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. 2003 Jan 31;32(2-3):85–99. doi: 10.1046/j.1365-2184.1999.32230085.x

Effects of glycosaminoglycans on proliferation of epithelial and fibroblast human malignant mesothelioma cells: a structure–function relationship

Christopher Potten, Zbigniew Darzynkiewicz, Kohsuke Sasaki, A Syrokou 1, G Tzanakakis 2, T Tsegenidis 1, A Hjerpe 2, N K Karamanos 1
PMCID: PMC6726324  PMID: 10535355

Abstract

Abstract. Proteoglycans interact with other effective macromolecules regulating a variety of cellular events via their glycosaminoglycan (GAG) chains. The effects of all known glycosaminoglycans (GAGs) produced by normal cells and tissues on the proliferation of two human malignant mesothelioma cell lines, one with fibroblast‐like morphology and the other with epithelial differentiation – both able to produce hyaluronan (HA), galactosaminoglycans (GalAGs) and heparan sulphate (HS) containing proteoglycans – have been studied. Cell proliferation was assessed by measuring [3H]thymidine incorporation and cell number. GalAGs, i.e. chondroitin sulphates (CSs) and dermatan sulphate (DS), strongly stimulate the proliferation of fibroblast‐like cells in a dose‐dependent manner (170–250% at 100 μg/ml), independently of their sulphation pattern. In epithelial cells, however, only DS stimulates cell proliferation. The effects of CSs on proliferation of epithelial cells are not depended on their sulphation pattern. Thus, CSs either with ‐[GlcA‐GalNAc‐(‐6‐O‐SO3 −)]‐ or ‐[GlcA‐GalNAc‐(‐4‐O‐SO3 −]‐ as the commonest unit, had no significant effect. l‐Iduronic acid (IdoA)‐rich heparin and fast‐moving HS (fm‐HS), a HS fraction with a heparin‐like structure, had significant antiproliferative effects on mesothelioma cells of both types (30–70% at 1.0 μg/ml and 85–90% at 100 μg/ml, respectively). GlcA‐rich HS, however, had no significant effects. HA inhibits only the proliferation of fibroblast‐like cells by 25% at 50 and 100 μg/ml. Keratan sulphate suppresses cell proliferation (10–30%) in both cell lines. In the view of these findings, a structure–function relationship of GAGs on cell proliferation of the two human malignant mesothelioma cell lines is discussed. Other factors, such as chain conformation and geometry, as well as interactions of growth factors with GAGs, possibly involved in the regulation of cell proliferation, are also discussed.

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This work has been presented in part in XVth Meeting, Federation of European Connective Tissue, Munchen, Germany, 4–9 August 1996.

References

  1. Adams JC, Watt F. (1993) Regulation of development and differentiation by the extracellular matrix. Development 117, 1183. [DOI] [PubMed] [Google Scholar]
  2. Arvaniti A, Karamanos NK, Dimitracopoulos G, Anastassiou ED. (1994) Isolation and characterisation of a novel 20‐kDa sulfated polysaccharide from the extracellular slime layer of Staphylococcus epidermidis . Arch. Biochem. Biophys. 308, 432. [DOI] [PubMed] [Google Scholar]
  3. Asplund T, Heldin P. (1994) Hyaluronan receptors are expressed on human malignant mesothelioma cells but not on normal mesothelial cells. Cancer Res. 54, 4516. [PubMed] [Google Scholar]
  4. Benitz WE, Lessler DS, Coulson JD, Bernfield M. (1986) Heparin inhibits proliferation of fetal vascular smooth muscle cells in the absence of platelet‐derived growth factor. J. Cell. Physiol. 127, 1. [DOI] [PubMed] [Google Scholar]
  5. Castellot JJ, Addonizio ML, Rosenberg RD, Karnovsky MJ. (1981) Cultured endothelial cells produce a heparin‐like inhibitor of smooth muscle cell growth. J. Cell. Biol. 90, 372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Castellot JJ, Hoover RL, Harper PA, Karnovsky MJ. (1985b) Heparin and glomerular epithelial cell‐secreted heparin like species inhibit mesanglial cell proliferation. Am. J. Path. 120, 427. [PMC free article] [PubMed] [Google Scholar]
  7. Castellot JJ, Wonk K, Herman B, Hoover RL, Albertini DF, Wright TC. (1985a) Binding and internalisation of heparin by vascular smooth muscle cells. J. Cell. Physiol. 124, 13. [DOI] [PubMed] [Google Scholar]
  8. David G. (1993) The integral membrane heparan sulphate proteoglycans. FASEB J. 7, 1023. [DOI] [PubMed] [Google Scholar]
  9. Engfeldt B, Hjerpe A, Mengarelli S, Reinholt FP, Wikstrom B. (1982) Morphological and biochemical analysis of biopsy specimens in disorders of skeletal development. Acta Paediat. Scand. 71, 353. [DOI] [PubMed] [Google Scholar]
  10. Fritze LM, Reilly CF, Rosenberg RD. (1985) An antiproliferative heparan sulphate species produced by postconfluent smooth muscle cells. J. Cell Biol. 100, 1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hata R, Nagai T. (1972) A rapid and micro method for separation of acidic glycosaminoglycans by two‐dimensional electrophoresis. Anal. Biochem. 45, 462. [DOI] [PubMed] [Google Scholar]
  12. Heldin C‐H, Westermark B. (1989) Growth factors as transforming proteins. Eur. J. Biochem. 184, 487. [DOI] [PubMed] [Google Scholar]
  13. Jackson RL, Bush SJ, Cardin AL. (1991) Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes. Physiol. Rev. 71, 481. [DOI] [PubMed] [Google Scholar]
  14. Karamanos NK, Axelsson S, Vanky P, Tzanakakis GN, Hjerpe A. (1995) Determination of hyaluronan and galactosaminoglycan disaccharides by high‐performance capillary electrophoresis at the attomole level. Applications to analyses of tissue and cell culture proteolycans. J. Chromatogr. A. 696, 295. [DOI] [PubMed] [Google Scholar]
  15. Karamanos NK, Hjerpe A. (1996) In: Balduini C, Cherubino P, De Luca G, eds. Advances in Biomedical Studies. Biology and Physiopathology of the Extracellular Matrix, Vol. II Pavia , Italy : La Goliardica Pavese, 71. [Google Scholar]
  16. Karamanos NK, Hjerpe A. (1997) High‐performance capillary electrophoretic analysis of hyaluronan in effusions from human malignant mesothelioma J. Chromatogr. B. 697, 277. [DOI] [PubMed] [Google Scholar]
  17. Karamanos NK, Hjerpe A, Tsegenidis T, Engfeldt B, Antonopoulos CA. (1988) Determination of iduronic acid and glucuronic acid in glycosaminoglycans after stoichiometric reduction and depolymerization using high‐performance liquid chromatography and ultraviolet detection. Anal. Biochem. 172, 410. [DOI] [PubMed] [Google Scholar]
  18. Karamanos NK, Syrokou A, Vanky P, Nurminen M, Hjerpe A. (1994) Determination of 24 variously sulfated galactosaminoglycan‐ and hyaluronan‐derived disaccharides by high‐performance liquid chromatography. Anal. Biochem. 221, 189. [DOI] [PubMed] [Google Scholar]
  19. Karamanos NK, Vanky P, Tzanakakis GN, Hjerpe A. (1996a) High‐performance capillary electrophoresis method to characterise heparin and heparan sulphate disaccharides, Electrophoresis 17, 391. [DOI] [PubMed] [Google Scholar]
  20. Karamanos NK, Vanky P, Tzanakakis G, Tsegenidis T, Hjerpe A. (1997) Ion‐pair high‐performance liquid chromatography for determining disaccharide composition in heparin and heparan sulphate J. Chromatogr. A. 765, 169. [DOI] [PubMed] [Google Scholar]
  21. Kjellen L, Lindhal U. (1991) Structure and functions of proteoglycans. Annu. Rev. Biochem. 60, 443. [DOI] [PubMed] [Google Scholar]
  22. Klominek J, Robert KH, Hjerpe A, Wickstrom B, Gahrton G. (1989) Serum‐dependent growth patterns of two, newly established human mesothelioma cell lines. Cancer Res. 49, 6118. [PubMed] [Google Scholar]
  23. Kraemer PM. (1971) Heparan sulphates of cultured cells. I. Membrane‐associated and cell‐sap species in Chinese hamster cells. Biochemistry 10, 1437. [DOI] [PubMed] [Google Scholar]
  24. Laurent TC, Laurent UB, Fraser JR. (1996) Serum hyaluronan as a disease marker. Ann. Med. 28, 241. [DOI] [PubMed] [Google Scholar]
  25. Nurminen M, Dejemk G, Matrensso G, Hjerpe A. (1994) Clinical utility of liquid‐chromatographic analysis of effusions for hyaluronate content. Clin. Chem. 40, 777. [PubMed] [Google Scholar]
  26. Petitou M, Lormeau JC, Choay L, Recherche S. (1991) Chemical synthesis of glycosaminoglycans: new approaches to antithrombotic drugs. Nature 350, 30. [DOI] [PubMed] [Google Scholar]
  27. Saksela O, Moscattelli D, Sommer A, Rifkin DB. (1988) Endothelial cell‐derived heparan sulphate binds basic fibroblast growth factor and protects it from proteolytic degradation. J. Cell Biol. 107, 743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Scott JE. (1994) On the polylactose nature of chondroitin and keratan sulphates. Biochem. J. 298, 221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shively JE, Conrad HE. (1976) Formation of anhydro‐sugars in the chemical depolymerization of heparin, Biochemistry 15, 3932. [DOI] [PubMed] [Google Scholar]
  30. Tsuji A, Kinoshita T, Hoshino M. (1969) Analytical chemical studies on amino sugars. II. Determination of hexosamines using 3‐methyl‐2‐benzothiazolone hydrazone hydrochloride. Chem. Pharm. Bull. 17, 1505. [DOI] [PubMed] [Google Scholar]
  31. Tzanakakis GN, Hjerpe A, Karamanos NK. (1997) Proteoglycan synthesis induced by transforming and basic fibroblast growth factors in human malignant mesothelioma is mediated through specific receptors and the tyrosine kinase intracellular pathway. Biochimie 79, 323. [DOI] [PubMed] [Google Scholar]
  32. Tzanakakis GN, Karamanos NK, Hjerpe A. (1995) Effects of glycosaminoglycan synthesis in cultured human mesothelioma cells of transforming, epidermal and fibroblast growth factors and their combinations with platelet‐derived growth factor. Exp. Cell Res. 220, 130. [DOI] [PubMed] [Google Scholar]
  33. Tzanakakis GN, Karamanos NK, Klominek J, Hjerpe A. (1995a) Glycosaminoglycans from human malignant mesothelioma cell lines: determination, distribution and effect of platelet‐derived growth factor on their synthesis. Biochem. Cell Biol. 73, 59. [DOI] [PubMed] [Google Scholar]
  34. Tzanakakis GN, Karamanos NK, Syrokou A, Hjerpe A. (1996) Effect of insulin and epidermal growth factors on the synthesis of glycosaminoglycans/proteoglycans in cultured human malignant mesothelioma cells of different phenotypic morphology, APMIS 104, 718. [DOI] [PubMed] [Google Scholar]
  35. Volpi N, Bolognani L, Conte A, Petrini M. (1993) Effects of chondroitin sulphates with different structures on leukaemia cells: U‐937 cell proliferation and differentiation. Leukaemia Res. 17, 789. [DOI] [PubMed] [Google Scholar]
  36. Volpi N, Petrini M, Conte A et al. (1994) Effects of glycosaminoglycans on U‐937 leukaemia cell proliferation and differentiation: Struction‐function relationship. Exp. Cell Res. 215, 119. [DOI] [PubMed] [Google Scholar]
  37. Westergren‐Thorsson G, Persson S, Isaksson A, Onnervik PO, Malmstrom A, Fransson LA. (1993) l‐iduronate‐rich glycosaminglycans inhibit growth of normal fibroblasts independently of serum or added growth factors. Exp. Cell Res. 206, 93. [DOI] [PubMed] [Google Scholar]
  38. Wight TN, Kinsella MG, Qwansrnstom EE. (1992) The role of PGs in cell adhesion, migration and proliferation. Cur. Opin. Cell Biol. 4, 793. [DOI] [PubMed] [Google Scholar]
  39. Wright TC, Castellot JJ, Petitou M, Lormeau J‐C, Choay J, Karnovsky MJ. (1989b) Structural determinants of heparin's growth inhibitory activity. Interdependence of oligosaccharide size and charge. J. Biol. Chem. 264, 1534. [PubMed] [Google Scholar]
  40. Wright TC, Castelot JJ, Diamond JR, Karnovsky MJ. (1989a). In: Lane DA, Lindahl U, eds. Heparin. Regulation of Cellular Proliferation by Heparin and Heparan Sulphate. London/Melbourne/Auckland : Arlond, 295316. [Google Scholar]
  41. Wright TC, Karnovsky MJ. (1987) Metabolic effects of heparin on rat cervical epithelial cells. J. Cell. Physiol. 132, 255. [DOI] [PubMed] [Google Scholar]
  42. Yayon A, Klagsburn M, Esko JD, Leder P, Ornitz DM. (1991) Cell surface, heparin‐like molecules are required for binding of basic fibroblast growth factor to its hgh affinity receptors. Cell 64, 841. [DOI] [PubMed] [Google Scholar]

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