Glucose deprivation, hypoxia and acidosis are characteristic features of the central core of most solid tumours. Myofibroblasts are stromal cells present in many such solid tumours, including those of the colon, and are known to be involved in all stages of tumour progression. HMGB1 is a nuclear protein with an important role in nucleosome stabilisation and gene transcription; it is also released from immune cells and is involved in the inflammatory process. We report that the microenvironmental condition of glucose deprivation is responsible for the active release of HMGB1 from various types of cancer cell lines (HT-29, MCF-7 and A549) under normoxic conditions. Recombinant HMGB1 (10 ng/ml) triggered proliferation in myofibroblast cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose-deprived HT-29 colon cancer cells stimulated the migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGB1, RAGE and TLR4, together with specific inhibitors of PI3K and MEK1/2. Our data suggest that HMGB1 released from cancer cells under glucose deprivation is involved in stimulating colonic myofibroblast migration and invasion and that this occurs through the activation of RAGE and TLR4, resulting in the activation of the MAPK and PI3K signalling pathways. Thus, HMGB1 might be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts and is a potential therapeutic target to inhibit solid tumour growth.

-dimethyl-3-(4-chlorophenyl)urea) is a non-selective phenylurea herbicide, widely used in developing countries although concerns have been raised about its toxicity and carcinogenicity. Monuron was evaluated by the National Toxicology Program in 1988 and shown to be a male rat-specific renal carcinogen. We report that oral administration of Monuron to male rats for 3 days, leads to a larger number of genes being differentially expressed in the renal-cortex than in the liver. Further, we observed up-regulation of cell cycle genes and genes involved in cell proliferation in the renalcortex while in the liver xenobiotic metabolising enzymes were up-regulated. We also identified one commonly down-regulated gene in both organs -fragile histidine triad gene (Fhit), a putative tumour suppressor gene; however the down-regulation was only significant at the protein level in the liver. In addition, we conducted in vitro wholegenome transcriptomics studies with human and rat renal cortical cells. Rat cells exposed to Monuron showed down-regulation of sterol biosynthesis, spliceosome and cell cycle genes and up-regulation of genes involved in amino acid metabolism and transport. No genes were found to be differentially expressed in human cells exposed to Monuron. Overall, the findings from the in vitro studies showed very little overlap with the whole animal findings.

No abstract

No abstract