Risk and risk reduction involving arginine intake and meat consumption in colorectal tumorigenesis and survival

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Abstract
Elevated polyamine and nitric oxide levels (both derived from arginine) promote tumorigenesis, whereas non‐steroidal anti‐inflammatory drugs (NSAIDs) inhibit colorectal cancer (CRC) incidence in experimental and epidemiologic studies. We investigated dietary arginine‐induced intestinal tumorigenesis and NSAID‐inhibitory effects in ApcMin/+ mice differentially expressing nitric oxide synthase‐2 (Nos2). We also studied effects of estimated arginine exposures through meat consumption on tumor characteristics and survival in human CRC cases. Dietary arginine increased high‐grade colon adenoma incidence in ApcMin/+Nos2+/+ mice, but not in Nos2 knockout mice. Additionally, celecoxib suppressed intestinal steady state ornithine decarboxylase RNA levels (p < 0.001), induced steady state spermidine/spermine N1‐acetyltransferase RNA levels (p = 0.002), decreased putrescine levels (p = 0.04) and decreased tumor number in the small intestines of ApcMin/+Nos2+/+ mice (p = 0.0003). Five hundred and eleven cases from our NCI‐supported CRC gene‐environment study were analyzed based on self‐reported meat (as a surrogate for arginine) consumption. Familial CRC cases (n = 144) in the highest meat consumption quartile (Q4) had no statistically significant differences in tumor grade compared to cases in Q1–Q3 (p = 0.32); however, they were observed to have decreased overall survival (OS) (10‐year OS = 42% vs. 65%; p = 0.017), and increased risk of death in an adjusted analysis (hazards ratio [HR] = 2.24; p = 0.007). No differences in tumor grade, OS or adjusted HR were observed for sporadic CRC cases (n = 367) based on meat consumption. Our results suggest important roles for arginine and meat consumption in CRC pathogenesis, and have implications for CRC prevention.