Tissue MMP-2/TIMP-2-complex are better prognostic factors than serum MMP-2, MMP-9 or TIMP-1 in Stage I–III lung carcinoma

Matrix metalloproteinases (MMPs) are involved in tumor growth and spreading. Here, we investigated the tumor immunoreactive protein of MMP-2, MMP-9 and TIMP-1 as well as the levels of circulating total TIMP-1 and MMP-2/TIMP-2-complex as prognostic factors in lung cancer patients. The material included 59 patients, 30 with a squamous cell carcinoma, 21 with an adenocarcinoma and eight with other histology. Circulating antigens were measured by ELISA assay and the protein expression in primary tumors was analyzed by streptavidin–biotin immunohistochemical staining using specific monoclonal antibodies. The strong positivity for MMP-2 or MMP-9 in tumor predicted poor prognosis. The 5-year survival rates were 83 or 85% in patients negative for MMP-2 or MMP-9, respectively. Only 17% of the patients with a tumor highly positive for MMP-2 and 43% of those with a high positivity for MMP-9 survived at that time (Cox regression P=0.042 for MMP-2 and log rank P=0.046 for MMP-9). On the contrary, strong tissue positivity for TIMP-1 demonstrated a tendency for a favorable survival, although the difference did not reach statistical significance. In patients with a squamous cell carcinoma Stage I, low serum TIMP-1 (≤300 ng/ml) also predicted unfavorable survival (log rank P=0.033). Further in subgroup of patients treated by lobectomy (n=29), the high levels of circulating MMP-2/TIMP-2-complex (≥300 ng/ml) associated with an increased survival rate, the 5-year survival being 81 versus 34% (log rank P=0.069) in patients with high or low serum levels for MMP-2/TIMP-2-complex, respectively. Tissue MMP-2 correlated to high expression of MMP-9 immunoreactive protein (P=0.003), but the serum levels of MMP-2/TIMP-2-complex or TIMP-1 did not correlate to the immunostaining of the corresponding tumors. We conclude that in lung carcinoma the best prognostic value is achieved by using immunohistochemistry for MMP-2 and MMP-9. In early disease, however, serum TIMP-1 or MMP-2/TIMP-2-complex could offer some further prognostic value.