Abstract
Abstract
Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood.
It has been previously shown that caloric restriction, which induces ketosis, reduces microvessel density in mouse and human brain tumor models, suggesting an anti-angiogenic effect. We now report that in animals fed KetoCal® (KC) (4:1 fat:protein/carbohydrates) ad libitum, peritumoral edema is significantly reduced early in tumor progression when compared to those fed a standard rodent diet (SD). Western blot analysis showed a reduction of platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) in tumors from animals maintained on KC. These results were supported by immunohistochemical staining for CD31 which also revealed abnormal vessel structure in the tumors from animals fed SD but not in those fed KC, suggesting a normalizing effect by the KC. Furthermore gene expression profiling demonstrated that KC decreases expression of a group of genes involved in angiogenesis and vessel structuring including the genes encoding vascular endothelial growth factor B (VEGFB) and angiopoetin 1 receptor (TEK), integrin beta 1 (ITGB1), urokinase-type plasminogen activator (PLAU) and tissue inhibitor of metalloproteases 1 (TIMP1). Taken together our data suggests that KC alters the angiogenic processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use.
Citation Format: Eric C. Woolf, Julie A. Charlton, Qingwei Liu, Gregory Turner, Mark C. Preul, Adrienne C. Scheck. Metabolic therapy reduces expression of PECAM-1/CD31 and decreases peritumoral edema in a mouse model of malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2014-1440