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

Malignant mesothelioma is associated with asbestos exposure and remains res istant to all therapeutic intervention. Previous studies have suggested an enhancing role for platelet-derived growth factor (PDGF) in mesothelial tum origenicity, although the mechanism by which PDGF facilitates tumorigenicit y is unknown. Here, we evaluate the contribution of PDGF-A expression to me sothelial tumorigenicity using ectopic modulation of PDGF-A expression. We find, in accordance with other reports, that the receptor for PDGF-A, altho ugh expressed at high levels in normal human mesothelial cells, is not easi ly detectable in mesothelioma. Further, we show that PDGF-A overexpression is responsible for autocrine downregulation of its receptor. Our data indic ate, surprisingly, that for mesothelioma cells in vitro, high-level activat ion 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 incidenc e and growth rate and decreases the latency period to tumor formation where as 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.