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. 2015 Oct 13;6(36):39196–39210. doi: 10.18632/oncotarget.5538

Figure 7. Schematic of the effect of lactate shuttling on the reprogramming and recruitment of macrophages.

Figure 7

Lactate was secreted into the tumor microenvironment via MCT4 and was then transported into macrophages via MCT1. Subsequently, lactate was metabolized to pyruvate by LDH1; then, pyruvate competitively inhibited the activity of PHDs, which prevented the ubiquitylation of hypoxia-inducible factor 1α (HIF-1α) and its destruction by the proteasome. Subsequently, HIF-1α may create “pseudo-hypoxia” by enhancing the transcription of a series of hypoxia-related genes, such as Arg-1, which metabolizes arginine to provide substrates for cancer cell proliferation. Additionally, HIF-1α may activate the transcription of the C-X-C chemokine receptor (CXCR) and Notch [25, 26], which are important signaling factors in cell migration. Furthermore, HIF-1α can promote matrix remodeling by increasing the secretion of MMPs.