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

Sinnamon MJ, Carter KJ, Fingleton B, Matrisian LM
Int J Exp Pathol. 2008 89 (6): 466-75

PMID: 19134056 · PMCID: PMC2669608 · DOI:10.1111/j.1365-2613.2008.00621.x

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.

MeSH Terms (16)

Adenomatous Polyposis Coli Animals Breeding Colonic Neoplasms Genes, APC Immunohistochemistry Intestinal Mucosa Matrix Metalloproteinase 2 Matrix Metalloproteinase 9 Matrix Metalloproteinase 12 Matrix Metalloproteinases, Secreted Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Fluorescence Neutrophils

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