AI Article Synopsis
- Cancer tissues create an acidic environment due to the buildup of protons and lactic acid, which influences lymphatic cancer metastasis.
- Treatment of human dermal lymphatic endothelial cells (HDLECs) with low pH revealed increased expression of inflammation-related genes, enhancing cell growth and adhesion to melanoma cells.
- The study identified G protein-coupled receptor 4 (GPR4) as a key player in this process, suggesting that targeting acid-sensing receptors could be a potential strategy for preventing or treating lymphatic cancer spread.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093208 | PMC |
| http://dx.doi.org/10.1111/cas.16098 | DOI Listing |
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