theme issue: Celebrating the ADF‐EXD partnership: A look back into the future of experimental dermatology

“…As Stolwijk et al [8] point out, the identification of characteristic expression patterns of different pH-sensing proteins in different skin cancers and elucidation of their function in the regulation of cell proliferation and migration may help to develop novel pH-targeting therapies to inhibit tumor cell proliferation and migration. [8,9] To round off this excursion into dermato-oncology, Stadler et al review the mutational landscape in cutaneous T-cell lymphomas (CTCL) and possible therapeutic targets. [10,11] The role of sebaceous glands and hair follicles in cutaneous physiology and pathobiology [12,13] is covered by two essays.…”

“…Furthermore, pH‐dysregulation in solid tumors has an impact on tumor growth, metastatic spread and immune escape. As Stolwijk et al [ 8] point out, the identification of characteristic expression patterns of different pH‐sensing proteins in different skin cancers and elucidation of their function in the regulation of cell proliferation and migration may help to develop novel pH‐targeting therapies to inhibit tumor cell proliferation and migration. [ 8,9] To round off this excursion into dermato‐oncology, Stadler et al review the mutational landscape in cutaneous T‐cell lymphomas (CTCL) and possible therapeutic targets.…”