Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.
Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.
Pàez-Ribes
Marta
M
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain.
Allen
Elizabeth
E
Hudock
James
J
Takeda
Takaaki
T
Okuyama
Hiroaki
H
Viñals
Francesc
F
Inoue
Masahiro
M
Bergers
Gabriele
G
Hanahan
Douglas
D
Casanovas
Oriol
O
D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D002986:Clinical Trials as Topic; D018450:Disease Progression; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A