Bowel irradiation: the effects on inflammation and matrix-metalloproteinases

Abstract: Background and aims: Radiotherapy is a valid treatment in cancer multimodal management but it is affected by severe systemic and local side effects. A murine small bowel model was used for the investigation of inflammatory features and apoptosis of local radiotherapy. Similarly the same model was used to analyze the combined effects of radiotherapy and antibiotics in the expression of matrilysin, MMP involved in murine bowel, in the production of antimicrobical peptides when it is exposed to bacteria. Matrilysin is furthermore expressed in human colorectal cancer and can be overxpressed by radiation exposure. Clinical studies of radiated and non radiated colorectal patients were used to correlate matrilysin expression with different tumor stages and different radiotherapy protocols.Results: Features of radiation injury observed in murine small bowel may be mainly summarized as early increases of inflammatory proteins as MIP-2, a decrease in leucocyte CD 45 positive cells over time and increased dose dependent cellular death. Not only radiotherapy or antibiotics alone, but the combination of both preoperative radiotherapy and antibiotics leads to marked increases in matrilysin expression in the rodent intestine. Higher levels of matrilysin in stage I/II adenocarcinoma compared to stage III/IV and varying grades of dysplasia were observed in non radiated colo-rectal cancers. Radiotherapy affects MMP-7 expression in different grade depending on the radiation dose delivered with long course therapy showing limited effect on MMP-7 expression.Conclusions: a murine model of local irradiation is effective in studying the early radiation-induced tissue injury of small bowel. Radiotherapy tends to override the effect of antibiotics and leads to an up-regulation of MMP-7 and TGF-β and MIP-2 expression in the murine intestine. Significantly increased concentrations of MMP-7 in tumor tissues, lymph nodes and in serum is associated with increasing grade of dysplasia and adenocarcinoma infiltration. Immunohistochemistry and ELISA are simple cost-benefit methods when examining tumor behaviour in resected specimens. High dose (50 Gy) radiotherapy administered in preoperatively long course induces significantly less MMP-7 over-expression compared to short term 25 Gy irradiation at surgery and which itself has an overriding effect of up regulation of MMP-7.