Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy
2 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
3 VIB-KU Leuven | CFM - VIB-KU Leuven Center for Microbiology
4 LKI - Leuven Cancer Institute [Leuven, Belgium]
5 University of Illinois College of Medicine
6 Oslo University Hospital [Oslo]
7 UiO - University of Oslo
8 Laboratory for translational genetics Leuven
9 LUMC - Leiden University Medical Center [Leiden]
10 CID - Center for Infectious Diseases [LUMC, Leiden]
11 ELEVM - LEIDEN - Einthoven Laboratory for Experimental Vascular Medicine
Résumé
Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as an 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.