title: Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the Apc(Min/+) model of colon cancer.
abstract: Thrombospondin 1 is a glycoprotein that regulates cellular phenotype through interactions with its cellular receptors and extracellular matrix-binding partners. Thrombospondin 1 locally regulates angiogenesis and inflammatory responses that contribute to colorectal carcinogenesis in Apc(Min/+) mice. The ability of thrombospondin 1 to regulate responses of cells and tissues to a variety of stresses suggested that loss of thrombospondin 1 may also have broader systemic effects on metabolism to modulate carcinogenesis. Apc(Min/+):Thbs1(-/-) mice exhibited decreased survival and higher tumor multiplicities in the small and large intestine relative to Apc(Min/+) mice when fed a low (5%) fat western diet. However, the protective effect of endogenous thrombospondin 1 was lost when the mice were fed a western diet containing 21% fat. Biochemical profiles of liver tissue identified systemic metabolic changes accompanying the effects of thrombospondin 1 and dietary lipid intake on tumorigenesis. A high-fat western diet differentially regulated elements of amino acid, energy and lipid metabolism in Apc(Min/+):Thbs1(-/-) mice relative to Apc(Min/+):Thbs1(+/+)mice. Metabolic changes in ketone body and tricarboxylic acid cycle intermediates indicate functional interactions between Apc and thrombospondin 1 signaling that control mitochondrial function. The cumulative diet-dependent differential changes observed in Apc(Min/+):Thbs1(-/-) versus Apc(Min/+) mice include altered amino acid and lipid metabolism, mitochondrial dysfunction, eicosanoids and ketone body formation. This metabolic profile suggests that the protective role of thrombospondin 1 to decrease adenoma formation in Apc(Min/+) mice results in part from improved mitochondrial function.
authors.affiliation: Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Surgery, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Soto-Pantoja
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Sipes
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Martin-Manso
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: B
authors.initials: B
authors.lastname: Westwood
authors.affiliation: Chemical Biology Laboratory, National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Morris
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Emenaker
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Roberts