Aim of E9-PPCF team:

The aim of E9-PPCF team (Prevention and promotion of carcinogenesis by food)» is to understand why red meat intake and processed meat intake are associated with cancer risk, in order to prevent colorectal cancer. In France, 100 people every day are found to bear a cancer as explained in the Context section below. To reach cancer prevention we test modifications of meat processing and addition of foods or agents that block meat-induced tumor promotion.

Hypothesis and mechanism:

E9-PPCF major hypothesis is that red meat intake and processed meat intake are risk factors for colorectal and other cancers because dietary heme iron promotes cancer. Heme makes beef meat red, and nitrosylated heme is the pink pigment in cooked ham and hot-dogs. Heme would promote cancer by two pathways:
(1) Heme enhances peroxidation of polyunsaturated fats and produces toxic aldehydes, e.g., 4-hydroxynonenal (4-HNE), that would induce or promote cancer.
(2) Nitrosylated heme in cured meat favors formation of N-nitrosated compounds (NOCs) that bind to DNA and can be carcinogenic.

Two complentary approaches:

- We study the effect of experimental diets in rodents that are initiated with a chemical carcinogen, on precancer aberrant crypt foci and mucin depleted foci (ACF, MDF) and on tumors. We also test mechanistic hypotheses on cell lines with apc mutation. Preventive cancer strategies (i.e., specific polyphenolic additives), are validated in human volunteer trials (CRNH Clermont), after screening in rodents studies.(leader: Fabrice Pierre)
- We also study production, metabolism and toxicity of 4-HNE and related alkenals, in animal and cellular models. In line with this approach, Laurence Huc studies 4-HNE effects on apoptosis-proliferation balance in early carcinogenesis steps, and molecular and cellular mechanisms of tumor promotion.(leader: Françoise Guéraud)

Context:

Every day in France, one hundred new colorectal cancer cases are detected, and similar figures are observed in affluent countries. Half of them will die within few years after detection: hence, prevention is not an option. According to the World Cancer Research Fund, the only food whose toxicity would cause colorectal cancer is meat (red meat and processed meat) [AICR/WCRF 2007]. The other convincing causes of colorectal cancer are alcoholic drinks and the excess of caloric intake (measured by obesity, sedentarity, and high caloric density foods).
The major hypotheses explaining how meat could cause colorectal cancer are Fat and heterocyclic amines have been widely studied, but cannot account for the majority of colorectal cancer cases. This is why we study NOC and heme effects, since three laboratories only study them abroad.
These research teams demonstrated that red meat and processed meat intake results in high fecal NOCs in mice and in volunteers (Sidney Mirvish, Omaha, NE ; Sheila Bingham, David Shuker, Cambridge, UK), and that dietary hemin raises cytotoxicity of fecal water and proliferation of rat colon mucosa (Roleof van-der-Meer, Wageningen, Netherlands). Our team collaborates with them all, and published in 2003 and 2004 that heme-loaded diets promote colorectal carcinogenesis in carcinogen-initiated rats, in a dose-dependant manner: The following dietary components promote colorectal carcinogenesis in rats: hemin, hemoglobin, beef meat and blood sausage. Carcinogenesis promotion was associated with fecal and urinary biomarkers: fecal water lipoperoxidation measured with the TBARs assay, fecal water cytotoxicity on three intestinal cell strains, and a urinary metabolite of 4-hydroxynonenal.