Alpha 1-antitrypsin: A Role in Cancer Progression

Alpha1-antitrypsin (AAT), a circulating single-chain glycoprotein is the most abundant serine proteinase inhibitor in human plasma. AAT is an acute phase protein, its levels increase rapidly to concentrations exceeding 50mM in response to inflammation, infection and malignant diseases. Since AAT is a powerful inhibitor of neutrophil elastase and proteinase 3, it is generally assumed that its physiological function is to protect host tissue from the proteolytic actions of these proteinases. However, in vivo AAT is found not only in the native, inhibitory form, but also modified non-inhibitory forms including polymerized, cleaved and/or degraded. Recent findings suggest that non-inhibitory forms of AAT may also express biological activity, un-related to serine proteinase inhibition. The overall aim of the studies upon which this thesis is based was to test a hypothesis that AAT in native and modified molecular forms may exert multiple biological effects on tumor cell behaviour, in vitro. Cancer patients with high levels of proteinase inhibitors are often characterized by a more disseminated disease and worse prognosis. We have found that plasma levels of AAT, alpha1-antichymotrypsin and secreted leukocyte proteinase inhibitor are significantly higher in newly diagnosed lung cancer patients, particularly in cases with metastases, compared to the age and gender matched controls. These results support the view that proteinase inhibitor levels may reflect or contribute to tumor progression. We next examined the effects of inhibitory (native) and non-inhibitory (polymerized and/or C-terminal fragment, C-36) forms of AAT on human neutrophil and lung cancer cell functional activities separately and in co-culture models, in vitro. Our data show that the C-36 peptide of AAT, in a concentration-dependent manner, induces neutrophil chemotaxis, adhesion, degranulation and superoxide generation, while native and polymerized AAT at similar and higher concentrations were without effect. In co-culture experiments we observed that interactions between neutrophil released content and lung cancer cells were modulated by exogenously added AAT and C-36 peptide. Similar experiments performed in vitro on lung, breast and pancreatic cancer cells showed that AAT, depending on its molecular form, may either promote or inhibit cancer cell proliferation, invasiveness and the ability to release certain biomarkers, such as growth factors, cytokines and matrix metalloproteinases. Together our findings support the hypothesis that AAT’s role in cancer progression might not only be limited to its property of inhibiting overexpressed proteinases but also to direct effects on inflammatory and tumor cells.