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Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy
- Source :
- Cancer Cell, 30(6), 968-985
- Publication Year :
- 2016
-
Abstract
- 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 hyperglycolytic 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-kB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors. publisher: Elsevier articletitle: Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy journaltitle: Cancer Cell articlelink: http://dx.doi.org/10.1016/j.ccell.2016.10.006 associatedlink: http://dx.doi.org/10.1016/j.ccell.2016.11.007 content_type: article copyright: © 2016 Elsevier Inc. ispartof: Cancer Cell vol:30 issue:6 pages:968-985 ispartof: location:United States status: published
- Subjects :
- 0301 basic medicine
Cancer Research
Endothelium
Angiogenesis
Phosphofructokinase-2
Biology
chemotherapy
Metastasis
03 medical and health sciences
Mice
angiogenesis
Downregulation and upregulation
Drug Therapy
Cell Movement
Cell Line, Tumor
Neoplasms
medicine
Human Umbilical Vein Endothelial Cells
Animals
Humans
metastasis
tumor endothelial cell metabolism
Neoplasm Invasiveness
Neoplasm Metastasis
tumor vessel normalization
Cell adhesion molecule
Activator (genetics)
Intravasation
Drug Synergism
Epithelial Cells
glycolysis
Cell Biology
medicine.disease
Cadherins
Gene Expression Regulation, Neoplastic
Tamoxifen
030104 developmental biology
medicine.anatomical_structure
Oncology
Cancer cell
Cancer research
Cisplatin
Neoplasm Transplantation
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cancer Cell, 30(6), 968-985
- Accession number :
- edsair.doi.dedup.....e7c09a7524dbfa29f31a1da1ac32cffa