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Review
. 2020 Mar;12(6):523-532.
doi: 10.4155/fmc-2019-0357. Epub 2020 Mar 2.

Proton-sensing G protein-coupled receptors: detectors of tumor acidosis and candidate drug targets

Paul A Insel  1   2 , Krishna Sriram  1 , Cristina Salmerón  1 , Shu Z Wiley  1
Affiliations
Review

Proton-sensing G protein-coupled receptors: detectors of tumor acidosis and candidate drug targets

Paul A Insel et al. Future Med Chem. 2020 Mar.

Abstract

Cells in tumor microenvironments (TMEs) use several mechanisms to sense their low pH (<7.0), including via proton-sensing G protein-coupled receptors (psGPCRs): GPR4, GPR65/TDAG8, GPR68/OGR1 and GPR132/G2A. Numerous cancers have increased expression of psGPCRs. The psGPCRs may contribute to features of the malignant phenotype via actions on specific cell-types in the TME and thereby promote tumor survival and growth. Here, we review data regarding psGPCR expression in tumors and cancer cells, impact of psGPCRs on survival in solid tumors and a bioinformatics approach to infer psGPCR expression in cell types in the TME. New tools are needed to help define contributions of psGPCRs in tumor biology and to identify potentially novel therapeutic agents for a variety of cancers.

Keywords: G protein-coupled receptors (GPCRs); acidosis; bioinformatics; cancer-associated fibroblasts; ion channels; pH; solid tumors; tumor microenvironment.

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Conflict of interest statement

Financial & competing interests disclosure

The authors would like to acknowledge that the work in their laboratory on this topic has previously been supported by the research and training grants from the National Institutes of Health, a Padres Pedal the Cause Award and a David Lehr Research Award from the American Society for Pharmacology and Experimental Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Proton-sensing G protein-coupled receptor expression in solid tumors.
(A) Median mRNA expression (Log2 TPM) of psGPCRs in 45 types of solid tumors. (B) Data for select tumors with high expression for one or more psGPCRs, shown as median with upper and lower quartiles. These data are adapted from analysis [54] of TCGA data [55]. ACC: Adrenocortical carcinoma; BCNM: Bronchoalveolar carcinoma non-mucinous; BLCA_np: Non-papillary bladder urothelial carcinoma; BLCA_p: Papillary bladder urothelial carcinoma; BRCA_IDC: Breast invasive carcinoma invasive ductal carcinoma; BRCA_ILC: Breast invasive carcinoma invasive lobullar carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: Colon adenocarcinoma; EndoAd: Endocervical adenocarcinoma; ESCA_AD: Esophageal cancer adenocarcinoma; ESCA_SQC: Esophageal cancer squamous cell carcinoma; HR+: Hormone receptor positive; INT: Intestinal; KICH: Kidney chromophobe; KIRC: Kidney clear cell carcinoma; KIRP: Kidney papillary cell carcinoma; LIHC: Liver hepatocellular carcinoma; LSQC: Lung squamous cell carcinoma; LUAD: Lung adenocarcinoma; MucAd: Mucinous adenocarcinoma; NOS: Not otherwise specified; OV: Ovarian serous cystadenocarcinoma; PDAC: Pancreatic ductal adenocarcinoma; psGPCR: Proton-sensing G protein-coupled receptor; PRAD: Prostate adenocarcinoma; SKCM: Skin cutaneous melanoma; SQC: Squamous cell carcinoma; STAD: Stomach adenocarcinoma; STAD_Signet: Signet ring STAD; TCGA: The Cancer Genome Atlas; TGCT: Testicular germ cell tumors; THCA: Thyroid carcinoma; TPM: Transcripts per million; UCS: Uterine corpus endometrial carcinoma.
Figure 2.
Figure 2.. mRNA expression of proton-sensing G protein-coupled receptors (log2 fold-change) in solid tumor types compared with corresponding normal tissue.
All nonzero fold changes are statistically significant (false discovery rate <0.05). Positive values indicate increased expression in tumors. These data are adapted from analysis presented in [54] of TCGA data [55]. ACC: Adrenocortical carcinoma; BCNM: Bronchoalveolar carcinoma non-mucinous; BLCA_np: Non-papillary bladder urothelial carcinoma; BLCA_p: Papillary bladder urothelial carcinoma; BRCA_IDC: Breast invasive carcinoma invasive ductal carcinoma; BRCA_ILC: Breast invasive carcinoma invasive lobullar carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: Colon adenocarcinoma; EndoAd: Endocervical adenocarcinoma; ESCA_AD: Esophageal cancer adenocarcinoma; ESCA_SQC: Esophageal cancer squamous cell carcinoma; HR+: Hormone receptor positive; INT: Intestinal; KICH: Kidney chromophobe; KIRC: Kidney clear cell carcinoma; KIRP: Kidney papillary cell carcinoma; LIHC: Liver hepatocellular carcinoma; LSQC: Lung squamous cell carcinoma; LUAD: Lung adenocarcinoma; MucAd: Mucinous adenocarcinoma; NOS: Not otherwise specified; OV: Ovarian serous cystadenocarcinoma; PDAC: Pancreatic ductal adenocarcinoma; PRAD: Prostate adenocarcinoma; SKCM: Skin cutaneous melanoma; SQC: Squamous cell carcinoma; STAD: Stomach adenocarcinoma; STAD_Signet: Signet ring STAD; TCGA: The Cancer Genome Atlas; TGCT: Testicular germ cell tumor; THCA: Thyroid carcinoma; UCS: Uterine corpus endometrial carcinoma.
Figure 3.
Figure 3.. mRNA expression (log2 transcripts per million) of proton-sensing G protein-coupled receptors in the Cancer Cell Line Encyclopedia cell lines of tumor types from different tissues.
The data are adapted from a prior analysis [63]. CLL: Chronic lymphocytic leukemia and other lymphocytic and T-cell leukemias; DLBC: Diffuse large B-cell lymphoma and other B-cell lymphomas.
Figure 4.
Figure 4.. Association of proton-sensing G protein-coupled receptor mRNA expression with markers for cell types in the tumor microenvironment.
Gene symbols for markers used for the different cell types are as follows: cancer cells (E-Cadherin); CAFs (COL1A1); general immune cells (CD45); T cells (CD3G); monocytes (CD14); myeloid cells (CD33); endothelial Cells (VWF). The dashed line indicates the threshold for the association to be statistically significant. CAF: Cancer-associated fibroblast; VWF: Von Willebrand factor.
Figure 5.
Figure 5.. Impact of proton-sensing G protein-coupled receptors on survival of patients with certain cancers.
A Kaplan–Meier survival curve for GPR68 in KIRC is shown as an example; instances of tumor types in which psGPCRs have a significant effect on survival is also shown. Statistics were calculated based on the Peto–Peto method for analyzing Kaplan–Meier curves. The data shown are adapted from [54]. BLCA: Bladder urothelial carcinoma; BRCA: Breast invasive adenocarcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; GPCR: G protein-coupled receptor; KIRC: Kidney renal clear cell carcinoma; LIHC: Liver hepatocellular carcinoma; psGPCR: Proton-sensing G protein-coupled receptor; THCA: Thyroid carcinoma.
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