Local Increase in Polymorphonuclear Leukocyte Elastase Is Associated With Tumor Invasiveness in Non-small Cell Lung Cancer

Abstract

The production of tumor cell proteases is implicated in tumor cell invasion and metastasis. To determine whether lung cancer cells can produce polymorphonuclear leukocyte elastase (PMN-E), we measured the concentration of immunoreactive (ir)-PMN-E in the conditioned medium of seven lines of non-small cell lung cancer cells, EBC-1, LC-1sq, LK-2, A-549, PC-3, RERF-LC-MS, and RERF-LC-OK, and three normal lung epithelial cell lines, CCD-8Lu, WI-1003, and LL-24, by using a recently developed enzyme immunoassay (EIA). We measured the concentration of ir-PMN-E in extracts of 40 non-small cell lung cancers, and evaluated its association with the clinicopathologic findings in these patients. The ir-PMN-E level in the culture medium increased with time in six of the seven lines of lung cancer cells; the exception was PC-3. No detectable ir-PMN-E was secreted into the culture medium of the three lines of normal lung epithelial cells. The ir-PMN-E was detected in tissue extracts from 34 to 40 specimens at concentrations ranging from 0.11 to 15.5 micrograms/100 mg of protein. When 40 specimens of lung cancer were categorized by clinical stage of disease, the ir-PMN-E concentration was significantly higher in stage IIIB vs stages I, II, or IIIA. Similarly, the ir-PMN-E concentration was significantly higher in stage IIIA than in stage I. Evaluation of correlations between the ir-PMN-E concentration and patient characteristics showed that the ir-PMN-E level was significantly higher in T3 and T4 tumors than in T1 or T2 tumors. Analysis of prognostic factors in a group of 101 patients with non-small cell lung cancer demonstrated that those with high ir-PMN-E had a significantly shorter overall survival vs those with a low ir-PMN-E at the cutoff point of 3.5 micrograms/100 mg of protein. Multivariate analysis showed that ir-PMN-E was a significant porgnostic factor for early death (hazard ratio, 4.04; 95% confidence interval, 1.65 to 9.95) (p = 0.005), suggesting it was an independent marker for prognosis. Results suggest that the local production of PMN-E may be involved in the tumor invasion associated with a poor prognosis in patients with non-small cell lung cancer.