Tumor-associated macrophages (TAMs) play a pivotal role in shaping the tumor microenvironment. Lactic acid (LA) has been identified as an influential factor in promoting immune escape and tumor progression. However, the mechanisms through which LA modulates TAMs in colorectal cancer (CRC) remain poorly understood. We used qRT-PCR to quantify the expression of LA-related genes (LDHA and LAMP2) in CRC tumor tissues and adjacent nontumor tissues (n = 64). The biological effects and mechanisms of LA on macrophages and tumors were evaluated via qRT-PCR, Western blot, RNA-seq, wound healing assay, colony formation assay in vitro, and allograft mouse tumor models in vivo. We found the expression of LDHA and LAMP2 was highly elevated in the tumor regions and positively associated with a poor clinical stage of CRC. A high concentration of LA was generated under hypoxia; it could promote tumor progression and metastasis with the involvement of macrophages. The inhibition of LA release impaired this protumor phenomenon. Mechanically, LA induced M2 macrophages through the AKT/ERK signaling pathway; subsequently, M2 macrophages secreted CCL8 and facilitated the proliferation and metastasis of CRC cells by activating the CCL8/CCR5/mTORC1 axis. This effect was inhibited by the antagonist or knockdown of CCR5. In conclusion, lactate-induced CCL8 in TAMs accelerated CRC proliferation and metastasis through the CCL8/CCR5/mTORC1 axis.
肿瘤相关巨噬细胞在塑造肿瘤微环境中发挥关键作用。乳酸已被证实是促进免疫逃逸和肿瘤进展的重要调控因子，但其在结直肠癌中调控肿瘤相关巨噬细胞的具体机制尚不明确。本研究采用qRT-PCR技术检测64例结直肠癌组织及癌旁正常组织中乳酸相关基因（LDHA和LAMP2）的表达水平。通过qRT-PCR、Western blot、RNA-seq、划痕实验、克隆形成实验等体外研究，以及同种异体移植小鼠模型的体内实验，系统评估乳酸对巨噬细胞及肿瘤的生物学效应与作用机制。研究发现LDHA和LAMP2在肿瘤区域表达显著升高，且与结直肠癌不良临床分期呈正相关。缺氧条件下产生的高浓度乳酸可通过巨噬细胞促进肿瘤进展和转移，而抑制乳酸释放可阻断这种促肿瘤现象。机制研究表明，乳酸通过AKT/ERK信号通路诱导M2型巨噬细胞极化；随后M2型巨噬细胞分泌CCL8，通过激活CCL8/CCR5/mTORC1轴促进结直肠癌细胞的增殖和转移。使用CCR5拮抗剂或敲低CCR5表达可有效抑制该效应。综上所述，乳酸诱导肿瘤相关巨噬细胞分泌CCL8，通过CCL8/CCR5/mTORC1信号轴加速结直肠癌的增殖和转移。
肿瘤(癌症)患者之家