Abstract
Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical characteristics of tumor progression. The relationship among metastasis, VM, and metabolic reprogramming remains unclear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of thymidine phosphorylase (TP) expression. TP promoted the extracellular metabolism of thymidine into ATP and amino acids through the pentose Warburg effect by coupling the pentose phosphate pathway and glycolysis. Moreover, Twist1 relied on TP-induced metabolic reprogramming to promote hepatocellular carcinoma (HCC) metastasis and VM formation mediated by VE–Cad, VEGFR1, and VEGFR2 in vitro and in vivo. The TP inhibitor tipiracil reduced the effect of TP on promoting HCC VM formation and metastasis. Hence, TP, when transcriptionally activated by Twist1, promotes HCC VM formation and metastasis through the pentose Warburg effect and contributes to tumor progression.
Highlights
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide; patients with hepatocellular carcinoma (HCC) die mainly due to vasculogenic mimicry (VM) formation and metastasis[1,2,3]
We explored whether thymidine phosphorylase (TP) upregulation affects the metabolic reprogramming of HCC and whether the transcriptional pattern of Twist1–TP could contribute to VM formation in HCC
Hepatic resection and liver transplantation have considerably improved the overall survival rate of patients with HCC, distant metastasis contributes to the failure of these treatments[26]
Summary
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide; patients with HCC die mainly due to vasculogenic mimicry (VM) formation and metastasis[1,2,3]. Under a deteriorated local tumor microenvironment, tumor cells are forced to reprogram cellular metabolism[7]. An obvious change in metabolism is the Warburg effect, where tumor cells mainly use glycolysis to generate energy even under aerobic conditions[8]. This metabolic reprogramming eliminates the threat of hypoxia to the survival of tumor cells. By inducing cellular autophagy in paracancerous tissues, starved cancer cells can obtain fuel from extracellular sources[13]. Distant metastases depend on the pentose phosphate pathway for reprogramming malignant gene expression and phenotype[14].
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