Inverse Prognostic Impact of Angiogenic Marker Expression in Tumor Cells versus Stromal Cells in Non–Small Cell Lung Cancer

• Published in: Clinical cancer research Vol. 13; no. 22; pp. 6649 - 6657
• Main Authors: DONNEM, Tom, AL-SAAD, Samer, AL-SHIBLI, Khalid, DELGHANDI, Marit P, PERSSON, Magnus, NILSEN, Marit N, BUSUND, Lill-Tove, BREMNES, Roy M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2007
• Subjects: Adult; Aged; Aged, 80 and over; angiogenesis; Antineoplastic agents; Biological and medical sciences; Biomarkers - analysis; Carcinoma, Non-Small-Cell Lung - blood supply; Carcinoma, Non-Small-Cell Lung - chemistry; Carcinoma, Non-Small-Cell Lung - pathology; Female; Humans; Lung Neoplasms - blood supply; Lung Neoplasms - chemistry; Lung Neoplasms - pathology; Male; Medical sciences; Middle Aged; Neovascularization, Pathologic - diagnosis; NSCLC; Pharmacology. Drug treatments; Pneumology; Prognosis; Receptors, Vascular Endothelial Growth Factor - analysis; stroma; Stromal Cells - chemistry; Stromal Cells - pathology; Tissue Array Analysis; Tumors of the respiratory system and mediastinum; Vascular Endothelial Growth Factors - analysis; VEGFRs; VEGFs; Lung disease; Prognosis; Respiratory disease; Lung cancer; Tumoral marker; Malignant tumor; non-small cell lung carcinoma; Gene expression; Angiogenesis; Bronchus disease; Neovascularization; Stromal tumor; Comparative study; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0414

Purpose: The vascular endothelial growth factors (VEGF-A, -C, -D) and the VEGF receptors (VEGFR-1, -2, and -3) are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected non–small cell lung cancer tumors. Experimental Design: Tumor tissue samples from 335 resected patients with stage I to IIIA disease were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Microvessel density was assessed by CD34 immunohistochemical staining. Results: In univariate analyses, high tumor cell expression of VEGF-A ( P = 0.0005), VEGFR-1 ( P = 0.013), VEGFR-2 ( P = 0.006), and VEGFR-3 ( P = 0.0003) were negative prognostic indicators for disease-specific survival (DSS). In tumor stroma, however, high expression of VEGF-A ( P = 0.017), VEGF-C ( P = 0.003), VEGF-D ( P = 0.009), VEGFR-1 ( P = 0.01), and VEGFR-2 ( P = 0.019) correlated with good prognosis. There was no significant correlation between microvessel density and DSS. In multivariate analyses, high expression in tumor cells of VEGFR-3 ( P = 0.007) was an independent negative prognostic factor for DSS, whereas in stromal cells, high VEGF-C ( P = 0.004) expression had an independent positive survival impact. Conclusion: These are the first tissue microarray data in non–small cell lung cancers showing a positive prognostic impact by highly expressed angiogenic markers in tumor stroma, with VEGF-C as a major independent prognostic indicator.