Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, 14115-154, Tehran, Iran.
Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Cell Mol Biol Lett. 2022 Jul 22;27(1):58. doi: 10.1186/s11658-022-00356-2.
Tumor-infiltrated lymphocytes are exposed to many toxic metabolites and molecules in the tumor microenvironment (TME) that suppress their anti-tumor activity. Toxic metabolites, such as lactate and ketone bodies, are produced mainly by catabolic cancer-associated fibroblasts (CAFs) to feed anabolic cancer cells. These catabolic and anabolic cells make a metabolic compartment through which high-energy metabolites like lactate can be transferred via the monocarboxylate transporter channel 4. Moreover, a decrease in molecules, including caveolin-1, has been reported to cause deep metabolic changes in normal fibroblasts toward myofibroblast differentiation. In this context, metformin is a promising drug in cancer therapy due to its effect on oncogenic signal transduction pathways, leading to the inhibition of tumor proliferation and downregulation of key oncometabolites like lactate and succinate. The cross-feeding and metabolic coupling of CAFs and tumor cells are also affected by metformin. Therefore, the importance of metabolic reprogramming of stromal cells and also the pivotal effects of metformin on TME and oncometabolites signaling pathways have been reviewed in this study.
浸润淋巴细胞暴露于肿瘤微环境（TME）中的许多毒性代谢物和分子中，这些代谢物和分子会抑制其抗肿瘤活性。毒性代谢物，如乳酸盐和酮体，主要由分解代谢的癌相关成纤维细胞（CAF）产生，以滋养合成代谢的癌细胞。这些分解代谢和合成代谢细胞通过单羧酸转运蛋白通道 4 形成代谢隔室，使高能量代谢物如乳酸盐能够在其中传递。此外，据报道，包括窖蛋白-1 在内的分子的减少会导致正常成纤维细胞向肌成纤维细胞分化的深层代谢变化。在这种情况下，二甲双胍由于其对致癌信号转导途径的影响，在癌症治疗中是一种很有前途的药物，导致肿瘤增殖的抑制和关键致癌代谢物如乳酸盐和琥珀酸盐的下调。CAF 和肿瘤细胞的交叉喂养和代谢偶联也受到二甲双胍的影响。因此，本研究综述了基质细胞代谢重编程的重要性以及二甲双胍对 TME 和致癌代谢物信号通路的关键作用。
