Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin.
Matrix metalloproteinases (MMPs) classically have been implicated in basement membrane destruction associated with late-stage tumor cell invasion and metastasis. However, recent studies have demonstrated that one MMP family member, matrilysin, is expressed in a high percentage of early-stage human colorectal tumors. We analyzed matrilysin expression in benign intestinal tumors from mice heterozygous for the ApcMin allele (Min/+) and found that the mRNA was induced in the majority (88%) of these adenomas. Protein was detected in the tumor cells, where, surprisingly, it was predominantly immunolocalized to the lumenal surface of dysplastic glands rather than the basement membrane or extracellular matrix. To address the role of matrilysin in Min intestinal tumorigenesis, we generated Min/+ mice deficient in this MMP by gene targeting and homologous recombination. The absence of matrilysin resulted in a reduction in mean tumor multiplicity in Min/+ animals of approximately 60% and a significant decrease in the average tumor diameter. Based on these findings, we conclude that matrilysin is a suppressor of the Min phenotype, possibly by functioning in a capacity independent of matrix degradation. These results argue for the use of MMP inhibitors in the treatment and prevention of early-stage colon cancer.
Wilson
C L
CL
Department of Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
Heppner
K J
KJ
Labosky
P A
PA
Hogan
B L
BL
Matrisian
L M
LM
D000236:Adenoma / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D002999:Clone Cells; D004195:Disease Models, Animal; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020783:Matrix Metalloproteinase 7; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D013234:Stem Cells; D014018:Tissue Distribution
D008666:Metalloendopeptidases; D020783:Matrix Metalloproteinase 7