Association Between Expression of Activated 72-Kilodalton Gelatinase and Tumor Spread in Non-Small-Cell Lung Carcinoma

Abstract

Matrix metalloproteinases, in particular the 92-kd and 72-kd gelatinases, have been implicated in the progression of breast, colorectal, and gastric carcinomas, but involvement of the gelatinases in progression of non-small-cell lung carcinoma has not been documented. Immunohistochemical studies have measured the overall expression of these enzymes in tumor tissue but have failed to determine the proportion of active enzyme to latent proenzyme. Because the conversion of the latent proenzyme to active enzyme results in removal of a 10-kd amino-terminal domain, the expression of each proteinase can be determined by zymography, which separates substances according to molecular weight. The purpose of this study was to examine the expression and activation of 92-kd and 72-kd proenzymes in non-small-cell lung carcinoma. Gelatin zymography was used to study the expression of 92-kd and 72-kd gelatinases in 22 samples of non-small-cell lung carcinoma and adjacent uninvolved tissue. Medium conditioned by human RPMI-7951 melanoma cells was used as a marker for the 72-kd proenzyme, and medium conditioned by concanavalin A-treated human HT-1080 fibrosarcoma cells was used as a marker for both the 92-kd proenzyme and the 62-kd activated form of the 72-kd proenzyme. Both 92-kd and 72-kd proenzymes were expressed to varying degrees in the samples studied. The 82-kd activated form of the 92-kd proenzyme was detected in eight tumor samples but in none of the matched uninvolved tissues. Expression of the 62-kd activated form of the 72-kd proenzyme ranged from a strong band in the tumor tissue, with little or none detectable in the adjacent uninvolved tissue, to the presence of only trace amounts of enzyme in both tumor and uninvolved tissue. There was, however, a highly significant statistical association between the level of expression of the 62-kd activated enzyme in the tumor tissue and evidence of tumor spread (P = .001). These results demonstrate elevated expression of the activated forms of both the 92-kd and 72-kd proenzymes in non-small-cell lung carcinoma tissue relative to adjacent uninvolved tissue. These results indicate that non-small-cell lung carcinoma should be considered as a possible target for metalloproteinase inhibitory therapy.