ABSTRACT
INTRODUCTION: We investigated the use of dietary omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the treatment of neuroblastoma both as a sole agent and in combination with sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor. RESULTS: Substitution of all dietary fat with menhaden oil (ω-3 PUFA rich) resulted in a 40-70% inhibition of tumor growth and a statistically significant difference in the levels of several PUFAs (18:2 ω-6, 20:4 ω-6, 22:4 ω-6, 20:5 ω-3) as compared with a control diet. Furthermore, tumors from animals on the ω-3 fatty acid (FA)-enriched diet had an elevated triene/tetraene ratio suggestive of a change in local eicosanoid metabolism in these tissues similar to that seen with essential fatty acid deficiency. The ω-3 FA-enriched diet also decreased tumor-associated inflammatory cells and induced mitochondrial changes suggestive of mitochondrial damage. Combination treatment with sunitinib resulted in further reduction in tumor proliferation and microvessel density. DISCUSSION: These findings suggest a potential role for ω-3 PUFAs in the combination treatment of neuroblastoma. METHODS: We used a murine model of orthotopic and subcutaneous human neuroblastoma and diets that differ in the FA content to define the optimal dietary ω-3/omega-6 (ω-6) FA ratio required for the inhibition of these tumors.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Cell Proliferation/drug effects , Diet , Fatty Acids, Omega-3/administration & dosage , Fish Oils/administration & dosage , Indoles/pharmacology , Neuroblastoma/diet therapy , Neuroblastoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrroles/pharmacology , Animals , Arachidonic Acid/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Fatty Acids, Omega-3/metabolism , Fish Oils/metabolism , Humans , Lipid Metabolism , Male , Mice , Mice, SCID , Microvessels/drug effects , Microvessels/pathology , Mitochondria/drug effects , Mitochondria/pathology , Neuroblastoma/blood supply , Neuroblastoma/enzymology , Neuroblastoma/pathology , Sunitinib , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The pathogenesis of infantile hemangioma is unknown. In recent years, much of the focus has been placed at identifying the cell type(s) responsible for tumor initiation. New discoveries in infantile hemangioma suggest an involvement of progenitor cells in the pathogenesis of this vascular tumor. Both embryonic and extra-embryonic tissues have been postulated as potential sources for these progenitor cells. This review focuses on the placental theory, which proposes that a fetal placental progenitor is the cell type of origin for infantile hemangioma. Special emphasis will be placed on placental vasculogenesis and the presence and transit of placental progenitor cells during gestation.
