Elsevier

The Lancet Oncology

Volume 5, Issue 3, March 2004, Pages 182-190
The Lancet Oncology

Review
Role of imbalance between neutrophil elastase and α1-antitrypsin in cancer development and progression

https://doi.org/10.1016/S1470-2045(04)01414-7Get rights and content

Summary

Neutrophil elastase and α1-antitrypsin are a pair of protease and protease inhibitor counterparts. The imbalance between the two counterparts is generally thought to cause tissue damage, which could create a favourable tissue environment for carcinogens and tumour progression. Laboratory research and clinical findings have indicated that a deficiency in α1-antitrypsin is associated with increased risk of liver cancer, bladder cancer, gall bladder cancer, malignant lymphoma, and lung cancer. Conversely, raised concentrations of neutrophil elastase might promote the development, invasion, and metastasis of many cancers. Several mechanisms of carcinogenesis have been postulated. Excess neutrophil elastase might facilitate cancer development by causing tissue damage and air trapping, which foster longer carcinogen exposure, might promote cancer progression by degrading the intercellular matrix barrier, and might directly lead to cancer development through the tumour-necrosis-factor signalling pathway

Section snippets

Serum concentrations

α1-antitrypsin is a secretory glycoprotein produced in the liver that neutralises the effects of proteases in several organ systems, mainly in the lung. The major physiological role of α1-antitrypsin in the lung is to bind and inhibit elastase, mainly elastase released from leucocytes in the lower respiratory tract, and thereby prevent the destruction of lung tissue.9 Concentrations of α1-antitrypsin as a mendelian codominant trait is determined by the protease inhibitor locus on chromosome

Serum concentration

Neutrophil elastase, also called serine elastase, leucocyte elastase, polymorphonuclear leucocyte elastase, or granulocyte elastase, is a serine hydrolytic protease (EC 3.4.21.37) secreted mainly by neutrophils. It is synthesised in neutrophil cell precursors in bone marrow and is encapsulated in the azurophil granules. On activation of the neutrophil, neutrophil elastase is rapidly released from the granules into the extracellular space. This single-chain glycoprotein with 218 aminoacid

Mechanisms underlying the imbalance in development and progression of cancer

Several potential mechanisms have been postulated to underlie the role of an imabalance between neutrophil elastase and α1-antitrypsin in cancer development and progression. They can be summarised in the following four aspects (figure 3)

Conclusion

The homozygous α1-antitrypsin-deficiency gene causes early onset of emphysema, especially for patients who smoke.1, 2, 3 Because of the shortened life span (median survivals were less than 45 and 65 years for smokers and those who had never smoked, respectively)35 and restrained exposure to cigarette smoking, no increased lung cancer risk is reported in these patients. Chronic liver disease occurs at a much younger age for 10% of homozygous α1-antitrypsin-deficiency gene patients19 and a third

Search strategy and selection criteria

Data for this review were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms “neutrophil elastase”, “alpha-1 antitrypsin”, “alpha-1 antitrypsin deficiency”, “tumor genesis”, and “tumor progression”. Abstracts and reports from meetings were included when they related directly to previously published work, and book chapters were included if they were pertinent to the search terms. Only papers published in English between 1963 and 2003 were

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