Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization

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  • Giorgia Nardo
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Elena Favaro
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Matteo Curtarello
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Lidia Moserle
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Elisabetta Zulato
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Luca Persano
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Elisabetta Rossi
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Giovanni Esposito
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Marika Crescenzi
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Oriol Casanovas
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Ulrike Sattler
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Wolfgang Mueller-Klieser
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Barbara Biesalski
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Oliver Thews
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Rossella Canese
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Egidio Iorio
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Paola Zanovello
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Alberto Amadori
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy
  • Stefano Indraccolo
    Authors' Affiliations: 1Department of Oncology and Surgical Sciences, Oncology Section, University of Padova; 2Istituto Oncologico Veneto–IRCCS, Padova, Italy; 3Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain; 4Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University, Mainz, Rhineland Palatinate; 5Institute of Physiology, University of Halle, Saxony-Anhalt, Germany; and 6Istituto Superiore di Sanità, Rome, Italy

Abstract

<jats:title>Abstract</jats:title> <jats:p>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. Cancer Res; 71(12); 4214–25. ©2011 AACR.</jats:p>

Journal

  • Cancer Research

    Cancer Research 71 (12), 4214-4225, 2011-06-14

    American Association for Cancer Research (AACR)

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