Abstract
Abstract Background: Epithelial to mesenchymal transition (EMT) is distinguished by the loss of epithelial cell junction proteins such as E-cadherin and the relative gain of mesenchymal markers such as vimentin. We hypothesized that EMT may play a role in resistance to viral oncolysis in non-small cell lung cancer (NSCLC). Methods: Multiple human NSCLC cell lines obtained from the American Tissue Culture Collection (H292, H358, H441, H1437, A549, H1703 and SW1573) were evaluated for cell surface expression of E-cadherin via Western blot. Vimentin and Zinc finger E-box binding-1 (Zeb-1) mRNA expression were measured in all of the NSCLC cell lines using RT-PCR to further analyze a molecular profile. Herpes viral infectivity was tested in vitro at varying multiplicity of infection (MOI) using both wild type Herpes (KOS) and an attenuated (ICP-6 defective) HSV-1 mutant (hrR3). Cell surface levels of nectin-1 and herpes virus entry mediator (HVEM) were measured by fluorescence-activating cell sorting (FACS). Results: Western Blots on cell lysates revealed the presence of E-cadherin in H292, H358, H441, and H1437. The cell lines SW1573 and H1703 lacked E-cadherin and expressed higher transcript levels of Vimentin and Zeb-1, suggesting a more mesenchymal phenotype. Cell lines harboring epithelial markers appeared more susceptible to viral oncolysis at low MOI compared to those with mesenchymal markers. The mesenchymal-phenotype cells were 10-1000 fold more resistant to both wild type HSV-1 and replication conditional hrR3, thus suggesting a cell-growth independent mechanism. Viral cytotoxicity did not appear to be Nectin-1 mediated since there was no differential cell surface expression in mesenchymal or epithelial phenotypes. Conclusion: Infectivity and viral oncolysis of NSCLC cell lines may be related to epithelial or mesenchymal phenotype. Nectin-1 does not appear to be the major receptor for viral infectivity in NSCLC. Current and future studies focus on ways to reverse EMT in NSCLC, thus rendering tumor cells more susceptible to viral oncolysis and perhaps chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2315.
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