Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels but also creating an acidic pH in extracellular milieu. Lactate and protons in tumor microenvironment are not innocuous bystander metabolites but have special roles in promoting tumor-cell proliferation and growth. Lactate functions as a signaling molecule by serving as an agonist for the G-protein-coupled receptor GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, cancer cell-generated lactate activates GPR81 on cancer cells; in the paracrine pathway, cancer cell-generated lactate activates GPR81 on immune cells, endothelial cells, and adipocytes present in tumor stroma. The end result of GPR81 activation is promotion of angiogenesis, immune evasion, and chemoresistance. The acidic pH creates an inwardly directed proton gradient across the cancer-cell plasma membrane, which provides driving force for proton-coupled transporters in cancer cells to enhance supply of selective nutrients. There are several molecular targets in the pathways involved in the generation of lactic acid by cancer cells and its role in tumor promotion for potential development of novel anticancer therapeutics.

中文翻译：

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乳酸/ GPR81信号和质子动力在癌症中的作用：在血管生成，免疫逃逸，营养和Warburg现象中起作用。

生化途径的重编程是癌细胞的标志，从葡萄糖/谷氨酰胺生成乳酸代表了这种代谢改变的后果之一。癌细胞将乳酸输出出去以防止细胞内酸化，这不仅增加了乳酸水平，而且还在细胞外环境中产生了酸性pH。肿瘤微环境中的乳酸和质子不是无害的旁观者代谢产物，但在促进肿瘤细胞的增殖和生长中具有特殊作用。乳酸通过充当G蛋白偶联受体GPR81的激动剂而发挥信号传导分子的作用，涉及自分泌和旁分泌机制。在自分泌途径中，癌细胞产生的乳酸激活了癌细胞上的GPR81。在旁分泌途径中，癌细胞产生的乳酸激活免疫细胞上的GPR81，肿瘤基质中存在内皮细胞和脂肪细胞。GPR81激活的最终结果是促进血管生成，免疫逃逸和化学抗性。酸性pH值会在癌细胞质膜上产生向内定向的质子梯度，从而为癌细胞中质子偶联的转运蛋白提供驱动力，以增强选择性营养素的供应。在癌细胞产生乳酸及其涉及的肿瘤促进作用中，有几种分子靶标参与了新型抗癌治疗剂的潜在开发。这为癌细胞中质子偶联的转运蛋白提供了驱动力，以增强选择性营养的供应。在癌细胞产生乳酸及其涉及的肿瘤促进作用中，有几种分子靶标参与了新型抗癌治疗剂的潜在开发。这为癌细胞中质子偶联的转运蛋白提供了驱动力，以增强选择性营养的供应。在癌细胞产生乳酸及其涉及的肿瘤促进作用中，有几种分子靶标参与了新型抗癌治疗剂的潜在开发。