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

Abstract

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.

Activity of type IV collagenases (MMP-2 and MMP-9) in primary pulmonary carcinomas: a quantitative analysis

“…The most important inference of our study is that both type IV collagenases tested are significantly overproduced in tumor tissue compared with uninvolved lung. Our results are only partially consistent with those obtained by others (Urbanski et al 1992;Nawrocki et al 1997;Kodate et al 1997;Brown et al 1993). Two studies on lung cancer using Northern analysis, immunohistochemistry, and in situ hybridization (Urbanski et al 1992;Nawrocki et al 1997) showed that MMP-9 was absent from normal lung parenchyma, whereas we detected this enzyme in all specimens tested, although the total MMP-9 activity was twofold higher in lung cancer preparations than in normal lung parenchyma, and the activation in half of the cases of lung cancer was visible.…”

“…Our results are only partially consistent with those obtained by others (Urbanski et al 1992;Nawrocki et al 1997;Kodate et al 1997;Brown et al 1993). Two studies on lung cancer using Northern analysis, immunohistochemistry, and in situ hybridization (Urbanski et al 1992;Nawrocki et al 1997) showed that MMP-9 was absent from normal lung parenchyma, whereas we detected this enzyme in all specimens tested, although the total MMP-9 activity was twofold higher in lung cancer preparations than in normal lung parenchyma, and the activation in half of the cases of lung cancer was visible. Contrary to the results obtained by other researchers (Urbanski et al 1992;Nawrocki et al 1997), Brown et al, using gelatin zymography, detected MMP-9 activity in all normal non-neoplastic lungs and in all specimens of non-small cell lung cancer (NSCLC) (Brown et al 1993).…”

Expression and activity of matrix metalloproteinases-2 and -9 in serum, core needle biopsies and tissue specimens of prostate cancer patients

“…Investigations on potential new prognostic markers are, therefore, an important prerequisite for the development of optimized therapy strategies. MMP-2 and MMP-9 have been reported to be associated with tumor progression in various types of cancer, and several studies have reported their role in PCa [4,5,6,15,19,21,25,35]. This is the first report in which the expression and activity of MMP-2 and MMP-9 has been investigated in prostatic tumor tissue from core needle biopsies and radical prostatectomies, as well as serum probes of the same patient group.…”

“…They specifically cleave type-IV collagen, the major structural component of basement membranes. Increased expression of MMP-2 and MMP-9 has been associated with malignant progression in various cancer types, such as breast, lung or colorectal cancers [4,6,15,19,25,35]. Studies on MMP-2 and MMP-9 expression and activity in human PCa have been focused on cell culture systems or blood specimens of cancer patients [5,8,14,21,33], although only sparse data is available for prostatic tissue directly [2,9,26,29,30].…”

Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro

“…The over-expression of MMPs, leading to a disruption of the balance between MMPs and TIMPs, has been extensively reported in various carcinoma types. In that way, MMPs have been implicated in early as well as in late stages of cancer progression, in particular in cell growth, invasion, angiogenesis, and metastasis (Chambers and Matrisian 1997;Curran and Murray 1999;Egeblad and Werb 2002;Nawrocki et al 1997;Park et al 2004). MMP over-expression is also associated with the acquisition of invasiveness by tumor cells in vitro.…”