Serum matrix metalloproteinases-2,-9 and tissue inhibitors of metalloproteinases-1,-2 in lung cancer - TIMP-1 as a prognostic marker

The immunoreactive protein for the tissue inhibitor of the metalloproteinas e (TIMP)-1 and -2 as well as for the matrix metalloproteinase (MMP)-2 and - 9 was quantified from the sera/plasma of 90 lung cancer patients and 20 con trol subjects with enzyme linked immnnoassays (ELISA)using specific monoclo nal antibodies. Free MMP-2 and that bound to the inhibitor, the MMP-2/TIMP- 2 complex were measured separately using different ELISAs. For the detectio n of MMP-9,TIMP-1 and TIMP-2 the total protein was measured to quantify bot h free and complex forms. Serum protein levels for TIMP-1, TIMP-2 and the M MP-2/TIMP-2 complex differed significantly in patients with lung cancer whe n compared to controls. TIMP-1 levels were found to be higher in king cance r than in controls, whereas TIMP-2 and MMP-2/TIMP-2 complex levels were low er in lung cancer than in the sera of the control subjects. High TIMP-1 (> 300 ng/ml) or MMP-9 (> 30 ng/ml) correlated to poor cumulative survival in lung cancer patients (log rank P < 0.05). High TIMP-1 indicated a poor prog nosis, especially in squammous cell cancer and in NSCLC patients with stage III: 66% and 70%, respectively, of the patients with low TIMP-1 serum leve ls survived for more than one year, when only 25% and 20%, respectively, of the patients with high serum levels for TIMP-1 protein survived at that ti me. 56% of lung cancer patients with a plasma MMP-9 level < 30 ng/ml surviv ed for 12 months when only 31% of the lung cancer patients with high MMP-9 plasma levels survived for more than one year Also this difference was sign ificant (log rank analysis, P < 0.05). Our results suggest that the factors of the metalloproteinase system might be important in lung cancer progress ion. TIMP-1 as well as MMP-9 could serve as prognostic markers, and their v alues could be investigated in the follow-np of lung cancer patients when s electing patients for systemic chemotherapy or other treatment modalities.