Abstract CN07-04: Neutrophil elastase as a chemopreventive target for lung cancer

Abstract

Abstract When combined, lung cancer and chronic obstructive pulmonary disease (COPD) account for >260,000 American deaths each year. Although the link between declining FEV1 and increased lung cancer incidence was identified over 20 years ago, the responsible mechanisms have not been deciphered. Two independent studies have recently demonstrated that it is the presence of emphysema, and not airflow obstruction, that is responsible for the increased risk of lung cancer in COPD patients. Emphysema, unlike COPD, has a strict anatomic definition: permanent enlargement of the peripheral airspaces distal to the terminal bronchioles. The prevailing theory regarding the pathogenesis of emphysema remains the proteinase:antiproteinase hypothesis. Inflammatory cells and inflammatory cell-derived proteinases are recruited to the lung upon chronic cigarette smoke exposure. When the proteinase burden exceeds the host's antiproteinase capacity, lung matrix tissue is destroyed and, in the absence of repair, emphysema results. When proteinase vs. antiproteinase activity is balanced, tissue homeostasis persists. We propose that the presence of radiographic emphysema on CT scan, which confers increased lung cancer risk, represents a case where the proteinase burden has surpassed the protective capability of the antiproteinase shield. As such, patient's displaying radiographic emphysema represent a group at increased risk for lung cancer, and therefore amenable to a chemopreventative strategy, especially one that would address a target common to both emphysema and lung cancer. We propose that that neutrophil-derived proteinase, neutrophil elastase (NE), is a viable chemopreventive target in COPD patients at risk for lung cancer. A role for this elastolytic enzyme in the pathogenesis of emphysema has been clearly established in both mouse and human studies. The presence of severe emphysema in A1AT deficient subjects has been attributed to uncontrolled NE activity, and is universally accepted as the pathogenic mechanism. Although previously unstudied, we have recently shown that NE promotes lung tumor growth in vivo (Nature Medicine 2010, 16:219-223). The mechanism by which NE promotes tumor growth represents an entirely new means by which a secreted proteinase can impact tumor behavior. NE is released near the tumor cell surface where it is internalized into tumor endosomes. NE degrades a target substrate, insulin receptor substrate-1 (IRS-1), within these tumor endosomes, which ultimately leads to PI3K activation and tumor cell proliferation. We propose that subjects displaying radiographic emphysema possess excessive proteinase burden, and therefore, increased NE activity. When lung cancers arise in these subjects, they will arise within a tumor microenvironment enriched for NE activity, and thus these cancers will display increased growth rates. Additional clinical studies are underway to establish NE as a bona fide therapeutic target for lung cancers arising in emphysematous subjects. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN07-04.