Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Medical Sciences

Major Professor

Dominic P. D'Agostino

Keywords

cancer metabolism, ketone, metastasis, Warburg effect

Abstract

Cancer cells exhibit an abnormal metabolic phenotype characterized by glycolysis and lactate fermentation in the presence of oxygen, a phenomenon known as the Warburg effect. This dysregulated metabolism plays an important role in every aspect of cancer progression, from tumorigenesis to invasion and metastasis. The Warburg effect is a common phenotype shared by most, if not all, cancer types. It is especially prominent in metastatic tumors, which are notoriously resistant to treatment and responsible for the majority of cancer-related deaths. Thus, metabolic therapies which target the Warburg effect could offer novel therapeutic options for most cancer patients, including those with aggressive or late-stage cancers. The ketogenic diet is a high fat, low carbohydrate diet that induces a physiological state of nutritional ketosis - decreased blood glucose and elevated blood ketones. It has been investigated as a cancer therapy for its potential to exploit the Warburg effect by restricting glucose availability to glycolysis-dependent tumors, and has been reported to slow cancer progression in some animal models as well as in anecdotal reports and small clinical studies in humans. Interestingly, there is some evidence that the elevation in blood ketones induced by the ketogenic diet contributes to its anti-cancer effects, suggesting that ketone supplementation could possibly inhibit cancer progression on its own. Rapid growth outstrips a tumor's ability to adequately perfuse its tissue, creating regions of tumor hypoxia which exacerbate the Warburg effect and promote a malignant phenotype. Hyperbaric oxygen therapy is the administration of 100% oxygen at elevated barometric pressure. It supersaturates the blood with oxygen, increasing its diffusion distance into the tissues, and can therefore be used to increase intratumoral pO2 and reverse tumor hypoxia. Here we present evidence that the ketogenic diet, ketone supplementation, and hyperbaric oxygen therapy work individually and in combination to slow progression and extend survival in the VM-M3 model of metastatic cancer. This study strongly suggests that these cost effective, non-toxic metabolic therapies should be further evaluated in animal and human studies to determine their potential clinical use.

Included in

Oncology Commons

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