EXPRESSION OF MATRIX METALLOPROTEINASES AND THEIR INHIBITORS IN HUMANBRONCHOPULMONARY CARCINOMAS - QUANTIFICATIVE AND MORPHOLOGICAL ANALYSES

The expression of various matrix metalloproteinases (MMPs) and their t issue inhibitors (TIMPs) in 88 primary bronchopulmonary cancers and in 13 neighbouring pulmonary parenchyma samples was quantified by Northe rn-blot analysis, and morphologically examined by in situ hybridizatio n and immunohistochemistry in order to evaluate the involvement of MMP s in the pathophysiology of these carcinomas and to look for potential markers of aggressivity of lung tumours. Northern-blot analysis showe d that the predominantly expressed MMPs in bronchopulmonary cancers we re gelatinase A (66%), its activator MTI-MMP (membrane type-1 matrix m etalloproteinase) (56%) and stromelysin-3 (61%). MMP expression freque ncies and mRNA levels increased progressively with malignant phenotype , lack of differentiation and TNM stage of the tumours, whereas TIMP e xpression decreased very early during tumour progression. Moreover, th e principal MMPs were significantly co-expressed in primary tumours, s uggesting their co-regulation. Morphological studies revealed the expr ession of MMPs and TIMPs essentially in stromal cells in close contact with tumour clusters. These results indicate that tumour progression in bronchopulmonary carcinomas implies a progressive disruption of the MMP/TIMP balance leading to an excess of several MMPs that act in con cert in vivo. Furthermore, the fact that stromal cells are the princip al source of MMPs emphasizes the close cooperation between host cells and cancer cells in tumour invasion. (C) 1997 Wiley-Liss, Inc.