VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells.
Anti-VEGF therapy perturbs tumor metabolism, severely impairing oxygen, glucose, and ATP levels. In this study, we investigated the effects of anti-VEGF therapy in multiple experimental tumor models that differ in their glycolytic phenotypes to gain insights into optimal modulation of the metabolic features of this therapy. Prolonged treatments induced vascular regression and necrosis in tumor xenograft models, with highly glycolytic tumors becoming treatment resistant more rapidly than poorly glycolytic tumors. By PET imaging, prolonged treatments yielded an increase in both hypoxic and proliferative regions of tumors. A selection for highly glycolytic cells was noted and this metabolic shift was stable and associated with increased tumor aggressiveness and resistance to VEGF blockade in serially transplanted mice. Our results support the hypothesis that the highly glycolytic phenotype of tumor cells studied in xenograft models, either primary or secondary, is a cell-autonomous trait conferring resistance to VEGF blockade. The finding that metabolic traits of tumors can be selected by antiangiogenic therapy suggests insights into the evolutionary dynamics of tumor metabolism.
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Matteo
M
Curtarello
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Elisabetta
E
Zulato
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Giorgia
G
Nardo
IBFM-CNR, Segrate, Italy; Tecnomed Foundation and Department of Health Sciences, University of Milan-Bicocca, Monza, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Silvia
S
Valtorta
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Giulia
G
Guzzo
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Elisabetta
E
Rossi
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Giovanni
G
Esposito
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Aichi
A
Msaki
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Anna
A
Pastò
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Andrea
A
Rasola
Onco-hematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.
Luca
L
Persano
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Francesco
F
Ciccarese
Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Roberta
R
Bertorelle
IBFM-CNR, Segrate, Italy; Tecnomed Foundation and Department of Health Sciences, University of Milan-Bicocca, Monza, Italy.
Sergio
S
Todde
Department of Laboratory Medicine, University-Hospital, Padova, Italy.
Mario
M
Plebani
Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Henrike
H
Schroer
Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Stefan
S
Walenta
Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Wolfgang
W
Mueller-Klieser
Istituto Oncologico Veneto, IRCCS, Padova, Italy. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Alberto
A
Amadori
IBFM-CNR, Segrate, Italy; Tecnomed Foundation and Department of Health Sciences, University of Milan-Bicocca, Monza, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Rosa Maria
RM
Moresco
Istituto Oncologico Veneto, IRCCS, Padova, Italy. stefano.indraccolo@unipd.it.
Stefano
S
Indraccolo
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism*; D010641:Phenotype; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab