Abstract 1202: Thrombospondin-1 regulates energy metabolism to increase carcinogenesis in an in vivo model of colorectal cancer

Abstract

Abstract Over 140,000 people will be diagnosed with colorectal cancer in the United States this year, indicating an urgent need to develop therapeutic and dietary strategies to prevent and improve outcomes of this disease. The goal of this study was to determine the biochemical profiles of large intestine originating from wild type, thrombospondin-1 (thbs1) null, ApcMin/+ and ApcMin/+thbs1-/-mice, with the aim of identifying metabolic changes associated with variation in dietary lipids in the presence/absence of thrombospondin-1 (TSP1) as impacting tumorigenesis and tumor burden in ApcMin/+ animals. Our data indicates that expression of TSP1 in the APC-min mouse prevents the development of adenomas in the large intestine in mice fed low fat or high fat diets. On the other hand, lack of TSP1 increases tumor multiplicity in these mice, and up-regulates Ki67 in intestinal tissue. In the current study, general indications of greater uptake and utilization of glucose through glycolysis, as suggested by accumulation of glucose and lactate, in large intestine tissue were noted in the thbs1 null, ApcMin/+, and Apcmin/+thbs1-/- groups upon feeding of a high-fat diet. However, in high fat diet-fed Apcmin/+thbs1-/- mice, reductions in the pentose phosphate pathway (PPP) intermediates 6-phosphogluconate and the isobaric compounds ribulose/xylulose 5-phosphate, along with elevations in ribulose and ribose were also observed. These findings may be indicative of increased glucose utilization through the PPP in Apcmin/+thbs1-/- mice fed a high-fat diet, presumably to support nucleotide synthesis and anabolic processes related to tumor growth and proliferation in the large intestine. Moreover, while elevations in several amino sugars (UDP-glucose, UDP-galactose, UDP-N-acetylglucosamine, and UDP-N-acetylgalactosamine) were noted in WT mice fed a high-fat diet, a marked reduction in these metabolites was observed in Apcmin/+thbs1-/- mice fed a high-fat diet. As amino sugars are synthesized from glucose and play an important role in extracellular matrix structure and cellular communication, changes in these metabolites may be related to alterations in rates of synthesis and/or tumor growth and proliferation. While increased glucose utilization through glycolysis was apparent in large intestine tissue from all of the groups genetically predisposed to development of cancerous lesions and fed a high-fat diet, changes in PPP activity and amino sugars were limited to the Apcmin/+thbs1-/- group. Therefore, these findings may be indicative of metabolic changes that are unique to Apcmin/+thbs1-/- mice, which are particularly susceptible to tumor formation. Therefore these data suggest that TSP1 regulates progression of colon carcinogenesis and define metabolic targets of TSP1 that may contribute to prevention of colorectal cancer. Citation Format: David R. Soto-Pantoja, John M. Sipes, Nicole Morris, Nancy J. Emmenaker, David D. Roberts. Thrombospondin-1 regulates energy metabolism to increase carcinogenesis in an in vivo model of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1202. doi:10.1158/1538-7445.AM2015-1202