Expression profiling of murine intestinal adenomas reveals early deregulation of multiple matrix metalloproteinase (Mmp) genes.
Initiation of intestinal tumours occurs as a consequence of aberrant Wnt signalling. This causes altered expression of a number of genes which provides the mechanistic basis of neoplastic change in normal epithelium. In order to identify these genes, expression profiles of normal intestinal mucosa and intestinal adenomas from multiple intestinal neoplasia (Min) mice were compared. A total of 116 genes were found to show significant changes in expression in adenomas compared with normal mucosa. Functional classification of these genes clearly identified the biological processes of cellular adhesion and matrix remodelling to be profoundly affected. Notably, three members of the matrix metalloproteinase (Mmp) gene family (Mmp10, Mmp13, and Mmp14) were consistently up-regulated in tumour tissue. To extend these data, expression of 17 Mmp genes was defined using quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR). Several Mmp genes were profoundly up-regulated and every tumour showed overexpression of at least four Mmp genes. These results underscore the probable importance of interactions between the intestinal epithelium and stroma in early tumour development. Furthermore, the inferred role of Mmps at the adenomatous stage of tumourigenesis suggests that this may represent the optimal therapeutic window for the use of Mmp antagonists as anti-cancer agents.
Martinez
Cristina
C
Oxford Molecular Pathology Group, The Women's Centre, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
Bhattacharya
Sumit
S
Freeman
Tom
T
Churchman
Michael
M
Ilyas
Mohammad
M
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017364:Collagenases / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D053506:Matrix Metalloproteinase 10; D053509:Matrix Metalloproteinase 13; D053511:Matrix Metalloproteinase 14; D020782:Matrix Metalloproteinases / Q000235:genetics*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
C507096:Mmp14 protein, mouse; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; C498537:Mmp17 protein, mouse; D053506:Matrix Metalloproteinase 10; D053511:Matrix Metalloproteinase 14