Tumor collagenase stimulatory factor (TCSF) expression and localization in human lung and breast cancers.

Tumor cell-derived collagenase stimulatory factor (TCSF) stimulates in vitro the biosynthesis of various matrix metalloproteinases involved in tumor invasion, such as interstitial collagenase, gelatinase A, and stromelysin 1. The expression of TCSF mRNAs was studied in vivo, using in situ hybridization and Northern blotting analysis, in seven normal tissues and in 22 squamous cell carcinomas of the lung, and in seven benign proliferations and in 22 ductal carcinomas of the mammary gland. By in situ hybridization, TCSF mRNAs were detected in 40 of 44 carcinomas, in pre-invasive and invasive cancer cells of both lung and breast cancers. TCSF mRNAs and gelatinase A mRNAs were both visualized in the same areas in serial sections in breast cancers, and were expressed by different cells, tumor cells, and fibroblasts. The histological results were confirmed by Northern blot analysis, which showed a higher expression of TCSF mRNAs in cancers than in benign and normal tissues. These observations support the hypothesis that TCSF is an important factor in lung and breast tumor progression

Matrix-metalloproteinases in bronchopulmonary carcinomas

Matrix metalloproteinases (MMPs) represent a group of enzymes involved in the degradation of most of the components of the extracellular matrix and therefore participate in tumoural invasion. MMPs, especially gelatinases A and B, MT1-MMP, the activator of gelatinase A, and stromelysin-3 were found overexpressed in many cancers including bronchopulmonary carcinomas. In vivo observations revealed that fibroblasts are the principal source of production of MMPs. Some of these enzymes such as MT1-MMP and stromelysin 3, displayed a focal stromal localisation near preinvasive and invasive tumour clusters. Futhermore, some tumour cell lines were shown to stimulate the expression of MT1-MMP by fibroblasts. All these in vivo and in vitro results suggest that certain tumour cells produce diffusible factors which could influence the MMP stromal expression. Among these factors, the TCSF (Tumor Collagenase Stimulatory Factor) which is known to upregulate some MMPs in vitro could be a good candidate for this stromal regulation, since it is produced by bronchial tumour cells in vivo. In this review, we address such a cooperation between tumour and stromal cells for the production of MMPs and emphasize their necessity for tumoural progression in bronchopulmonary carcinomas

Regulation of membrane-type 1 matrix metalloproteinase expression by zonula occludens-2 in human lung cancer cells.

During tumor invasion, tumor epithelial cells acquire migratory and invasive properties involving important phenotypic alterations. Among these changes, one can observe reorganization or a loss of cell-cell adhesion complexes such as tight junctions (TJs). TJs are composed of transmembrane proteins (occludin, claudins) linked to the actin cytoskeleton through cytoplasmic adaptor molecules including those of the zonula occludens family (ZO-1, -2, -3). We here evaluated the potential role of ZO-2 in the acquisition of invasive properties by tumor cells. In vivo, we showed a decrease of ZO-2 expression in bronchopulmonary cancers, with a preferential localization in the cytoplasm. In addition, in vitro, the localization of ZO-2 varied according to invasive properties of tumor cells, with a cytoplasmic localization correlating with invasion. In addition, we demonstrated that ZO-2 inhibition increases invasive and migrative capacities of invasive tumor cells. This was associated with an increase of MT1-MMP. These results suggest that ZO-2, besides its structural role in tight junction assembly, can act also as a repressor of tumor progression through its ability to reduce the expression of tumor-promoting genes in invasive tumor cells