Inhibitory effect of acetylsalicylic acid on metalloproteinase activity in human lung adenocarcinoma at different stages of differentiation.

The mechanism underlying the anticancer effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is not clear. We addressed the question whether the alterations in collagen content in lung adenocarcinomas reported in previous studies result from dysregulation of gelatinolytic activity and whether the activity is altered by acetylsalicylic acid in vitro. Human lung adenocarcinomas were divided into three groups: well-differentiated (G1), moderately differentiated (G2) and poorly differentiated (G3) tumors. Each group was compared with normal lung tissue with respect to tissue collagen and collagen degradation product content (hydroxyproline assay), gelatinolytic activity (zymography) and the expression of matrix metalloproteinases, MMP-2 and MMP-9 (Western immunoblot). Moreover, in the studied tissues, the effect of acetylsalicylic acid on gelatinolytic activity was measured. The lung adenocarcinoma G1 had a similar collagen content as normal lung tissue but increased amounts of collagen degradation products and free hydroxyproline. These phenomena were accompanied by a marked increase in gelatinolytic activity (MMP-2 and MMP-9) in the G1 tumor. In adenocarcinoma G2, the free hydroxyproline content and gelatinolytic activity were increased, while the collagen and collagen degradation product contents were not markedly altered, compared to control. In contrast, adenocarcinoma G3 had an increased tissue collagen content (by about 60%), decreased percentage of collagen degradation products and similar gelatinolytic activity, compared to normal lung. Acetylsalicylic acid was found to inhibit gelatinolytic activity both in control and adenocarcinoma tissues, preferentially the active forms of gelatinases MMP-2 and MMP-9. The results suggest that human lung adenocarcinoma G1, through an elevated expression of the activated forms of both MMP-2 and MMP-9, may represent a more invasive phenotype than less differentiated tumors G2 or G3. It indicates that lung adenocarcinoma G1 should be considered as a possible target for metalloproteinase inhibitory therapy. Acetylsalicylic acid may be such a therapeutical agent in cancer prevention or early stages of tumor growth.