In established tumors, tumor-associated macrophages (TAM) orchestrate nonresolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis, and angiogenesis. However, the factors conferring inflammatory and protumor properties on human macrophages remain largely unknown. Most solid tumors have high lactate content. We therefore analyzed the impact of lactate on human monocyte differentiation. We report that prolonged lactic acidosis induces the differentiation of monocytes into macrophages with a phenotype including protumor and inflammatory characteristics. These cells produce tumor growth factors, inflammatory cytokines, and chemokines as well as low amounts of IL10. These effects of lactate require its metabolism and are associated with hypoxia-inducible factor-1α stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with protumor and inflammatory characteristics (VEGFhigh CXCL8+ IL1β+) are found in solid ovarian tumors. These results show that tumor-derived lactate links the protumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumor-associated acidosis may help combat cancer.

中文翻译：

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乳酸性酸中毒与GM-CSF和M-CSF一起诱导人类巨噬细胞趋向于炎症性肿瘤表型。

在已建立的肿瘤中，肿瘤相关巨噬细胞（TAM）协调无法解决的癌症相关炎症，并产生有利于肿瘤生长，转移和血管生成的介质。然而，赋予人类巨噬细胞炎性和肿瘤性质的因素仍然未知。大多数实体瘤的乳酸含量很高。因此，我们分析了乳酸对人单核细胞分化的影响。我们报告说，长时间的乳酸性酸中毒诱导单核细胞分化为具有表型包括肿瘤和炎症特征的巨噬细胞。这些细胞产生肿瘤生长因子，炎性细胞因子和趋化因子以及少量的IL10。乳酸的这些作用需要其代谢，并与缺氧诱导因子-1α稳定有关。某些乳酸诱导的基因的表达取决于自分泌M-CSF的消耗。最后，在实体卵巢肿瘤中发现了具有肿瘤和炎症特征的TAM（VEGFhigh CXCL8 +IL1β+）。这些结果表明，肿瘤来源的乳酸将TAM的炎症特征与TAM的肿瘤特征联系在一起。减少肿瘤糖酵解或肿瘤相关酸中毒的治疗方法可能有助于抗击癌症。