Substances causing persistent inflammation (asbestos, viruses and pathogens) are often carcinogenic even if they are not directly mutagenic. Reactive oxygen species from inflammatory cells injure DNA and are cell-proliferative leading to accelerated carcinogenesis. Lipid mediators in the linoleic acid (LA) cascade through arachidonic acid (n-6) and some cytokines form amplification cascades to stimulate these processes, whereas the fatty acids of n-3 type competitively suppress the LA cascade and carcinogenesis. This interpretation is consistent with the observations that (1) dietary oils with low n-6/n-3 ratios are suppressive compared with high-LA oils, (2) inhibitors of the LA cascade are suppressive, and (3) manipulations to knockout genes related to the LA cascade are suppressive for carcinogenesis. On the other hand, many kinds of genes are affected differently by the chain length and unsaturation of fatty acids regardless of the n-6 or n-3 type. Saturates, monounsaturates and LA up-regulate cholesterol synthesis leading to enhanced prenylation of oncogene products, cell-proliferation and carcinogenesis. Dietary cholesterol and high tissue cholesterol levels feedback suppress cholesterol synthesis and cell-proliferative stimuli, which partly accounts for epidemiological observations that cancer mortality is lower in the group with higher cholesterol level. For the cancers, the incidence of which is high in the US and has been increasing rapidly in Japan, reducing the intake of LA to half while maintaining those of n-3 fatty acids and animal fats at the levels of average Japanese is recommended.
