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Cancer tissues exhibit an acidic microenvironment owing to the accumulation of protons and lactic acid produced by cancer and inflammatory cells. To examine the role of an acidic microenvironment in lymphatic cancer metastasis, gene expression profiling was conducted using human dermal lymphatic endothelial cells (HDLECs) treated with a low pH medium. Microarray and gene set enrichment analysis revealed that acid treatment induced the expression of inflammation-related genes in HDLECs, including genes encoding chemokines and adhesion molecules. Acid treatment-induced chemokines C-X3-C motif chemokine ligand 1 (CX3CL1) and C-X-C motif chemokine ligand 6 (CXCL6) autocrinally promoted the growth and tube formation of HDLECs. The expression of vascular cell adhesion molecule 1 (VCAM-1) increased in HDLECs after acid treatment in a time-dependent manner, which, in turn, enhanced their adhesion to melanoma cells. Among various acid-sensing receptors, HDLECs basally expressed G protein-coupled receptor 4 (GPR4), which was augmented under the acidic microenvironment. The induction of chemokines or VCAM-1 under acidic conditions was attenuated by GPR4 knockdown in HDLECs. In addition, lymph node metastases in a mouse melanoma model were suppressed by administering an anti-VCAM-1 antibody or a GPR4 antagonist. These results suggest that an acidic microenvironment modifies the function of lymphatic endothelial cells via GPR4, thereby promoting lymphatic cancer metastasis. Acid-sensing receptors and their downstream molecules might serve as preventive or therapeutic targets in cancer., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Reduced response of beta adrenergic receptors, especially beta-2 receptors, has been suggested as a contributing factor in the etiology of asthma. Cyclic adenosine monophosphate (AMP) production in lymphocytes after exposure to 10(-3) M salbutamol, predominantly a beta-2 receptor stimulant, was significantly less in asthmatic subjects than in normal subjects, while there was no significant difference in cyclic AMP response to 10(-3) M norepinephrine, predominantly a beta-1 receptor stimulant. Both drugs evoked the maximum response at 10(-3) M. The cyclic AMP response to salbutamol of 5 asthmatic subjects being treated with steroids was diminished significantly compared with that of 7 patients not treated with steroids; however, the response to norepinephrine was similar in both groups. The degree of the abnormality in the beta-2 receptor response seems to be related to the severity of the asthma.