Nutritive carbohydrates determine tumor progression in murine hepatocellular carcinoma: An innovative approach for therapy?

• Applicant: Professor Dr. Thorsten Cramer
• Subject Area: General and Visceral Surgery ; Gastroenterology ; Hematology, Oncology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 300071103

Hepatocellular carcinoma (HCC) is becoming a major health problem in Western societies due to constantly rising incidence and lack of effective long-term treatment options. HCC is characterized by robust therapy resistance, resulting in very poor prognosis of patients with inoperable tumors. Detailed molecular and biochemical analysis of HCC pathogenesis is of pivotal importance to identify new therapy targets. Deregulated energetics and alterations of cellular metabolism represent emerging hallmarks of cancer. In previous work, we and others obtained experimental evidence for activation of glycolysis in human HCC and murine model systems. Against this background, we decided to characterize the effect of the established chemical glycolysis inhibitor 2-deoxy-D-gluocse (2-DG) on HCC growth. While 2-DG was indeed able to inhibit HCC growth in vitro, the substance failed to exert significant growth inhibiting properties in two murine HCC models. Enhanced glucose uptake has been described to mediate resistance towards 2-DG. Indeed, reducing glucose levels in cell culture media by 75% resulted in significantly enhanced antiproliferative efficacy of 2-DG. In order to analyze this effect in vivo, we fed a diet with reduced carbohydrate content (15% as compared to 50% in standard chow) to HCC-bearing mice. While the diet did not modify the in vivo efficacy of 2-DG, carbohydrate restriction per se resulted in significantly reduced tumor progression and survival. These results are especially intriguing as the applied murine HCC model is completely resistant towards conventional chemotherapy (e.g. etoposide and doxorubicin) as well as sorafenib. Given the activated glycolysis we hypothesized that the dietary intervention would inhibit tumor growth via reduced glucose availability. However, neither glucose levels in blood nor in tumor tissue (determined via mass spectrometry-based metabolomics) was significantly reduced via dietary carbohydrate restriction. Carbohydrate consumption is the most important determinant of insulin secretion and insulin represents an established pro-tumorigenic growth factor in HCC. Indeed, we were able to show significantly reduced activation of the insulin receptor/Akt/mTOR pathway upon carbohydrate restriction. Taken together, our results support a critical role of macronutrient composition, especially carbohydrate content, for HCC pathogenesis. As low carbohydrate diets have been safely used for almost a century, clinical application of these results seems feasible. Taken together, the following key questions emerge: Are the tumor inhibiting effects of the dietary intervention reproducible in additional rodent HCC models? Is carbohydrate restriction safe and effective in HCCs associated with liver fibrosis? How effective is carbohydrate restriction in combination with sorafenib, the standard therapy of inoperable HCC? These questions will be addressed in detail in the outlined project proposal.

• DFG Programme: Research Grants