Cancer-Induced Metabolic Rewiring of Tumor Endothelial Cells

Abstract

Cancer is a leading cause of death worldwide. If left untreated, tumors tend to grow and spread uncontrolled until the patient dies. To support this growth, cancer cells need large amounts of nutrients and growth factors that are supplied and distributed to the tumor tissue by the vascular system. The aberrant tumor vasculature shows deep morphological, molecular, and metabolic differences compared to the blood vessels belonging to the non-malignant tissues (also referred as normal). A better understanding of the metabolic mechanisms driving the differences between normal and tumor vasculature will allow the designing of new drugs with a higher specificity of action and fewer side effects to target tumors and improve a patient's life expectancy. In this review, we aim to summarize the main features of tumor endothelial cells (TECs) and shed light on the critical metabolic pathways that characterize these cells. A better understanding of such mechanisms will help to design innovative therapeutic strategies in healthy and diseased angiogenesis.

Keywords: endothelial metabolism in cancer; tumor endothelial cells; tumor vasculature.

Figure 1

Overview of tumor endothelial cell (TEC) metabolism. (A) Phenotypically, TECs show a high replication rate coupled to invasiveness, over-expression of receptors, and pro-angiogenic growth factors such as the vascular endothelial growth factor/vascular endothelial growth factor receptor 2 (VEGF/VEGFR2) axis, cytogenetic alterations, stemness and chemotherapy resistance, the ability to grow in serum-free media, and reduced senescence and apoptosis. (B) The main metabolic pathways reported so far in the remodeling of endothelial cell metabolism in cancer context. Proliferating TECs strongly depend on glycolysis and glucose uptake to produce adenosine triphosphate (ATP). Glycolysis provides the energy necessary to guide TEC proliferation and migration; lactate present in tumor microenvironment is imported into TECs through monocarboxylate transporter 1 (MCT-1) and can fuel vessel sprouting by two ways. By activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway that up-regulates interleukin 8 (IL-8) and leads to the IL-8 self-stimulation, or by converting into pyruvate that inhibits prolyl hydroxylase (PHD2) activating hypoxia-inducible factor 1 alpha (HIF1α); Fatty acids oxidation (FAO) provides intermediate metabolites and biomass to support sprouting vessels. The EC-specific deletion of both carnitine palmitoyltransferase 1a and 2 (CPT1a and CPT2, respectively), genes that regulate the carnitine shuttle, cause vessel leakage; gasotransmitters such as hydrogen sulfide (H₂S) and nitric oxide (NO) play a pleiotropic role by altering the proteome of cells and their pro-angiogenic action affects metabolism; extracellular matrix stiffness promotes tumor vessels formation by yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) activation and leads to angiogenesis. The enzymes/transporters directly involved in tumor angiogenesis are highlighted in red. (C) Metabolic interaction within individual pathways in TECs. The Figure was partly generated using Servier Medical Art.Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/, accessed on 30 March 2022). ↑: High. GLUT1: glucose transporter 1; HK2: hexokinase 2; PPP: pentose phosphate pathway; HBP: hexosamine biosynthetic pathway; G6P: glucose-6-phosphate; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; F2,6-BP: Fructose 2,6-bisphosphate; F6P: fructose 6-phosphate; F1,6-BP: fructose 1,6-bisphosphate; OXPHOS: oxidative phosphorylation; FAs: fatty acids; FABP: fatty acid binding protein; TCA cycle: tricaboxylic cycle; dNTPs: deoxyribonucleoside triphosphates; SLC1A5: solute carrier family 1 member 5; GLS: glutaminase; NMDAR: N-methyl-D-aspartate receptor; eNOS: endothelial nitric oxide synthase; ROS: reactive oxygen species; BH4: tetrahydrobiopterin; GSH: glutathione.