Role of Matrix Metalloproteinases in Colorectal Carcinogenesis

Abstract

ObjectiveTo measure coexpression of matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9 genes by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in benign and malignant phases of colorectal carcinogenesis. Summary Background DataMatrix metalloproteinases degrade and remodel the extracellular matrix and have been implicated in facilitating carcinoma cells to invade and metastasize. MMP-2, MMP-7, and MMP-9 have been shown to be overexpressed in various carcinomas; however, simultaneous examination of these enzymes in human normal mucosa, adenoma, and carcinoma has not been performed to date. MethodsBetween January 1, 1998, and June 15, 2000, 40 patients underwent colectomy and harvest and snap-freezing of normal mucosa, adenoma, and carcinoma. Five patients had adenoma and carcinoma in the same specimen; 35 had either adenoma (n ϭ 6) or carcinoma (n ϭ 29). Taqman qRT-PCR methodology was used to measure MMP gene copy number and normalized to ␤-actin RNA expression. ResultsThe mean age was 62 Ϯ 4 years, with 22 men and 18 women. One fifth of the adenomas exhibited severe dysplasia. MMP-7 gene expression was significantly increased in adenomas (43 times normal mucosa) but did not increase further in carcinomas (50 times normal mucosa). MMP-2 and MMP-9 were not different in adenomas (1.8 and 1.4 times normal mucosa, respectively) but were elevated in carcinomas (2.2 and 1.8 times normal mucosa, respectively). There was no correlation between size or dysplasia in adenomas or AJCC stage in carcinomas and MMP gene expression. ConclusionsOverexpression of MMP-7 is an early event in the adenomato-carcinoma pathway, and expression does not appear to increase further in carcinomas. MMP-2 and MMP-9 appear to be primarily overexpressed in carcinomas. This may be one mechanism by which adenoma cells gain the ability to invade and carcinoma cells to metastasize.Colorectal cancer is a major health concern, with approximately 140,000 new cases and 56,000 cancer deaths each year. There are clear genetic syndromes, such as familial adenomatous polyposis and hereditary nonpolyposis colon cancer, that increase the risk of colon cancer, primarily by the early onset and increased number of adenomatous polyps.1 These syndromes are estimated to account for approximately 15% of all colon cancers and therefore make up the minority. Outside of known genetic predisposition, the largest risk for the development of colon cancer is in the patient with sporadic adenomatous polyps. 2 These adenomatous polyps and subsequent carcinoma appear to develop with sequential genetic alterations.3 Multiple genes including p53, deleted in colon cancer, 2 and more recently alterations in matrix metalloproteinase (MMP) 4 have been associated with polyp development. The interrelationships between these alterations, polyp development, and progression to carcinoma are not well understood.MMPs generally function to degrade proteoglycans and matrix glycoproteins. This process of remodeling of the extracellular matrix is an integral...

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