Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy

Abstract

Summary Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as anti-cancer treatment. Here, we show that tumor endothelial cells (ECs) have a hyper-glycolytic metabolism, shunting intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell invasion, intravasation and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs, and rendering pericytes more quiescent and adhesive (via upregulation of N-cadherin) through glycolysis reduction; it also lowered the expression of cancer cell adhesion molecules in ECs by decreasing NF-κB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors.

Endothelial cell metabolism in health and disease: impact of hypoxia

“…Mechanistically, lowering PFKFB3‐driven glycolysis in TECs reduces the (glycolytic) ATP‐consuming endocytosis process and turnover of VE‐cadherin, thereby stabilizing VE‐cadherin‐positive adherens junctions and tightening the endothelial barrier in tumour vessels, and impairing cancer cell intravasation and metastasis (Cantelmo et al , ; Cruys et al , ). In addition, decreasing tumour EC glycolysis reduces NF‐κB‐dependent vascular inflammation, thereby impairing cancer cell adhesion to and transmigration through ECs (Cantelmo et al , ). Furthermore, using a pharmacological inhibitor of PFKFB3 inhibitor (3PO) also improved pericyte coverage of vessels via lowering of glycolysis in pericytes, promoting quiescence (Cantelmo et al , ).…”

Tumor angiogenesis revisited: Regulators and clinical implications

“…This effect is mainly due to increased tumor vessel normalization, improved vessel maturation, and perfusion. Indeed, PFKFB3 inhibition lowers the expression of cancer cell adhesion molecules in ECs, tightens the vascular barrier by reducing VE‐cadherin endocytosis, and renders pericytes more quiescent and adhesive …”

Endothelial Metabolic Control of Lymphangiogenesis

“…Similarly, genetic and pharmacological inhibition of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), an important enzyme in glycolysis, causes obvious angiogenic defects in mice and zebrafish . Notably, partial suppression of glycolysis reduces pathological ocular angiogenesis and leads to tumor vessel normalization and decreased cancer cell dissemination …”