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

Authors' Affiliations: Departments of ¹ Molecular Oncology, ² Pathology, ³ Bioinformatics and Assay, and ⁴ Automation Technology, Genentech, Inc., South San Francisco, California

Requests for reprints: Napoleone Ferrara, Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: 650-225-2968; Fax: 650-225-6443; E-mail: nf{at}gene.com.

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 PDGFR ligands correlate strongly with the degree of stromal fibroblast infiltration into the tumor mass. The most intense expression of PDGFR was observed in fibroblasts in the tumor outer rim. We subsequently showed that disrupting PDGFR-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 PDGFR in human lung tumors. We propose that therapies targeting this stromal cell type may be effective in treating certain types of solid tumors.

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