LOCALIZATION OF TRANSFORMING GROWTH-FACTOR BETA(1) MESSENGER-RNA IN COLORECTAL NEOPLASIA - CORRELATION WITH ANTIGEN EXPRESSION OF GELATINASE AND TISSUE INHIBITORS OF METALLOPROTEINASE

Transforming growth factor beta(1) is a growth modulator which acts as a strong inhibitor of epithelial cells and promotes connective tissue formation by stimulating the synthesis of extracellular matrix compon ents and by suppressing proteolytic activity through reduced proteinas e synthesis and by increased inhibitor expression. To investigate the relationship between TGF-beta(1) and extracellular matrix components, we analysed by in situ hybridisation mRNA TGF-beta(1) and by immunohis tochemistry TGF-beta(1) protein expression in 24 colorectal neoplasias (10 adenocarcinomas and 14 adenomas, 2 of which were associated with moderate and 1 with severe dysplasia) and correlated TGF-beta(1) with the antigenic expression and distribution of metalloproteinase (72 kDa gelatinase type IV collagenase (MMP-2), anti-stromelysin 3 (MMP-3)) a nd of the MMP tissue inhibitors (MMP-1 and -2). All adenocarcinomas co ntained higher TGF-beta(1) and MMP levels, and 90% expressed TIMPs. In contrast, 71% of the adenomas expressed TGF-beta(1), 93% MMP-2, 71% M MP-3, 93% TIMP-1 and 64% TIMP-2. In colonic adenocarcinoma TGF-beta(1) , MMPs and TIMPs correlated significantly with Duke's staging and hist ological differentiation. In addition, tubular adenoma associated with moderate and severe dysplasia showed greater expression of TGF-alpha( 1), MMPs and TIMPs than adenoma and non neoplastic colonic mucosa. Our findings suggest that, like other growth modulators, TGF-beta(1) prot ects extracellular matrix degradation under physiological conditions a nd enhances its proteolytic activity during various pathological condi tions, thus regulating MMP and TIMP activity. The increased expression of metalloproteinases and their inhibitors found in colorectal carcin omas indicates that these antibodies could be used as markers of human colorectal tumor invasiveness and malignant changes.