Endothelial inhibition of the glycolytic activator PFKFB3 induces tumor vessel normalization, impairs metastasis and improves chemotherapy

ABSTRACT: Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) by targeting endothelial cells (ECs) is emerging as anti-cancer treatment. Here, we show that tumor ECs (TECs) have a hyper-glycolytic metabolism, shunting glycolytic intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell intra- and extravasation 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 glycolytic pericytes more quiescent; it also lowered the expression of cancer cell adhesion molecules in ECs. Additionally, PF

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Mus musculus

SUBMITTER: Peter Carmeliet 

PROVIDER: E-MTAB-4842 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress