Dietary factors and growth and metabolism in experimental tumors

Abstract 

Development of a diet that provides adequate nutrition and effective cancer prevention is an important goal in nutrition and cancer research. A confounding aspect of dietary control of tumor growth is the fact that some nutrients may up-regulate tumor growth, whereas other nutrients and nonnutrients down-regulate growth. Both up- and down-regulators may be present in the same foodstuff. Identification of these substances, determination of their mechanisms of action and potencies, as well as the interactions among the different mechanisms are topics of ongoing research. In this review, we describe results obtained in vivo or during perfusion in situ using solid tissue-isolated rodent tumors and human cancer xenografts in nude rats. Linoleic acid (LA), an essential n-6 polyunsaturated fatty acid (PUFA), was identified as an agent in dietary fat that is responsible for an up-regulation of tumor growth in vivo. Tumor LA uptake, mediated by high intratumor cAMP, stimulated formation of the mitogen, 13-hydroxyoctadecadienoic acid (13-HODE) and also increased ERK1/2 phosphorylation, [³H]thymidine incorporation and growth. A mechanism for control of this growth-promoting pathway was revealed during studies of the effects of dietary nutrients and nonnutrients known to inhibit tumor growth. These included four groups of lipophilic agents: n-3 fatty acids, melatonin, conjugated LA isomers and trans fatty acids. Each of these agents activated an inhibitory G protein-coupled receptor-mediated pathway that specifically suppressed tumor uptake of saturated, monounsaturated and n-6 PUFAs, thereby inhibiting an early step in the LA-dependent growth-promoting pathway.

Abbreviations: 8-Br-cAMP, 8-bromo-cyclic adenosine monophosphate, CLA, conjugated linoleic acid, COX-2, cyclooxygenase-2, DHA, docosahexaenoic acid, EFA, essential fatty acid, EFAD, essential fatty acid-deficient, EPA, eicosapentaenoic acid, ER, estrogen receptor, FATP, fatty acid transport protein, GPCRs, G protein-coupled receptors, LCACS, long-chain acyl-CoA synthetase, pAkt, phosphorylated-amino kinase terminal kinase, pERK1/2, phosphorylated extracellular signal-regulated kinase1/2, pMEK, phosphorylated-mitogen activated protein kinase, FA, fatty acid, 13-HODE, 13-hydroxyoctadecadienoic acid, LA, linoleic acid, PTX, pertussis toxin, PUFA, polyunsaturated fatty acid

Keywords: Linoleic acid, n-3 Fatty acids, Dietary fish oil, Melatonin, CLA isomers