Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance

Abstract

Antiangiogenic therapies, such as treatment with bevacizumab, display modest survival benefits in ovarian cancer (OC) patients. After a transient response, the upregulation of compensatory proangiogenic pathways and the adoption of alternative vascularization processes lead to the development of resistance. Considering the high mortality rate of OC, there is an urgent need to uncover the underlying mechanisms of antiangiogenic resistance for the development of novel and effective treatment strategies. Recent investigations have confirmed that metabolic reprogramming in the tumor microenvironment (TME) exerts an essential effect on tumor aggressiveness and angiogenesis. In this review, we provide an overview of the metabolic crosstalk between OC and the TME, highlighting the regulatory mechanisms underlying the development of antiangiogenic resistance. Metabolic interventions may interrupt this complex and dynamic interactive network, providing a promising therapeutic option to improve clinical outcome in OC patients.

Keywords: antiangiogenic therapy; metabolism; ovarian cancer; tumor microenvironment.

Figure 1

Key regulatory enzymes of the metabolic pathways in OC cells The main steps of glycolysis, OXPHOS, amino acid and lipid metabolism in OC cells, as well as key regulatory enzymes are summarized. SLC7A5: solute carrier family 7 member 5. GLS: glutaminase. GLUT: glucose transporter. HK2: hexokinase 2. PKM2: pyruvate kinase M2. PDH: pyruvate dehydrogenase. CD36: cluster of differentiation 36. FABP4: fatty acid binding protein 4. CPT1: Carnitine palmitoyltransferase 1. TCA: tricarboxylic acid cycle. FAO: fatty acid oxidation. OXPHOS: oxidative phosphorylation.

Figure 2

Overview of the metabolic crosstalk in the OC microenvironment On one hand, OC cells compete for the availability of glucose with CAFs and immune cells, which further reshapes their protumor and proangiogenic phenotypes. On the other hand, energy-rich metabolites mediate the interaction between the OC cells and the stromal cells, facilitating the metabolic synergy in the OC microenvironment.