Cxcr2 Expression In Tumor Cells Is A Poor Prognostic Factor and Promotes Invasion and Metastasis In Lung Adenocarcinoma

<p>CXC chemokine receptor 2 (CXCR2) is a G-protein coupled receptor which mediates signaling by binding to CXC chemokines CXCL1-3 and 5-8. In non-small cell lung cancer CXCR2 has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. However, there is controversial data in the literature about CXCR2 expression in tumor cells and its role in the tumor microenvironment. We hypothesized that tumoral expression of CXCR2 and its ligands promote tumor invasion and metastasis in non-small cell lung cancer. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from a murine <em>KRAS/p53</em>–mutant lung adenocarcinoma cell line (344SQ) with high metastatic potential and an orthotopic syngeneic mouse model and <em>in vitro </em>using a CXCR2 small molecule antagonist (SB225002). We showed that <em>in vivo</em> CXCR2 inhibition by knock-down reduces its invasive ability. In a murine model of orthotopic syngeneic lung adenocarcinoma CXCR2 knock-down 344SQ cell line was found to be associated with decreased tumor burden, local and distant metastases. In order to translate our preclinical discoveries to human NSCLC, we explored CXCR2 tumoral immunohistochemical expression in 262 tissue microarrays created from tumor specimens of patients with surgically resected stage I-II lung adenocarcinoma and correlated it with patient clinic-pathological characteristics including smoking status, histological differentiation and survival outcomes. We considered also localization of CXCR2 expression in the cytoplasm, membrane and nucleus. High cytoplasmic CXCR2 was associated with smoking history, aggressive histological differentiation and worse survival. When we screened a publicly available large database of human NSCLC cell lines (N=52) and human lung adenocarcinomas (N=442), we found that at the gene expression level, <em>CXCL5</em>, a CXCR2-ligand, was the main driver of a cluster of cell lines and lung adenocarcinomas with high-risk features, including <em>RAS</em> and MET pathway activation, epithelial-to-mesenchimal transition and resistance to epidermal growth factor inhibition (i.e., gefitinib). We studied promoter methylation in 70 human non-small cell lung cancer cell lines and discovered that <em>CXCL5</em> was regulated by promoter methylation. We concluded that the <em>CXCR2 </em>axis may be an important target in smoking-related lung adenocarcinoma.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2013

Author dc:creator

• Massarelli, Erminia

Contributors dc:contributor

• Jonathan M. Kurie
• Faye M. Johnson
• Gregory Lizee

• Lung adenocarcinoma
• CXCR2
• CXCL5
• NSCLC
• lung cancer metastases
• CXCR2 ligands
• Medical Cell Biology
• Medicine and Health Sciences
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/409

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1448