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-a2 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. Ó2011 AACR.

Hyperpolarized 13C Spectroscopy Detects Early Changes in Tumor Vasculature and Metabolism after VEGF Neutralization

“…Furthermore, the decrease in median tumor ADC and narrowing of the ADC histogram observed here (Fig. 5) has been observed previously after anti-VEGF treatment in both preclinical (22) and clinical (23,50) studies, in which it has been attributed to a variety of factors, including cell swelling (22), atypical necrosis, and chronic hypoxia (50), as well as decreased edema (23).…”

“…The interplay between tumor vascularity and metabolism is of significant interest, as high glucose metabolism with low blood flow correlates with poorer patient outcomes (20,21). The glycolytic phenotype of tumor xenografts was recently found to play a role in the response of preclinical tumor models to anti-VEGF therapy (22). Furthermore, metabolic changes measured with proton magnetic resonance spectroscopy (MRS) in glioblastoma multiforme tumors treated with cediranib are highly predictive of 6-month overall survival (23).…”

VEGF-Targeted Therapy Stably Modulates the Glycolytic Phenotype of Tumor Cells

“…We recently reported that short-term anti-VEGF therapy causes severe impairment of glucose and ATP levels in tumors (14). In this study, we also found that the response to short-term VEGF blockade is strongly dependent on the glycolytic phenotype of the tumor.…”

“…Metabolic alterations in cancer cells may derive from genetic changes associated with cell transformation such as dysregulated activity of HIF1 (9), loss of p53 or altered expression of c-Myc or Akt (10), or be triggered by inhibition of mitochondrial respiration (11). Moreover, changes in tumor metabolism can also follow reduction in energy sources (O 2 , glucose, glutamine) in the tumor microenvironment associated with antiangiogenic therapy (12)(13)(14).…”

“…In this study, we also found that the response to short-term VEGF blockade is strongly dependent on the glycolytic phenotype of the tumor. Specifically, highly glycolytic tumor xenografts developed large necrotic areas following shortcourse VEGF neutralization, whereas xenografts characterized by relatively low glycolytic activity remained substantially viable (14). To investigate whether metabolic features could affect the therapeutic outcome, here we analyzed long-term effects of anti-VEGF treatment on tumor xenografts characterized by different levels of glucose addiction.…”