Matrix metalloproteinase‐9 contributes to intestinal tumourigenesis in the adenomatous polyposis coli multiple intestinal neoplasia mouse

Matrix metalloproteinases (MMPs) are a family of 23 extracellular proteases that are best known for their collective ability to degrade all components of the extracellular matrix. We previously demonstrated that genetic ablation of MMP‐7 reduced tumour multiplicity in multiple intestinal neoplasia (Min) mice possessing a genetic alteration in the adenomatous polyposis coli gene (APC). These mice, commonly referred to as APC‐Min mice, are a frequently used model of early intestinal tumourigenesis. To examine further the role of MMPs in intestinal tumour development, we generated APC‐Min mice genetically deficient in MMP‐2, ‐9, ‐12 or ‐19. Genetic ablation of MMP‐2, ‐12 or ‐19 did not affect multiplicity or size of intestinal tumours when crossed into the APC‐Min system. However, MMP‐9 deficient animals developed 40% fewer tumours than littermate controls, although tumour size distribution remained unaffected. Intestinal adenomas from MMP‐9 deficient mice demonstrated a 50% decrease in proliferating cells compared with control tissues, with no difference in apoptosis. To determine the cellular origin of MMP‐9 in these tumours, immunofluorescent co‐staining with markers for different leucocyte lineages was used to demonstrate that intratumoural MMP‐9 is largely a product of neutrophils. These studies extend the potential targets for chemoprevention of intestinal adenomas to MMP‐9 in addition to MMP‐7 and exclude MMP‐2,‐12,‐19 as attractive targets for intervention.