Intestinal flora and cancer rates in p53-deficient mice

As animal facilities of research institutions strive to provide ever cleaner and microbiologically better controlled conditions researchers observe a decrease of tumor frequencies, multiplicity and increases in latency in transgenic mouse strains susceptible to spontaneous tumor development. In parallel, they also observe a reduction in intestinal microbial diversity. A causal link between reduced microflora diversity and decreased tumor rates has not yet been established experimentally. If established, it is not explained by elimination of pathogenic species since original conditions were considered pathogen-free already. Instead it is conceivably an indirect effect in which some species evoke a stronger immune response than others and the associated release of radical oxygen species is detrimental. In any case, if a link between intestinal microbial diversity and tumor rates is corroborated it might have general implications for lymphomagenesis and colon cancer formation. We propose testing this possible link by studying tumor frequencies, DNA damage, cell proliferation, apoptosis and lymphocyte development in p53 knock-out mice kept under differing maintenance conditions. The p53 tumor suppressor gene is central to cellular damage response by regulating cell cycle arrest and apoptosis upon cellular stress conditions. Half or more of all human tumors examined show mutations in p53. In colon carcinoma more than 75% have p53 mutations. Mice deficient for p53 are viable and developmentally normal but highly susceptible to early onset of cancer. They show mostly malignant lymphoma, soft tissue sarcomas or osteosarcoma. The p53(+/-) heterozygous mice are an accepted model by several regulatory agencies as alternative model for oncogenicity bioassays. Mice deficient for p53 are therefore ideally suited to investigate the possible link between intestinal microbial diversity and spontaneous tumor development. Our approach is a comprehensive evaluation of the effects of intestinal flora on genetic instability by measuring the occurrence of DNA-deletions in vivo, monitoring changes in cell proliferation, cell cycle, T-cell maturation and of programmed cell death in lymphatic tissue. We will compare mice with conventional microflora to mice with limited intestinal flora (LF) of 4 bacterial species only and LF mice sensitized with sodium dextrane sulphate. A link between intestinal microbial diversity and tumor rates, if corroborated, might have implications for our understanding of lymphomagenesis and colon cancer formation in general. In addition, it would disclose another important health aspect in the relationship between intestinal microflora and host.