Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer.

PURPOSE: The aim of this study was to evaluate the correlation between type I collagen degradation marker ICTP, MMP (matrix metalloproteinase)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 and to compare their value as prognostic factors in lung cancer. EXPERIMENTAL DESIGN: From the sera of 141 lung cancer patients, we assessed markers of type I collagen synthesis (PINP and PICP) and degradation (ICTP) by radioimmunoassays, and we assessed MMP-9 and its tissue inhibitor TIMP-1 by ELISA. There were 62 squamous cell carcinomas, 42 adenocarcinomas, 14 small cell carcinomas, and 23 cases with other histology. Seventeen of these patients had advanced disease. Sixty-seven patients had been operated on, 33 had received radiation therapy, 7 had received chemotherapy, and the rest had received other treatment combinations. RESULTS: We examined the relationship between these markers and found a correlation between ICTP and MMP-9 (r = 0.201; P = 0.01) or TIMP-1 (r = 0.415; P = 0.00). Elevated serum concentrations of ICTP (>5 microg/liter) and/or TIMP-1 (>300 ng/ml) correlated with poor prognosis. In univariate regression analysis, ICTP had prognostic value (odds ratio, 1.6462; P < 0.03): the patients with elevated serum concentrations of ICTP (>5 microg/liter) had a 64% higher risk of dying from lung cancer than did patients with opposite values. CONCLUSIONS: Our results indicated that ICTP and TIMP-1 are good prognostic markers in lung cancer. The association between serum MMP-9 and ICTP suggests that MMP-9 could play a role in the degradation of the extracellular matrix producing ICTP in this pathological situation.

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 metalloproteinase (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 control subjects with enzyme linked immunoassays (ELISA) using specific monoclonal antibodies. Free MMP-2 and that bound to the inhibitor, the MMP-2/TIMP-2 complex were measured separately using different ELISAs. For the detection of MMP-9, TIMP-1 and TIMP-2, the total protein was measured to quantify both free and complex forms. Serum protein levels for TIMP-1, TIMP-2 and the MMP-2/TIMP-2 complex differed significantly in patients with lung cancer when compared to controls. TIMP-1 levels were found to be higher in lung cancer than in controls, whereas TIMP-2 and MMP-2/TIMP-2 complex levels were lower 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 prognosis, especially in squamous cell cancer and in NSCLC patients with stage III: 66% and 70%, respectively, of the patients with low TIMP-l serum levels 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 time. 56% of lung cancer patients with a plasma MMP-9 level < 30 ng/ml survived 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 significant (log rank analysis, P < 0.05). Our results suggest that the factors of the metalloproteinase system might be important in lung cancer progression. TIMP-1 as well as MMP-9 could serve as prognostic markers, and their values could be investigated in the follow-up of lung cancer patients when selecting patients for systemic chemotherapy or other treatment modalities.

Serum type I collagen degradation markers, ICTP and CrossLaps, are factors for poor survival in lung cancer.

We investigated the prognostic value of the serum markers of type I collagen synthesis (PINP and PICP) and degradation (ICTP and CrossLaps) in 143 lung cancer patients with a local or locally advanced disease or a metastatic disease. The mean values of ICTP, CrossLaps, PINP and PICP were significantly higher in patients with bone metastases than in those without metastases or with only soft tissue metastases. The patients with ICTP < or = 5.0 micrograms/l or CrossLaps < or = 5000 pmol/l had a better prognosis. The histopathological type, the site of metastases or the stage of the disease had no influence on these results. In multivariate regression analysis, both ICTP and CrossLaps in contrast to PINP or PICP, were prognostic factors for poor survival in lung cancer patients. ICTP, CrossLaps, sedimentation rate, hemoglobin and AFOS reached separately weaker, but statistically significant values as predictors of survival with stage and operation.