Proteoglycans in human malignant mesothelioma. Stimulation of their synthesis induced by epidermal, insulin and platelet-derived growth factors involves receptors with tyrosine kinase activity

Our plain-English summary of Proteoglycans in human malignant mesothelioma. Stimulation of their synthesis induced by epidermal, insulin and platelet-derived growth factors involves receptors with tyrosine kinase activity, by A. Syrokou, G.N. Tzanakakis, A. Hjerpe, et al (Biochimie, 1999).

The study

• Authors: A. Syrokou, G.N. Tzanakakis, A. Hjerpe, N.K. Karamanos
• Journal: Biochimie
• Published: 1999;81(7):733-44
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Identification of proteoglycans in two human malignant mesothelioma cell lines, one with epithelial differentiation and the other with fibroblast-like phenotype, and the effects of epidermal (EGF), insulin-like (IGF-I) and platelet-derived (PDGF-BB) growth factors on the synthesis of hyaluronan (HA) and proteoglycans (PGs) were studied. Both cell lines synthesize HA and PGs: these last were recovered both as secreted and cell-associated compounds. Chondroitin sulfate (CS) containing PGs are mainly organized as versican in the extracellular medium and as thrombomodulin and syndecan in the cell membrane. Heparan sulfate (HS) containing PGs are mainly in the form of perlecan in the culture medium, whereas cell-associated HSPGs were recovered mainly as syndecan-1, -2 and -4. Receptors for EGF, IGF-I and PDGF-BB were identified in both cell lines. In addition to cell proliferation, these growth factors stimulated the synthesis of HA and PGs, the pattern of stimulation being unique for each of them and depending on the cell phenotype. EGF increased the synthesis of HA and PGs. IGF-I showed similar stimulatory effects on the synthesis of CSPGs, whereas higher amounts were needed to influence the synthesis of HA and HSPGs, the latter only being stimulated in the epithelial cell line. PDGF-BB stimulated the synthesis of HA, HSPGs and CSPGs at low concentrations, while the stimulatory effect was abolished at higher levels. Incubation with genistein inhibited the HA and PG synthesis induced by growth factors in a mode depending on both growth factor and genistein concentrations. The results clearly suggest that the stimulatory effects of EGF, IGF-I and PDGF-BB on matrix synthesis, expressed as proteoglycan synthesis, are mediated via receptor-growth factor complexes and the protein tyrosine kinase intracellular pathway.

In plain English

This laboratory study examined two cell lines grown from a human malignant pleural mesothelioma. One had a fibroblast-like appearance (STAV-FCS) and one had epithelial features (STAV-AB). The article does not study asbestos or any other cause of mesothelioma. The authors identified the proteoglycans (proteins carrying long sugar chains) that the cells made. Versican made up 48% (STAV-FCS) and 32% (STAV-AB) of the total secreted glycosaminoglycans and proteoglycans, and perlecan made up 22% and 30%. Syndecans-1, -2 and -4 and thrombomodulin were found on the cells. Both cell lines carried receptors for three growth factors: EGF, IGF-I and PDGF-BB. Adding these factors often raised production of hyaluronan and proteoglycans, but responses differed by factor and by cell line. For example, PDGF-BB raised hyaluronan only at 1.5 ng/mL in STAV-FCS. In STAV-AB it did not stimulate hyaluronan or most proteoglycans. Genistein, which blocks tyrosine kinase enzymes, reduced production and largely blocked the growth-factor effects. The authors suggested that tyrosine kinase activation is the main pathway for these effects. They noted that only two doses of EGF and IGF-I were tested.

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 cell culture experiment
• Who was studied: two human malignant mesothelioma cell lines, STAV-FCS (fibroblast-like) and STAV-AB (epithelial), established from a malignant pleural mesothelioma
• Exposure: no asbestos exposure was studied; cells were treated with the growth factors EGF and IGF-I (0, 10 and 100 ng/mL) and PDGF-BB (0, 1.5 and 8 ng/mL), after pretreatment with the tyrosine kinase inhibitor genistein (10, 30 and 100 µg/mL)
• Main results:
  • Versican made up 48% (STAV-FCS) and 32% (STAV-AB) of total secreted glycosaminoglycans and proteoglycans (GAGs/PGs); perlecan made up 22% and 30% respectively
  • Cell-associated proteoglycans were 48% (STAV-FCS) and 36% (STAV-AB) of total proteoglycans made
  • Both cell lines had receptors for EGF, IGF-I and PDGF-BB, regardless of cell shape
  • In both cell lines, hyaluronan secretion rose with increasing amounts of EGF and IGF-I
  • PDGF-BB stimulated hyaluronan only at 1.5 ng/mL in STAV-FCS
  • In STAV-AB cells, PDGF-BB had no effect on hyaluronan and did not stimulate proteoglycan synthesis, except for cell-bound CSPGs
  • EGF stimulated versican production only at the highest concentration tested, 100 ng/mL
  • IGF-I gave no significant increase in secreted or cell-associated HSPGs in the STAV-FCS line
  • Genistein reduced hyaluronan and proteoglycan production in untreated control cells
  • Genistein almost completely inhibited the growth-factor effects. The exception was EGF-induced hyaluronan, versican and syndecans in STAV-AB cells, where inhibition was partial.
• The authors' conclusion: The authors suggested that tyrosine kinase activation is the main pathway through which EGF, IGF-I and PDGF-BB affect proteoglycan synthesis in these cells
• Limitations the authors state:
  • Only a low and a high dose of EGF and IGF-I were tested, and bell-shaped dose responses could not be excluded
  • It was not clarified whether EGF and IGF-I act through their own receptors or through cell-bound proteoglycans

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Platelet-Derived Growth Factor (PDGF), Fibroblast.

Related studies

• Effect of insulin and epidermal growth factors on the synthesis of glycosaminoglycans/proteoglycans in cultured human malignant mesothelioma cells of different phenotypic morphology — G.N. Tzanakakis, N.K. Karamanos, et al. (1996)
• Glycosaminoglycans from two human malignant mesothelioma cell lines: determination, distribution, and effect of platelet-derived growth factor on their synthesis — G.N. Tzanakakis, N.K. Karamanos, et al. (1995)
• 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)
• Paradoxical effects of platelet-derived growth factor-A overexpression in malignant mesothelioma. Antiproliferative effects in vitro and tumorigenic stimulation in vivo — L.J. Metheny-Barlow, B. Flynn, et al. (2001)
• 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)
• Chrysotile asbestos upregulates gene expression and production of alpha-receptors for platelet-derived growth factor (PDGF-AA) on rat lung fibroblasts — J.C. Bonner, A.L. Goodell, et al. (1993)

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