Advertisement

Role of proteoglycans in tumor progression

  • Jósef Timár
  • András Jeney
  • Ilona Kovalszky
  • László Kopper
Huzella Memorial Lecture

Abstract

Data is now starting to accumulate on the differential expression of PGs in tumor cells of various invasive/metastatic potential. This is not so surprising if one considers the key functions that PGs play in the regulation of cell proliferation, adhesion and motility. However, characterization of PG expression in individual tumor types still awaits further detailed studies. Data on melanomas clearly indicate that PG phenotype is both specific and also promiscuous in a sense that ectopic expression of certain tissue specific PGs can occur in various tumors. Expression of a metastatic phenotype-specific splice variants of CD44 provides an example for the possible marker-function of PG. This also raises the hope that some PGs could be used as diagnostic/prognostic tools in pathology or even as a therapeutic targets against tumor dissemination. On the other hand, specific glycanation inhibitors may also be used for the modulation of tumor PG exist and the invasive phenotype.

Key words

proteoglycan metastasis glycosaminoglycan invasion 

Abbreviation

CS

chondroitin sulphate

CSPG

chondroitin sulphate proteoglycan

DS

dermatan sulphate

DSPG

dermatan sulphate proteoglycante]

ECM

extracellular matrixte]

FGF

fibroblast, growth factor

GAG

glycosaminoglycan

galNac

N-acetylgalactosamine

glcA

glucosamine

glcNac

N-acetyl-glucosamine

glcUA

uronic acid

glcIA

iduronic acid

HA

hylauronic acid

HBP

heparin-binding protein

HCGF

hepatocyte growth factor

HS

heparan sulphate

HSPG

heparan sulphate proteoglycan

IL

interleukin

MAA

melanoma-associated antigen

PG

proteoglycan

TGF

transforming growth factor

References

  1. 1.
    Liotta L: Tumor invasion and metastasis—role of the extracellular matrix. Cancer Res 46: 1–7, 1986.PubMedCrossRefGoogle Scholar
  2. 2.
    Nicolson GL: Metastatic tumor cell intercations with endothelium, basement membrane and tissue. Curr Op Cell Biol 1: 1009–1019, 1989.PubMedCrossRefGoogle Scholar
  3. 3.
    Akivama SK, Nagata K and Yamada KM: Cell surface receptors for extracellular matrix. Biochim Biophys Acta 1031: 91–110, 1990.Google Scholar
  4. 4.
    Hynes RO: Integrins: a family of cell surface receptors. Cell 48: 549–554, 1987.PubMedCrossRefGoogle Scholar
  5. 5.
    Ruoslahti E: Fibronectin and its receptos. Ann Rev Biochem 57: 375–413, 1988.PubMedCrossRefGoogle Scholar
  6. 6.
    Ruoslahti E and Giacontti FG: Integrins and tumor dissemination. Cancer Cells 1: 119–126, 1989.PubMedGoogle Scholar
  7. 7.
    Ruoslahti E: Structure and biology of proteoglycans. Ann Rev Cell Biol 4: 229–253, 1988.PubMedGoogle Scholar
  8. 8.
    Kjellen L and Lidahl U: Proteoglycans: structure and interactions. Ann Rev Biochem 60: 443–475, 1991.PubMedCrossRefGoogle Scholar
  9. 9.
    Steeg PS, Bevilaqua G, Kopper L, Thoirgeirsson UP.Talmadge JE, Liotta LA and Sobel ME: Evidence for a novel gene associated with low tumor metastasis potential. J Natl Canc Inst 80: 200–204, 1988.CrossRefGoogle Scholar
  10. 10.
    Günther U, Hoffman M, Rudy W, Reber S, Zöller M, Haubman I, Marzku S, Wenzel A, Ponta H and Herrlieh P: A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65: 13–24, 1991.CrossRefGoogle Scholar
  11. 11.
    Tulchinsky E, Gregorian M, Ebralidze A, Milshina N and Lukanidin E: Structure of gene MTS1 transcribed in metastatic mouse tumor cells. Gene 1: 219–223, 1990.CrossRefGoogle Scholar
  12. 12.
    Knudson CB and Knudson W: Hyaluronan-binding proteins in development, tissue homeostasis and disease. FASEB J 7: 1233–1241, 1993.PubMedGoogle Scholar
  13. 13.
    Barry F: Proteoglycans: structure and function. Biochem Soc Trans 18: 197–198, 1990.PubMedGoogle Scholar
  14. 14.
    Gallagher JT: The extended family of proteoglycans: social residents of the pericellular Zone. Curr Op Cell Biol 1: 1201–1218, 1989.PubMedCrossRefGoogle Scholar
  15. 15.
    Kopper L Hahn TV and Lapis K: Experimental model for liver metastasis formation using Lewis lung tumor. J Cancer Res Clin Oncol 103: 31–38, 1982.PubMedCrossRefGoogle Scholar
  16. 16.
    Lapis K, Timár J, Timár F, Pál K and Kopper L: Differences in cell surface characteristics of poorly and highly metastatic Lewis lung tumor variants. In: Biochemistry and Molecular Genetics of Cancer Metastasis, eds: Lapis K, Liotta LAand Rabson AS, Martinus Nijhoff Publ. Co., Boston, 1985, pp 225–235.Google Scholar
  17. 17.
    Timár J, Moczar E, Timár F, Pál K, Kopper L, Jeney A and Lapis K: Comparative study on Lewis lung tumor lines with low and high metastatic capacity. II. Cytochemical and biochemical differences of glycosaminoglycans. Clin Exptl Metast 5: 79–87, 1987.CrossRefGoogle Scholar
  18. 18.
    Pogány G, Moczr E, Jeney A, Timár J, Timár F, Ditroi K and Lapis K: Comparative study on Lewis lung tumor lines with low and high metastatic capacity. III. Glycosaminoglycan synthesis transport and degradation in cell lines. Clin Exptl Metast 7: 659–669, 1989.CrossRefGoogle Scholar
  19. 19.
    Timár J and Lapis K: Flow cytometric measurements of proteoglycan epitopes in murine tumor cells of different metastatic capacity. Anticancer Res 10: 785–788, 1990.PubMedGoogle Scholar
  20. 20.
    Timár J, Moczar M, Lapis K and Moczar E: Interaction of exogenous heparan sulphate with tumor cells of different metastatic phenotype. Invasion Metast 10: 301–315, 1990.Google Scholar
  21. 21.
    Nakajima M, Welch DR, Irimura T and Nicolson GL: Basement membrane degradative enzymes as possible markers of tumor metastasis. Cancer Metastasis: Experimental and Clinical Strategies, Alan Liss Inc 1986, pp 113–122.Google Scholar
  22. 22.
    Redini F, Moczar E, Antoine E and Poupon ME: Binding and internalization of exogenous glycosaminoglycans in weakly and highly metastatic rhabdomyosarcoma cells. BBA 991: 359–366. 1989.PubMedGoogle Scholar
  23. 23.
    Rouslahti E and Yamaguchi Y: Proteoglycans as modulators of growth factor activities. Cell 64: 867–869, 1991.CrossRefGoogle Scholar
  24. 24.
    Yamagishita M and Hascall VC: Cell surface heparan sulfate proteoglycans. J Biol Chem 267: 9451–9454 1992.Google Scholar
  25. 25.
    Lyon M, Deakin J, Nakamura T and Gallagher JT: The interaction of heparan sulfate with hepatocyte growth factor. Annual research report of Christie Hospital and Paterson Institute. pp 104–105, 1992.Google Scholar
  26. 26.
    Folkman J, Klagsbtirn M, Gasse J, Wadzinnsky M, Ingler D and Vodavsky I: A heparin-binding angiogenic protein—basic fibroblast growth factor—is stored within basement membrane. Am J Pathol 130: 393–400, 1988.PubMedGoogle Scholar
  27. 27.
    Perotti D, Cimino L, Ferrari G and Sacchi A: Differential expression of transforming growth factor bl gene in 3LL metastatic variants. Cancer Res 51: 5491–5494, 1991.Google Scholar
  28. 28.
    Lapis K, Timár J, Pál K, Kopper L, Jeney A and Timár F: Membrane properties of Lewis lung tumor cells with low and high metastatic capacity. Selective antimetastatic effect of a new glycoconjugate-glycosaminoglycan blocking agent 5-hexyl-2-deo.xyuridine (HUdR). In: Cancer Biology and Therapeutics, ed by J.G. Coryand A. Szentivanyi. Plenum Press Publ.Co. NY. 1987, pp 79–94.Google Scholar
  29. 29.
    Lapis K, Kovalszky I, Jeney A, Pogány G, Molnár G, Répássy D, Szécsény A and Karácsony S: Alterations of GAGs in human liver and kidney tumors. Tokai J Expt Clin Med. 15: 155–165, 1990.Google Scholar
  30. 30.
    Sobue M, Takeuchi J, Yoshida K, Akao S, Fukatsu T, Nagasaka T amdNakashima N: Isolation and characterisation of proteoglycans from human non-epithelial tumors. Cancer Res 47: 160–168, 1987.PubMedGoogle Scholar
  31. 31.
    Kundson W and Kundson CB: Assembly of a chondrocyte-like pericellular matrix on non-chondrogenic cells. J Cell Sci 99: 227–235, 1991.Google Scholar
  32. 32.
    Nemee RE, Toole BP and Kundson W: The cell surface of hyaluronate binding sites ol invasive human bladder carcinoma cells. BBRC 149: 249–257, 1987.Google Scholar
  33. 33.
    Günther U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H and Herrlieh P: A new variant of glycoprotein CD44 confers metastatie potential to rat carcinoma cells. Cell 65: 13–24, 1991.CrossRefGoogle Scholar
  34. 34.
    Sy MS, Guo YJ and Stamenkovic I: Distinst effects of two CD44 isoforms on tumor growth in vivo. J Exptl Med 174: 859–866, 1991.CrossRefGoogle Scholar
  35. 35.
    Thomas L, Bxers HR, Vink J and Stamenkovic I: CD44H regulates tumor cell migration on hyaluronate-coated substrate. J Cell Biol 118: 971–977, 1992.PubMedCrossRefGoogle Scholar
  36. 36.
    Hofmann M, Rudy W, Zöller M, Tölg C, Ponta H, Herrlich P and Günther U: CD44 splice variants confer metastatie behavior in rats: homologous sequences are expressed in human tumor cell lines. Cancer Res 51: 5292–5297, 1991.PubMedGoogle Scholar
  37. 37.
    Wielenga VJM, Hehler K-H, Offerhaus GJA, Adolf GR.van den Berg M, Ponta H, Herrlich P and Pals ST: Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res 53: 4754–4756, 1993.PubMedGoogle Scholar
  38. 38.
    Heider K-H, Hofmann M, Hors E, van den Berg F, Ponta H, Herrlich P, Pals ST: A human homologue of rat metastasisassociated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps. J Cell Biol 120: 227–233, 1993.PubMedCrossRefGoogle Scholar
  39. 39.
    Gross N, Beretta C, Peruisseau G, Jackson D, Simmons D and Beek D. Cancer Res 54: 4238–4242, 1994.PubMedGoogle Scholar
  40. 40.
    Koppman G, Heider K-H, Horst E, Adolf GR, van den Berg F, Ponta H, Herrlich P and Pals ST: Activated human lymphocytes and aggressive non-Hodgkin’s lymphomas express a homologue of the rat metastasis-associated variant of CD44. J Exp Med 177: 897–904, 1993.CrossRefGoogle Scholar
  41. 41.
    Bumol TF, Walker LE and Reisfeld RA: Biosynthetic studies of proteoglycans in human melanoma cells with a monoclonal antibody to a core glycoprotein of chondroitin sulphate proteoglycan. J Biol Chem 259: 12733–12741, 1984.PubMedGoogle Scholar
  42. 42.
    Harper JR and Reisfeld RA: Cell-associated proteoglycans in human malignant melanoma In: Biology of Proteoglycans. eds. Wight TNand Mecham RP. Acad Press Inc., Orlando, 1987, pp345–366.Google Scholar
  43. 43.
    Godal A.Bruland O.Hang E, Aas M and Fodstad O: Unexpected expression of the 250 kD melanoma-associated antigen in human sarcoma cells.Br J Cancer 53: 839–841, 1986.PubMedGoogle Scholar
  44. 44.
    Garin-Chesa P, Beresford HR, Carrato-Mena A, Oettgen HF, Old LJ, Melamed MR and Rettig WJ: Cell surface molecules of human melanoma Immunohistochemical analysis of the gp57. GD3 and mel-CSproteoglikán systems. Am J Pathol 134: 295–303, 1989.PubMedGoogle Scholar
  45. 45.
    Nagelhus TA and Rofstad EK: Expression of the chondroitin sulphate proteoglycan molecular complex in six human melanoma xenogralt lines studied by flow cytometry and immunohistochemistry. Melanoma Res 3: 187–194, 1993.PubMedCrossRefGoogle Scholar
  46. 46.
    Iida J, Skubitz APN, Furcht LT, Wayner EA andMcCarthy JB: Coordinate role for cell surface chondroitin sulfate proteoglycan and β4bl integrin in mediating melanoma cell adhesion to fibronectin. J Cell Biol 118: 431–444, 1992.PubMedCrossRefGoogle Scholar
  47. 47.
    Dodge GR, Kovalszky I, Chu ML, Hassell JR, McBride WO, Yi HF and Iozzo R.V. Heparan sulphate proteoglycans of human colon: partial molecular cloning, cellular expression and mapping of the gene (HS proteoglycan 2) to the short arm of human chromosome 1.Genomics 10: 673–680, 1991.PubMedCrossRefGoogle Scholar
  48. 48.
    Schrappe M, Klier FG, Spiro RC, Waltz TA, Reisfeld RA and Gladson CL: Correlation of chondroitin sulphate proteoglycan expression on proliferating brain capillary endothelial cells with the malignant phenotype of astroglial cells. Cancer Res 51: 4986–4993, 1991.PubMedGoogle Scholar
  49. 49.
    Steck PA, Moser RP Bruner JM, Liang L. Freidman AN, Hwang T-Land Young WKA: Altered expression and distribution of heparan sulphate proteoglycans in human gliomas. Cancer Res 2096–2103, 1989.Google Scholar
  50. 50.
    Roberts DD: Interactions of thrombospondin with sulphated glycolipids and proteoglycans of human melanoma cells. Cancer Res 48:6785–6793. 1989.Google Scholar
  51. 51.
    Tímár J, Kovalszky I.Paku S, Lapis K and Kopper L: Two human melanoma xenografts with different metastatic capacity and glycosaminoglycan pattern. J Cancer Res Clin Oncol 115: 554–557, 1989.PubMedCrossRefGoogle Scholar
  52. 52.
    Ladányi A, Tímár J, Paku S, Molnár G and Lapis K: Selection and characterisation of human melanoma lines with different liver-colonizing capacity. Int. J Cancer 46: 456–461, 1990.PubMedCrossRefGoogle Scholar
  53. 53.
    Tímár J, and Kovalszky I: Differential expression of proteoglycans on the surface of malignant cells and in the tumor stroma. In: Tumor Matrix Biology, chapter 2., ed. By R. Adany, CRC Press. Boca Raton. 1995. pp 23–53Google Scholar
  54. 54.
    Timár J, Ladányi A.Lapis K and Moczar M: Differential expression of proteoglycans on the surface of human melanoma cells characterized by altered experimental metastatie potential. Am J Pathol 141: 467–474, 1992PubMedGoogle Scholar
  55. 55.
    Caux F, Timar J, Vigny M and Moczar M: Heparan sulfate synthesized by human melanoma cell variants. The Cancer Journal 5: 111–117, 1992.Google Scholar
  56. 56.
    Caux F, Timár J, Lapis K and Moczar M: Proteochondroitin sulphate in human melanoma cell cultures. Biochem Soc Transact 18: 293–294, 1990.Google Scholar
  57. 57.
    Inki P, Stenbäck F.Talve L and Jalkanen M: Immunohistochemical localization of syndecan in mouse skin tumors induced by UV irradiation. Am J Pathol 139: 1333–1340, 1991.PubMedGoogle Scholar
  58. 58.
    Cohen IR, Murdock AD, Naso MF, Marchetti D, Berd D, Lozzo RV: Abnormal expression of perleean proteoglycan in metastatic melanomas, Cancer Res 54: 5771–5774. 1994.PubMedGoogle Scholar
  59. 59.
    Turley LA and Irclitik M: ( ilćosaminoLiKcaii production ol nini'ine melanoma Tretiak M. Glycosaminoglycan in vivo and in vitro. cancer Res 45: 5098–5105, 1986.Google Scholar
  60. 60.
    Manigla CA, Gomaz JJ, Luikart SD, and Sartorelli AC, Glycosammoglyean production and distribution in cloned B 16 murine melanoma cell lines exhibiting different lung colony forming efficiences. J Natl Canc Inst 75: 111–120, 1985Google Scholar
  61. 61.
    Schwartz-Albiez R, Steffen L, Lison A, Güler N, Schirrmacher V and Keller R: Expression and enhanced secretion of proteochondroitin sulfate in a melastatic variant of a mouse lymphoma cell line. Br. J Cancer 57: 569–575, 1988.PubMedGoogle Scholar
  62. 62.
    Redini F, Verelle P, Hillova J, Poupon MF and Moczar E: Cell surface glycosammoglycans of tumor cell line and its DNA transfected differing in their lung colonization potential. Glycoconjugate J 4: 191–201, 1987.CrossRefGoogle Scholar
  63. 63.
    Jeney A.Tímár J, Pogany G, Paku S, Moczar M, Mareel M. Ötvöy L, Kopper L and Lapis K: Glycosaminoglycans as novel target in antitumertherapy. Tokai J Exp Clin Med 15: 167–177, 1990.PubMedGoogle Scholar
  64. 64.
    Moczar M, Caux F, Bailly M, Berthier O and J.T. DoIhre Accumulation of heparan sulfate in the culture of human melanoma cells with different metastic ability. J Clin Exp Metast 11: 462–472.1993.CrossRefGoogle Scholar
  65. 65.
    Tímár J, Pogány G, Balázs M.Szöllô.si J, Ladányi A.Oláh J, Tímár J, Lapis K and, Jeney A: Modulation of membrane phenotype, matrix adhesion and microinvasiveness of metastatic tumour cells In HUdR. Cell Biochem Funct 8: 211–220. 1990.PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 1995

Authors and Affiliations

  • Jósef Timár
    • 1
  • András Jeney
    • 1
  • Ilona Kovalszky
    • 1
  • László Kopper
    • 1
  1. 1.1st Institute of Pathology and Experimental Cancer ResearchSemmelweis University of MedicineBudapestHungary

Personalised recommendations