Paradoxical effects of platelet-derived growth factor-A overexpression in malignant mesothelioma. Antiproliferative effects in vitro and tumorigenic stimulation in vivo

Am J Respir Cell Mol Biol. 2001 Jun;24(6):694-702. doi: 10.1165/ajrcmb.24.6.4334.

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.

MeSH terms

  • Animals
  • Autocrine Communication
  • Cell Transformation, Neoplastic*
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mesothelioma / etiology*
  • Mice
  • Mice, Nude
  • Paracrine Communication
  • Platelet-Derived Growth Factor / biosynthesis*
  • Receptor, Platelet-Derived Growth Factor alpha / biosynthesis

Substances

  • Platelet-Derived Growth Factor
  • platelet-derived growth factor A
  • Receptor, Platelet-Derived Growth Factor alpha