RESUMO
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.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Bevacizumab , Linhagem Celular Tumoral , Feminino , Glicólise/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Terapia de Alvo Molecular , Neoplasias/irrigação sanguínea , Fenótipo , Distribuição Aleatória , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Oral mucositis is a severe complication of radiotherapy. Hence, it may constitute a serious medical safety risk for astronauts during extended space flights, such as missions to Mars, during which they are exposed to heavy-ion irradiation. For risk assessment of developing radiation-induced mucositis, a three-dimensional (3D) organotypic oral mucosa model was irradiated with 12C heavy ions or Xrays. The present study focused mainly on early radiationinduced effects, such as the activation of nuclear factor κB (NFκB) and the expression or release of pro-inflammatory marker molecules. The 3D oral mucosa models with or without peripheral blood mononuclear cells (PBMCs) were irradiated with Xrays or 12C heavy ions followed by snap freezing. Subsequently, cryosections were derived from the specimens, which were immunostained for analysis of compactness, DNA double strand breaks (DSB) and activation of NFκB. Radiationinduced release of interleukin 6 (IL6) and interleukin 8 (IL8) was quantified by ELISA. Quantification of the DNA damage in irradiated mucosa models revealed distinctly more DSB after heavy-ion irradiation compared to Xrays at definite time points, suggesting a higher gene toxicity of heavy ions. NFκB activation was observed after treatment with Xrays or 12C particles. ELISA analyses showed significantly higher IL6 and IL8 levels after irradiation with Xrays and 12C particles compared to non-irradiated controls, whereas cocultures including PBMCs released 2 to 3-fold higher interleukin concentrations compared to mucosa models without PBMCs. In this study, we demonstrated that several pro-inflammatory markers are induced by Xrays and heavy-ion irradiation within an oral mucosa model. This suggests that oral mucositis indeed poses a risk for astronauts on extended space flights.