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

Our plain-English summary of Paradoxical effects of platelet-derived growth factor-A overexpression in malignant mesothelioma. Antiproliferative effects in vitro and tumorigenic stimulation in vivo, by L.J. Metheny-Barlow, B. Flynn, H.E. van Gijssel, et al (American Journal of Respiratory Cell and Molecular Biology, 2001).

The study

• Authors: L.J. Metheny-Barlow, B. Flynn, H.E. van Gijssel, A. Marrogi, B.I. Gerwin
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2001;24(6):694-702
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study used human cell lines and mice. No asbestos exposure was tested. The authors studied the growth factor PDGF-A in malignant mesothelioma. PDGF-A was overexpressed in 13 of 13 mesothelioma cell lines tested. The PDGF-A receptor was readily detected in normal mesothelial cells but was significantly reduced or absent in all mesothelioma lines tested, and high PDGF-A levels lowered it. In culture, mesothelioma cells (line VAMT-1) engineered to make extra PDGF-A formed fewer colonies. Cells engineered to block it formed the most. In nude mice the pattern reversed. Tumor probability was 77.8% for extra-PDGF-A cells, 64.3% for controls and 47.1% for PDGF-A-blocked cells. Mean time to a measurable tumor was 8.4 (plus or minus 1.4), 12.1 (plus or minus 2.6) and 13.8 (plus or minus 1.8) weeks respectively. The authors reported the longer time for blocked cells as statistically significant. Tumors from the extra-PDGF-A cells also grew faster. The authors concluded that PDGF-A acts on surrounding tissue, as a paracrine factor, in early tumor formation. They noted it is only one of many factors that may contribute.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on human cell lines in culture plus a tumor-formation experiment in mice
• Who was studied: Eighteen established human malignant mesothelioma cell lines, plus normal human mesothelial cells cultured from pleural effusions of donors with no history of malignancy, plus athymic nude mice (20 injected per cell line)
• Exposure: No asbestos exposure was studied. PDGF-A levels were changed experimentally. VAMT-1 mesothelioma cells were made to carry extra PDGF-A (sense), a construct blocking PDGF-A (antisense), or an empty vector (control), then grown in culture or injected into mice.
• Main results:
  • PDGF-A was overexpressed in 13 of 13 mesothelioma cell lines tested
  • The PDGF-A receptor protein was readily detected in normal mesothelial cells but significantly reduced or absent in all mesothelioma lines tested
  • In normal mesothelial cells, high levels of PDGF-AA and medium conditioned by several mesothelioma cell lines both reduced receptor detection
  • Mesothelioma clones with PDGF-A blocked (antisense) expressed between two and 12 times more receptor protein than vector control clones
  • In culture, the PDGF-A-blocked (antisense) clone had the highest colony-forming efficiency, and the PDGF-A-overexpressing clone showed decreased colony-forming efficiency
  • The authors could not obtain VAMT-1 clones that stably expressed the receptor in the presence of excess PDGF-A ligand
  • In nude mice, probability of tumor formation was 77.8% for PDGF-A-overexpressing (sense) cells versus 64.3% for vector control cells
  • In nude mice, probability of tumor formation was 47.1% for PDGF-A-blocked (antisense) cells
  • Mean latency from injection to measurable tumor was 12.1 (plus or minus 2.6) weeks for vector control cells and 8.4 (plus or minus 1.4) weeks for PDGF-A-overexpressing cells
  • Mean latency for PDGF-A-blocked (antisense) cells was 13.8 (plus or minus 1.8). The authors reported this increase as statistically significant by two-tailed t test.
  • Tumors from PDGF-A-overexpressing cells grew faster than control or antisense tumors, and the difference was significant at later weeks. Control and antisense tumors differed little in growth rate.
  • Cells from a tumor that formed from antisense cells remained negative for PDGF-A
• The authors' conclusion: The authors concluded that PDGF-A inhibits mesothelioma cell growth in culture but stimulates tumor formation in mice, acting as a paracrine factor in the early stages of tumor formation
• Limitations the authors state:
  • The authors could not rule out that PDGF-A signaling gives mesothelioma cells some other biologic advantage
  • The authors noted PDGF-A is only one of many factors that may contribute to mesothelioma

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Platelet-Derived Growth Factor (PDGF), Malignant Mesothelioma, Asbestos Exposure, Mesothelial Cells, Mesothelioma, Latency.

Related studies

• Chrysotile asbestos stimulates platelet-derived growth factor-AA production by rat lung fibroblasts in vitro: evidence for an autocrine loop — J.A. Lasky, P.G. Coin, et al. (1995)
• Proteoglycans in human malignant mesothelioma. Stimulation of their synthesis induced by epidermal, insulin and platelet-derived growth factors involves receptors with tyrosine kinase activity — A. Syrokou, G.N. Tzanakakis, et al. (1999)
• Expression of the Wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression — A.W. Langerak, K.A. Williamson, et al. (1995)
• Inorganic particles induce secretion of a macrophage homologue of platelet-derived growth factor in a density-and time-dependent manner in vitro — R.M. Schapira, A.R. Osornio-Vargas, et al. (1991)
• Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages — J.C. Bonner, A.R. Osornio-Vargas, et al. (1991)
• Immunoreactivity for the beta chain of the platelet-derived growth factor receptor in malignant mesothelioma and non-neoplastic mesothelium — M. Ramael, C. Buysse, et al. (1992)

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