Figure 1.

Impact of lactic acid on tumor angiogenesis. Tumor cells generate large amounts of lactic acid that are exported by MCT1 and MCT4. The accumulation of lactic acid in the extracellular milieu promotes several cancer processes leading to cell survival, tumor growth and metastasis. Lactic acid stimulates angiogenesis by polarizing TAMs to the M2-like phenotype; inducing the expression of high levels of VEGF and arginase I (Arg1) that support tumor growth, metastasis, and angiogenesis; and inhibiting antitumor immunity (45, 46); Within monocytes, lactic acid enhances the production of IL-23 (47), and IL-23 stimulates macrophages to produce IL-10, TGF-β, and VEGF (48). IL-23 also induces MMP9 expression, which contributes to angiogenesis. Within endothelial cells, lactic acid activates the NF-κB pathway, which triggers the production of proangiogenic IL-8, drives the migration of endothelial cells and increases the capacity of endothelial cells to form tubes (44). Within the tumor cells, lactic acid activates GPR81 to enhance the secretion of AREG, a member of the EGFR family. AREG contributes to neovascularization by increasing the production of VEGF, which promotes angiogenesis (30, 31). Lactic acid also supports the activation of normoxic HIF-1α in tumors and endothelial cells by inhibiting PHDs with 2-oxoglutarate (49), resulting in the increased expression of relevant pro-angiogenic targets, including VEGF (50). Abbreviations: LDHB, lactate dehydrogenase B; PI3K, phosphatidylinositol 3-kinase; Akt, serine/threonine kinase; TAM, tumor-associated macrophage; VEGF, vascular endothelial growth factor; Arg1, arginase 1; MMP9, matrix metalloprotease 9; AREG, amphiregulin; EGFR, epidermal growth factor receptor; IL-23, interleukin-23; NF-κB, nuclear factor-kappa B; IL-8, interleukin-8; HIF-1α, hypoxia-inducible factor 1α; and PHDs, prolyl hydroxylases.