Expression of matrix metalloproteinases and their inhibitors in human bronchopulmonary carcinomas: quantificative and morphological analyses.

The expression of various matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in 88 primary bronchopulmonary cancers and in 13 neighbouring pulmonary parenchyma samples was quantified by Northern-blot analysis, and morphologically examined by in situ hybridization and immunohistochemistry in order to evaluate the involvement of MMPs in the pathophysiology of these carcinomas and to look for potential markers of aggressivity of lung tumours. Northern-blot analysis showed that the predominantly expressed MMPs in bronchopulmonary cancers were gelatinase A (66%), its activator MT1-MMP (membrane-type-1 matrix metalloproteinase) (56%) and stromelysin-3 (61%). MMP expression frequencies and mRNA levels increased progressively with malignant phenotype, lack of differentiation and TNM stage of the tumours, whereas TIMP expression decreased very early during tumour progression. Moreover, the principal MMPs were significantly co-expressed in primary tumours, suggesting their co-regulation. Morphological studies revealed the expression 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 concert in vivo. Furthermore, the fact that stromal cells are the principal source of MMPs emphasizes the close cooperation between host cells and cancer cells in tumour invasion.