Tumor neutrophil elastase is closely associated with the direct extension of non-small cell lung cancer into the aorta

Objective: Neutrophil elastase (NE) is the only neutral protease that is able to degrade insoluble elastin and other extracellular matric; constituents, and thus, may be involved in tumor invasion and metastasis. Using a highly specific and sensitive enzyme immunoassay (EIA), we recently demonstrated that immunoreactive (ir)-NE is produced by non-small cell lung cancer cell lines. We have measured the ir-NE concentration in non-small cell lung cancer tumor extracts and have evaluated its association with disease stage. Methods: We measured the ir-NE concentration in 144 non-small cell lung cancer tumor extracts using EIA, which permits the rapid measurement of both the free and alpha(1)-protease inhibitor (alpha 1-PI) complexed form of ir-NE. In 15 clinical T4 (cT4) patients, we also determined the concentration of free ir-NE in tumor extracts using a kit that detects only NE complexed with alpha 1-PI and subtracting that value from the total NE concentration. Results: ir-NE was detected in tumor extracts from 115 of 144 patients, ranging from 0.21 to 23.35 mu g/100 mg protein, When the 144 specimens were grouped according to the clinical stage of disease, the ir-NE concentration (mean +/- SE) was significantly higher in those with cT4 disease (n = 15; 7.90 +/- 1.88 mu g/100 mg protein) than in those with cT1 (n = 29; 1.27 +/- 0.27; p<0.001), cT2 (n = 64; 1.18 +/- 0.17; p<0.001), or cT3 disease (n = 26; 1.99 +/- 0.38; p<0.003). There was no significant association between the ir-NE concentration and cN-factor or any other clinical features, When the ir-NE concentration in the tumor extracts of the cT4 patients was compared with respect to the tumor invasion sites, the ir-NE level was significantly higher in those with surgical T4 (sT4) disease with aortic invasion (n = 4; 17.4 +/- 3.10) than in those who were down-staged postoperatively (n = 5; 4.9 +/- 1.33; p = 0.005) or those with sT4 disease with involvement of other sites (n = 6; 4.07 +/- 1.83; p = 0.004). Similar results were observed for the free form of ir-NE. Conclusions: These data suggest that NE may be involved in tumor progression of non-small cell lung cancer, Since the aorta is one of the richest sources of polymeric and insoluble elastin, this enzyme may play an active role in the direct extension of the tumor into the aorta.