Data from Snail Promotes CXCR2 LigandDependent Tumor Progression in NonSmall Cell Lung Carcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> As a transcriptional repressor of E-cadherin, Snail has predominantly been associated with epithelial-mesenchymal transition, invasion, and metastasis. However, other important Snail-dependent malignant phenotypes have not been fully explored. Here, we investigate the contributions of Snail to the progression of nonsmall cell lung cancer (NSCLC).</p><p><b>Experimental Design:</b> Immunohistochemistry was done to quantify and localize Snail in human lung cancer tissues, and tissue microarray analysis was used to correlate these findings with survival. NSCLC cell lines gene-modified to stably overexpress Snail were evaluated <i>in vivo</i> in two severe combined immunodeficiency murine tumor models. Differential gene expression between Snail-overexpressing and control cell lines was evaluated using gene expression microarray analysis.</p><p><b>Results:</b> Snail is upregulated in human NSCLC tissue, and high levels of Snail expression correlate with decreased survival (<i>P</i> < 0.026). In a heterotopic model, mice bearing Snail-overexpressing tumors developed increased primary tumor burden (<i>P</i> = 0.008). In an orthotopic model, mice bearing Snail-overexpressing tumors also showed a trend toward increased metastases. In addition, Snail overexpression led to increased angiogenesis in primary tumors as measured by MECA-32 (<i>P</i> < 0.05) positivity and CXCL8 (<i>P</i> = 0.002) and CXCL5 (<i>P</i> = 0.0003) concentrations in tumor homogenates. Demonstrating the importance of these proangiogenic chemokines, the Snail-mediated increase in tumor burden was abrogated with CXCR2 blockade. Gene expression analysis also revealed Snail-associated differential gene expression with the potential to affect angiogenesis and diverse aspects of lung cancer progression.</p><p><b>Conclusion:</b> Snail upregulation plays a role in human NSCLC by promoting tumor progression mediated by CXCR2 ligands. (Clin Cancer Res 2009;15(22):68209)</p></div>