Total cyclooxygenase‐2 mRNA levels correlate with vascular endothelial growth factor mRNA levels, tumor angiogenesis and prognosis in non‐small cell lung cancer patients

• Published in: International journal of cancer 2005-07, Vol.115 (4), p.545-555
• Main Authors: Yuan, Ang, Yu, Chong‐Jen, Shun, Chia‐Tung, Luh, Kwen‐Tay, Kuo, Sow‐Hsong, Lee, Yung‐Chie, Yang, Pan‐Chyr
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - surgery; Aged; Biological and medical sciences; cancer cell; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - surgery; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - surgery; COX‐2 mRNA; Cyclooxygenase 2; Female; Humans; lung cancer; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - surgery; Male; Medical sciences; Membrane Proteins; microvessel count; Middle Aged; Pneumology; prognosis; Prostaglandin-Endoperoxide Synthases - genetics; real‐time quantitative RT‐PCR; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; stromal cell; Stromal Cells - enzymology; Survival Analysis; Tumors; Tumors of the respiratory system and mediastinum; Vascular Endothelial Growth Factor A - genetics; VEGF mRNA
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.20898

Interaction between cancer cells and adjacent stromal cells is important to promote tumor development. Our aim was to study total COX‐2 mRNA expression in both cancer cells and surrounding stromal cells and its association with angiogenic factor VEGF mRNA expression, tumor angiogenesis and prognosis in patients with NSCLC. COX‐2 mRNA expression in both cancer cells and stromal tissue was analyzed using real‐time quantitative (RTQ) RT‐PCR in 60 NSCLC surgical specimens. Immunohistochemistry (IHC) was used to localize COX‐2 protein in tumor specimens. Correlations between tumoral total COX‐2 mRNA expression and VEGF mRNA expression (measured by RTQ RT‐PCR), intratumoral microvessel counts (evaluated by IHC), other clinicopathologic variables, survival and relapse were tested. COX‐2 protein expression was found in cancer as well as the surrounding stromal cells (including infiltrating inflammatory cells and endothelial cells of tumor‐associated microvessels). VEGF protein expression was mainly located in cancer cells. There was a significant association between high tumoral total COX‐2 mRNA expression and high VEGF mRNA expression (p = 0.01) or high intratumoral MVC (p < 0.001) but not other clinicopathologic variables, including tumor status and lymph node metastasis. Patients with higher tumoral total COX‐2 mRNA expression had a statistically shorter survival time (median 15.0 ± 2.61 months) and relapse time (median 5.0 ± 1.37 months) than those with lower tumoral total COX‐2 mRNA expression (median 40.0 ± 3.12 and 34.0 ± 3.11 months; p < 0.0001 and p < 0.0001, respectively, log‐rank test). A significant difference in survival and relapse time was also seen between patients with high and low tumoral VEGF mRNA expression and between those with high and low intratumoral MVC (p = 0.0046 and p = 0.0038, respectively). After stratification by disease stage or histologic subtype, the prognostic significance of high total COX‐2 mRNA expression was still apparent in both stage I and stage II–IV and in both squamous cell carcinoma and adenocarcinoma (p ≤ 0.01 for all). Multivariate analysis using the Cox regression model with backward elimination showed that tumoral total COX‐2 mRNA expression and lymph node status were the 2 most important independent prognostic predictors for survival and disease relapse. We report that total COX‐2 mRNA expression in cancer cells and surrounding stromal cells correlates strongly and positively with VEGF mRNA expression, intratumor