title: Paradoxical effects of platelet-derived growth factor-A overexpression in malignant mesothelioma. Antiproliferative effects in vitro and tumorigenic stimulation in vivo.
abstract: Malignant mesothelioma is associated with asbestos exposure and remains resistant to all therapeutic intervention. Previous studies have suggested an enhancing role for platelet-derived growth factor (PDGF) in mesothelial tumorigenicity, although the mechanism by which PDGF facilitates tumorigenicity is unknown. Here, we evaluate the contribution of PDGF-A expression to mesothelial tumorigenicity using ectopic modulation of PDGF-A expression. We find, in accordance with other reports, that the receptor for PDGF-A, although expressed at high levels in normal human mesothelial cells, is not easily detectable in mesothelioma. Further, we show that PDGF-A overexpression is responsible for autocrine downregulation of its receptor. Our data indicate, surprisingly, that for mesothelioma cells in vitro, high-level activation of a PDGF-A-PDGF receptor loop is antiproliferative whereas abrogation of PDGF-A expression stimulates growth. These data suggest that PDGF-A does not contribute to tumorigenicity by autocrine stimulation of proliferation. In contrast, increased PDGF-A expression in vivo increases tumor incidence and growth rate and decreases the latency period to tumor formation whereas abrogation of PDGF-A expression decreases tumor incidence and increases latency. Thus, the tumorigenic effect of PDGF-A must act through paracrine mechanisms relevant at early stages of tumor initiation.
authors: Laboratory of Human Carcinogenesis; and Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland, USA. ljm@gunet.georgetown.edu
authors: L J
authors: LJ
authors: Metheny-Barlow
authors: B
authors: B
authors: Flynn
authors: H E
authors: HE
authors: van Gijssel
authors: A
authors: A
authors: Marrogi
authors: B I
authors: BI
authors: Gerwin
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008654:Mesothelioma / Q000209:etiology*; D051379:Mice; D008819:Mice, Nude; D019899:Paracrine Communication; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis
chemical_list: D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha