Introduction: Lung cancer (LC), the most common cause of cancer death is associated mainly with tobacco smoking, as well as with radon and asbestos exposure. Malignant mesothelioma (MM) is a highly aggressive tumor caused by exposure to asbestos. Extra cellular matrix metalloproteinases (MMPs), particularly MMP-2 (gelatinase A) and MMP-9 (gelatinase B), secreted by LC and MM play crucial roles in tumor invasion and metastasis. Gelatinases have been shown to be regulated by cytokines, mitogens and inhibitors. However their role in two related cancers, LC and MM has been barely unveiled.
 Objective: This study examined the role of cytokines, mitogens and inhibitors in regulation of MMPs in LC and MM cell lines.
 Methods: Human LC (A 549) and MM (MSTO-211H) cell lines (ATCC) were cultured in F12 K and RPMI media respectively, supplemented with 10% FBS and antibiotics in 24-well cultured plates. At near confluence, cells were washed with PBS and incubated in serum free medium at various doses with: PMA (10-200 ng/ml), TNF-alpha (0.1-25 ng/ml), Il-1 beta (0.1- 25 ng/ml), LPS (10-100 µg/ml, EGCG and doxycycline (10-100 µg/ml) without and with PMA, actinomycin-D, cyclohexamide, retinoic acid, and dexamethasone. In addition some cells were exposed to a nutrient mixture (NM), containing lysine, proline, ascorbic acid and green tea extract without and with PMA. After 24 hrs the medium was removed and analyzed for MMP-2 and MMP-9 by zymography and quantified by densitometry.
 Results: LC expressed only one band corresponding to MMP-2 whereas MM expressed two bands, a major band (MMP-2) and a faint band (MMP-9). PMA moderately stimulated MMP-2 secretion and profoundly stimulated MMP-9 in LC cells. In contrast PMA had a moderate suppressing effect on MMP-2 and a stimulatory dose dependent effect on MMP-9 in the MM cell line. TNF-alpha had a stimulatory effect on MMP-2 in LC and moderate inhibitory effect on MM cell lines. Il-1 had no effect on MMP-2 in LC cell line, but an inhibitory effect in MM cell line. TNF-alpha and Il-1 had no effect on MMP-9 secretion in both cancer cell lines. LPS up-regulated MMP-2 in a dose dependent fashion in LC whereas it has an opposite effect in MM. EGCG and doxycycline without and with PMA down regulated the expression of MMP-2 and MMP-9 in a dose dependent manner. In addition, actinomycin-D, cyclohexamide, retinoic acid and dexamethasone also had inhibitory effects on MMP-2 in both cancer cell lines. NM without and with PMA showed a dose dependent decrease in MMP-2 and MMP-9 secretion in both cell lines.
 Conclusions: Our results showed that cytokines had variable regulatory effects on MMP secretion in LC and MM, while inhibitors suppressed MMP secretion in both cell lines. These results suggest use of these regulators as therapeutic strategies in the management of LC and MM,

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA