Airway epithelium serves as a protective barrier between the environment and the lung parenchyma. Inhaled substances are concentrated in the airways rendering the airway epithelium susceptible to injury and to the concentrated effects of tobacco carcinogens. The normal proliferative responses of the airway are highly regulated through interactions with extracellular cues and during chemical transformation, loss of that regulation may eventually result in neoplasia. The integrin family of cell surface adhesion receptors is a large family of molecules that may play a central role in cellular proliferative responses to cues contained with in the extracellular matrix. Of the integins, the alpha-v subfamily has been shown to be of particular importance in cell proliferation and signaling. However, little is known of the role that integrins play in negative regulation of cell proliferation. Our data suggests that the alphavbeta8 integrin is important in inhibition of lung epithelial proliferation. We find that the expression of alphavbeta8 is confined to normal airway epithelium and is lost in carcinomas. In addition, we have in vitro and in vivo evidence that expression of the alphavbeta8 integrin inhibits lung cancer cell proliferation independent of apoptosis. Preliminary data suggests that alphavbeta8 inhibits growth through two independent mechanisms, the first is mediated through a novel mechanism of direct activation of TGFbeta, a potent inhibitor of airway epithelial cell growth; the second is through a novel mechanism involving inhibitory signals generated through the beta8 cytoplasmic domain. Taken together, our data suggest that alphavbeta8 generates signals that negatively regulate airway epithelial cell proliferation that are sufficient to suppress a neoplastic airway phenotype. The work proposed addresses the following Hypothesis: The integrin alphavbeta8 negatively regulates airway epithelial and lung cancer cell proliferation though two novel and independent mechanisms, the first involving the direct activation of TGFbeta and second, involving the divergent beta8 cytoplasmic domain.
Specific Aims : 1) To test the hypothesis that the integrin alphavbeta8 mediates activation of TGFbeta and does so through a novel mechanism; 2) To test the hypothesis that the integrin alphavbeta8 inhibits epithelial cell proliferation through activation of TGFbeta; 3) To test the hypothesis that the unique cytoplasmic domain of beta8 mediates growth inhibition through a mechanism independent of TGFbeta.
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