CYTOKINE REGULATION OF GELATINASE PRODUCTION BY HEAD AND NECK SQUAMOUS-CELL CARCINOMA - THE ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA

Gelatinases (GLs) belong to a family of enzymes known as matrix metall oproteinases (MMPs), which are produced by both normal and neoplastic cells. These enzymes have been implicated in tumor invasion and metast asis, although the mechanism of regulation of tumor MMP production is unknown. Since our previous studies have shown that numerous cytokines are present in the tumor microenvironment, our goal was to establish the effect of selected cytokines on GL production by both established tumor cell lines and primary cultures of head and neck squamous cell c arcinoma (HNSCC). Supernatants of HNSCC cell lines SCC-25 and FADU sti mulated with interleukin (IL)-1 alpha and IL-1 beta demonstrated modes t induction of 92 kd GL production by zymogram analysis when compared with controls; IL-2, IL-6, and interferon-gamma had no consistent effe ct on MMP production. Stimulation of cell lines with tumor necrosis fa ctor (TNF)-alpha (10(4) to 10 U/mL), however, dramatically enhanced pr oduction of 92 kd GL by both cell lines in a dose-dependent fashion, a lthough tissue inhibitor of metalloproteinase (TIMP) expression was un affected. Northern blot analysis showed that this enhancement of 92 kd GL occurred at the messenger RNA level. Stimulation of short-term pri mary tumor cultures with TNF-alpha resulted in significant enhancement of 92 kd GL expression in one of four cultures and enhancement of 72 kd GL expression in all cultures. The observed increase in GL expressi on by TNF-alpha suggests a role for this cytokine in the regulation of GL expression by tumor cells during invasion and metastasis.