Abstract 5064: Pulmonary emphysema as a tumor-friendly microenvironment: Role of the MT1-MMP/MMP-2 axis.
Authors: Murakami Junichi , Ueda Kazuhiro , Hayashi Masataro , Hamano Kimikazu 
Published: August 2014

Abstract
Background: We previously demonstrated that human lung cancer arising in pulmonary emphysema is associated with early recurrence and poor prognosis. In pulmonary emphysema, the excessive proteolyses may be involved in the development of alveolar wall destruction, which potentially act as a tumor-friendly microenvironment because degradation of the extracellular matrix by proteolysis is an essential process for tumor progression. Recent data suggest that coordinated action of MT1-MMP and MMP-2 may facilitate pericellular proteolysis and enhance not only tumor invasion/migration but also tumor cell growth. Thus, we hypothesized that tumor progression is accelerated in emphysematous lungs via the MT1-MMP/MMP-2 axis. Experimental study: A mouse model of pulmonary emphysema was induced by intratracheal nebulization of elastase. Intravenous administration of Lewis lung carcinoma (3LL) cells in the mice resulted in higher lung weight and three-fold increase in metastatic foci with a diameter of no less than 2 mm on the surface of the lungs. In addition, visceral pleural invasion was more frequently observed in the model mice than in the control mice. Interestingly, larger metastatic foci were found predominantly at the lung portion possessing severe emphysema. According to an in vitro study, proliferation of 3LL cells was promoted by incubation with the conditioned medium containing pneumocytes of the model mice for 48 hours. The latent form of MMP-2 was overexpressed in monocultures of the pneumocytes from the model mice. The active form of MMP-2 and MT1-MMP were synchronously increased in the conditioned medium with the incubation of 3LL cells. Clinical study: We evaluated the expression of PCNA, MMP-2, MMP-9 and MT1-MMP by immunohistochemistry in tumor specimens obtained from 48 patients who underwent lung lobectomy with lymphadenectomy for clinical stage I non-small cell lung cancer. We also evaluated signal intensity and localization of MMPs-expressed cells in the tumor specimen. The results were compared between patients with pulmonary emphysema and those without. As a result, the PCNA proliferation index was higher in cancer cells from patients with emphysema than in those from patients without (52.3% vs. 38.4%, p&lt;0.05). The MMP-2 expression intensity was also stronger in cancer cells and cancer stromal cells from patients with emphysema than in those from patients without (both p&lt;0.05), while there were no significant differences in MMP-9 and MT1-MMP expression between the two groups. Conclusion: These results indicate that tumor progression is accelerated in emphysematous lungs because the MT1-MMP/MMP-2 axis, which contributes to enhancing tumor progression, is stimulated in tumors arising in this environment.
Citation Format: Junichi Murakami, Kazuhiro Ueda, Masataro Hayashi, Kimikazu Hamano. Pulmonary emphysema as a tumor-friendly microenvironment: Role of the MT1-MMP/MMP-2 axis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5064. doi:10.1158/1538-7445.AM2013-5064