Tumor-Driven Paracrine Platelet-Derived Growth Factor Receptor α Signaling Is a Key Determinant of Stromal Cell Recruitment in a Model of Human Lung Carcinoma

• Published in: Clinical cancer research 2006-05, Vol.12 (9), p.2676-2688
• Main Authors: TEJADA, Max L, LANLAN YU, FERRARA, Napoleone, JIANYING DONG, JUNG, Kenneth, MENG, Gloria, PEALE, Franklin V, FRANTZ, Gretchen D, HALL, Linda, XIAOHUAN LIANG, GERBER, Hans-Peter
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antibodies; Antineoplastic agents; Biological and medical sciences; Cell Division; Cell Line, Tumor; Culture Media, Conditioned; DNA Primers; fibroblast; Gene Expression Regulation, Neoplastic; Humans; Lung - cytology; Lung - physiology; Lung Neoplasms - pathology; Lung Neoplasms - physiopathology; Lymphokines - genetics; Medical sciences; Mice; PDGF; Pharmacology. Drug treatments; Platelet-Derived Growth Factor - genetics; Pneumology; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - isolation & purification; recruitment; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; stroma; Stromal Cells - pathology; Tumors of the respiratory system and mediastinum
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1770

Activated fibroblasts are thought to play important roles in the progression of many solid tumors, but little is known about the mechanisms responsible for the recruitment of fibroblasts in tumors. Using several methods, we identified platelet-derived growth factor A (PDGFA) as the major fibroblast chemoattractant and mitogen from conditioned medium generated by the Calu-6 lung carcinoma cell line. In addition, we showed that Calu-6 tumors express significant levels of PDGFC, and that the levels of expression of these two PDGFRα ligands correlate strongly with the degree of stromal fibroblast infiltration into the tumor mass. The most intense expression of PDGFRα was observed in fibroblasts in the tumor outer rim. We subsequently showed that disrupting PDGFRα-mediated signaling results in significant inhibition of tumor growth in vivo . Furthermore, analysis of a compendium of microarray data revealed significant expression of PDGFA, PDGFC, and PDGFRα in human lung tumors. We propose that therapies targeting this stromal cell type may be effective in treating certain types of solid tumors.