title: Glycolytic phenotype and AMP kinase modify the pathologic response of tumor xenografts to VEGF neutralization.
abstract: VEGF antagonists are now widely used cancer therapeutics, but predictive biomarkers of response or toxicity remain unavailable. In this study, we analyzed the effects of anti-VEGF therapy on tumor metabolism and therapeutic response by using an integrated set of imaging techniques, including bioluminescence metabolic imaging, 18-fluorodeoxyglucose positron emission tomography, and MRI imaging and spectroscopy. Our results revealed that anti-VEGF therapy caused a dramatic depletion of glucose and an exhaustion of ATP levels in tumors, although glucose uptake was maintained. These metabolic changes selectively accompanied the presence of large necrotic areas and partial tumor regression in highly glycolytic tumors. In addition, we found that the central metabolic protein kinase AMP-activated protein kinase (AMPK)-a cellular sensor of ATP levels that supports cell viability in response to energy stress-was activated by anti-VEGF therapy in experimental tumors. AMPK-α2 attenuation increased glucose consumption, tumor cell sensitivity to glucose starvation, and tumor necrosis following anti-VEGF therapy. Taken together, our findings reveal functional links between the Warburg effect and the AMPK pathway with therapeutic responses to VEGF neutralization in tumor xenograft models.
authors.affiliation: Department of Oncology and Surgical Sciences, Oncology Section, University of Padova, Padova, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Nardo
authors.forename: Elena
authors.initials: E
authors.lastname: Favaro
authors.forename: Matteo
authors.initials: M
authors.lastname: Curtarello
authors.forename: Lidia
authors.initials: L
authors.lastname: Moserle
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zulato
authors.forename: Luca
authors.initials: L
authors.lastname: Persano
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rossi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Marika
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sattler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller-Klieser
authors.forename: Barbara
authors.initials: B
authors.lastname: Biesalski
authors.forename: Oliver
authors.initials: O
authors.lastname: Thews
authors.forename: Rossella
authors.initials: R
authors.lastname: Canese
authors.forename: Egidio
authors.initials: E
authors.lastname: Iorio
authors.forename: Paola
authors.initials: P
authors.lastname: Zanovello
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
mesh_terms: D000263:Adenylate Kinase / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006019:Glycolysis; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D019788:Fluorodeoxyglucose F18; D000263:Adenylate Kinase