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酸感应受体 GPR4 在淋巴癌转移中起着关键作用。

Acid-sensing receptor GPR4 plays a crucial role in lymphatic cancer metastasis.

机构信息

Department of Pathology, School of Medicine, Wakayama Medical University, Wakayama, Japan.

出版信息

Cancer Sci. 2024 May;115(5):1551-1563. doi: 10.1111/cas.16098. Epub 2024 Feb 27.

DOI:10.1111/cas.16098
PMID:38410865
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11093208/
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.

摘要

肿瘤组织由于质子和乳酸的积累而呈现酸性微环境，这些质子和乳酸是由肿瘤和炎症细胞产生的。为了研究酸性微环境在淋巴癌转移中的作用，我们使用低 pH 培养基处理人真皮淋巴管内皮细胞（HDLEC）进行了基因表达谱分析。微阵列和基因集富集分析显示，酸处理诱导 HDLEC 中炎症相关基因的表达，包括编码趋化因子和粘附分子的基因。酸处理诱导的趋化因子 C-X3-C 基序趋化因子配体 1（CX3CL1）和 C-X-C 基序趋化因子配体 6（CXCL6）自分泌促进 HDLEC 的生长和管形成。HDLEC 在酸处理后 VCAM-1 的表达呈时间依赖性增加，这反过来又增强了它们与黑色素瘤细胞的粘附。在各种酸感应受体中，HDLEC 基础表达 G 蛋白偶联受体 4（GPR4），在酸性微环境下其表达增强。在 HDLEC 中敲低 GPR4 可减弱趋化因子或 VCAM-1 在酸性条件下的诱导。此外，在小鼠黑色素瘤模型中，通过给予抗 VCAM-1 抗体或 GPR4 拮抗剂可抑制淋巴结转移。这些结果表明，酸性微环境通过 GPR4 改变淋巴管内皮细胞的功能，从而促进淋巴癌转移。酸感应受体及其下游分子可能成为癌症的预防或治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/caf2e92325ad/CAS-115-1551-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/ed56374fcd88/CAS-115-1551-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/dfb0ed2f9f6b/CAS-115-1551-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/9df4fde79d6e/CAS-115-1551-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/caf2e92325ad/CAS-115-1551-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/ed56374fcd88/CAS-115-1551-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/dc53d7a4e1bf/CAS-115-1551-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/100c0d184188/CAS-115-1551-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/22b2d5c979f3/CAS-115-1551-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/dfb0ed2f9f6b/CAS-115-1551-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/9df4fde79d6e/CAS-115-1551-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a21/11093208/caf2e92325ad/CAS-115-1551-g003.jpg

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