Abstract
The frequently occurring alteration of ganglioside expression in tumor cells has been implicated to play a role in the uncontrolled growth of these cells; antibodies to such gangliosides might affect tumor cell growth. We have studied the effect of IgM monoclonal antibodies to two glioma-associated gangliosides, GD3 and GM2, on cell proliferation of four human glioma cell lines and one renal tumor cell line. Of the two anti-ganglioside antibodies tested, only the anti-GD3 antibody resulted in a significant (p<0.005) inhibition of cell proliferation as measured by thymidine incorporation and Brd-U labeling, after 24[emsp4 ]h incubation. The effect was not dependent on any serum factor and no increased cell death was observed. All cell lines contained higher or similar amounts of GM2 than GD3, and both antigens were shown to be expressed on the cell surface and accessible to antibodies. The selective effect of anti-GD3 antibodies as contrasted to the inactivity of anti-GM2 antibodies suggests a possible role for ganglioside GD3 in tumor cell proliferation.
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References
Hakomori S-I, Aberrant glycosylation in tumors and tumorassociated carbohydrate antigens, Adv Cancer Res 52, 257–331 (1989).
Yates AJ, Thompson DK, Boesel CP, Albrightson C, Hart RW, Lipid composition of human neural tumors, J Lipid Res 20, 428–36 (1979).
Fredman P, Gangliosides in human malignant gliomas, New Trends in Ganglioside Research 14, 151–61 (1988).
von Holst H, Nygren C, Boström K, Collins VP, Fredman P, The presence of fetal ganglioside antigens, 3'-isoLM1 and 3'6'-isoLD1, in both glioma tissue and surrounding areas from human brain, Acta Neurochir 139, 141–5 (1997).
Svennerholm L, Boström K, Fredman P, MÅnsson J-E, Rosengren B, Rynmark B-M, Human brain gangliosides: developmental changes from early fetal stage to advanced age, Biochim Biophys Acta 1005, 109–17 (1989).
Fredman P, MÅnsson J-E, Bigner SH, Wikstrand CJ, Bigner DD, Svennerholm L, Gangliosides in the human glioma cell line U-118 MG grown in culture or as xenografts in nude rats, Biochim Biophys Acta 1045, 239–44 (1990).
Hakomori S-I, Igarashi Y, Gangliosides and glycosphingolipids as modulators of cell growth, adhesion, and transmembrane signaling, Adv Lipid Res 25, 147–62 (1993).
Bjerkvig R, Engebraaten O, Laerum OD, Fredman P, Svennerholm L, Vrionis FD, Wikstrand CJ, Bigner DD, Anti-GM2 monoclonal antibodies induce necrosis in GM2-rich cultures of a human glioma cell line, Cancer Res 51, 4643–8 (1991).
Houghton AN, Mintzer D, Cordon-Cardo C, Welt S, Fliegel B, Vadhan S, Carswell E, Melamed MR, Oettgen HF, Old LJ, Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: a phase I trial in patients with malignant melanoma, Proc Natl Acad Sci USA 82, 1242–6 (1985).
Dippold WG, Bernhard H, Dienes HP, zum Buschenfelde K-HM, Treatment of patients with malignant melanoma by monoclonal ganglioside antibodies, Eur J Cancer Clin Oncol 24, S65–7 (1988).
Dippold WG, Knuth A, zum Buschenfelde K-HM, Inhibition of human melanoma cell growth in vitro by monoclonal anti-GD3-ganglioside antibody, Cancer Res 44, 806–10 (1984).
Katano M, Irie RF, Human monoclonal antibody to tumor-associated ganglioside GD2: suppressed growth of human melanoma in nude mice, Immunol Lett 8, 169–74 (1984).
Cheung N-KV, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, Spitzer T, Strandjord SE, Coccia PF, Berger NA, Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma, J Clin Oncol 5, 1430–40 (1987).
Lund-Johansen M, Bjerkvig R, Humphrey PA, Bigner SH, Bigner DD, Laerum O-D, Effect of epidermal growth factor on glioma cell growth, migration, and invasion in vitro, Cancer Res 50, 6039–44 (1990).
Engebraaten O, Bjerkvig R, Pedersen P-H, Laerum OD, Effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain-tumour biopsies in vitro, Int J Cancer 53, 209–14 (1993).
Pedersen P-H, Ness GO, Engebraaten O, Bjerkvig R, Lillehaug JR, Laerum OD, Heterogeneous response to the growth factors (EGF, PDGF(bb), TGF-α, bFGF, IL-2) on glioma spheroid growth, migration and invasion, Int J Cancer 56, 255–61 (1994).
Yates AJ, Saqr HE, van Brocklyn J, Ganglioside modulation of the PDGF receptor, J Neurooncol 24, 65–73 (1995).
Kasahara K, Watanabe Y, Yamamoto T, Sanai Y, Association of Src family tyrosine kinase Lyn with ganglioside GD3 in rat brain, J Biol Chem 272, 29947–53 (1997).
Hakomori S-I, Handa K, Iwabuchi K, Yamamura S, Prinetti A, New insights in glycosphingolipid function: “glycosignaling domain,” a cell surface assembly of glycosphingolipids with signal transducer molecules, involved in cell adhesion coupled with signaling, Glycobiology 8, xi–xix (1998).
Slagel DE, Dittmer JC, Wilson CM, Lipid composition of human glial tumour and adjacent brain, J Neurochem 14, 789–98 (1967).
Kostic’ D, Bucheit F, Gangliosides in human brain tumours, Life Sci 9, 589–96 (1970).
Traylor TD, Hogan EL, Gangliosides of human cerebral astrocytomas, J Neurochem 34, 126–31 (1980).
Eto Y, Shinoda S, Gangliosides and neutral glycosphingolipids in human brain tumors: specificity and their significance, Adv Exp Med Biol 152, 279–90 (1982).
Berra B, Gaini SM, Riboni L, Correlation between ganglioside distribution and histological grading of human astrocytomas, Int J Cancer 36, 363–66 (1985).
Fredman P, von Holst H, Collins VP, Ammar A, Dellheden B, Wahren B, Granholm L, Svennerholm L, Potential ganglioside antigens associated with human gliomas, Neurol Res 8, 123–6 (1986).
Fredman P, von Holst H, Collins VP, Dellheden B, Svennerholm L, Expression of gangliosides GD3 and 3'-isoLM1 in autopsy brains from patients with malignant tumors, J Neurochem 60, 99–105 (1993).
Rosengren B, MÅnsson J-E, Svennerholm L, Composition of gangliosides and neutral glycosphingolipids of brain in classical Tay-Sachs and Sandhoff disease: more lyso-GM2 in Sandhoff disease? J Neurochem 49, 834–40 (1987).
MÅnsson J-E, Fredman P, Bigner DD, Molin K, Rosengren B, Friedman HS, Svennerholm L, Characterization of new gangliosides of the lactotetraose series in murine xenografts of a human glioma cell line, FEBS Lett 201, 109–13 (1986a).
MÅnsson J-E, Mo H, Egge H, Svennerholm L, Trisialosyllactosylceramide (GT3) is a ganglioside of human lung, FEBS Lett 196, 259–62 (1986b).
Karlsson G, MÅnsson J-E, Wikstrand C, Bigner D, Svennerholm L, Characterization of the binding epitope of the monoclonal antibody DMAb-1 to ganglioside GM2, BBA 1043, 267–72 (1990).
Fredman P, MÅnsson J-E, Wikstrand CJ, Vrionis FD, Rynmark B-M, Bigner DD, Svennerholm L, A new ganglioside of the lactotetraose series, Gal-NAc-3'-isoLM1, detected in human meconium, J Biol Chem 264, 12122–25 (1989).
He X, Wikstrand CJ, Fredman P, MaÊnsson J-E, Svennerholm L, Bigner DD, GD3 expression by cultured human tumor cells of neuroectodermal origin, Acta Neuropathol 79, 317–25 (1989).
Premkumar E, Potter M, Singer PA, Sklar MD, Synthesis, surface deposition, and secretion of immunoglobulins by Abelson virustransformed lymphosarcoma cell lines, Cell 6, 149–59 (1975).
Brismar T, Collins VP, Inward rectifying potassium channels in human malignant glioma cells, Brain Res 480, 249–58 (1989).
Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH, Dosik H, Parks WP, In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors, J Natl Cancer Inst 51, 1417–23 (1973).
Wikstrand CJ, Bigner SH, Bigner DD, Demonstration of complex antigenic heterogeneity in a human glioma cell line and eight derived clones by specific monoclonal antibodies, Cancer Res 43, 3327–34 (1983).
Pontén J, MacIntyre EH, Long term culture of normal and neoplastic human glia, Acta Path Microbiol Scandinav 74, 465–86 (1968).
Bullard DE, Schold SC, Bigner SH, Bigner DD, Growth and chemotherapeutic response in athymic mice of tumors arising from human glioma-derived cell lines, J Neuropathol Exp Neurol 40, 410–27 (1981).
Miyao N, Tsukamoto T, Kumamoto Y, Establishment of three human renal cell carcinoma cell lines (SMKT-R-1, SMKT-R-2, and SMKT-R-3) and their characters, Urol Res 17, 317–24 (1989).
Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC, Measurement of protein using bicinchoninic acid, Anal Biochem 150, 76–85 (1985).
Mosmann T, Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays, J Immunol Methods 65, 55–63 (1983).
Miltenburger HG, Sachse G, Schliermann M, S-phase cell detection with a monoclonal antibody, Dev Biol Stand 66, 91–9 (1987).
Dean PN, Dolbeare F, Gratzner H, Rice GC, Gray JW, Cell-cycle analysis using a monoclonal antibody to BrdUrd, Cell Tissue Kinet 17, 427–36 (1984).
Gratzner HG, Monoclonal antibody to 5-bromo-and 5-iododeoxyuridine: a new reagent for detection of DNA replication, Science 218, 474–5 (1982).
Muir D, Varon S, Manthorpe M, An enzyme-linked immunosorbent assay for bromodeoxyuridine incorporation using fixed microcultures, Anal Biochem 185, 377–82 (1990).
Svennerholm L, Fredman P, A procedure for the quantitative isolation of brain gangliosides, Biochim Biophys Acta 617, 97–109 (1980).
Davidsson P, Fredman P, Collins PV, von Holst H, MÅnsson J-E, Svennerholm L, Ganglioside composition in human meningiomas, J Neurochem 53, 705–9 (1989).
Fredman P, Nilsson O, Tayot J-L, Svennerholm L, Separation of gangliosides on a new type of anion-exchange resin, Biochim Biophys Acta 618, 42–52 (1980).
Svennerholm L, MÅnsson J-E, Li Y-T, Isolation and structural determination of a novel ganglioside, a disialosylpentahexosylceramide from human brain, J Biol Chem 248, 740–2 (1973).
Holmgren J, Lindblad M, Fredman P, Svennerholm L, Myrvold H, Comparison of receptors for Cholera and Escherichia coli enterotoxins in human intestine, Gastroenterology 89, 27–35 (1985).
Hakomori S, Cell density-dependent changes of glycolipid concentrations in fibroblasts, and loss of this response in virus-transformed cells, PNAS 67, 1741–7 (1970).
Sakiyama H, Gross SK, Robbins PW, Glycolipid synthesis in normal and virus-transformed hamster cell lines, PNAS 69, 872–6 (1972).
Birklé S, Gao L, Zeng G, Yu RK, Down-regulation of GD3 ganglioside and its O-acetylated derivative by stable transfection with antisense vector against GD3-synthase gene expression in hamster melanoma cells: Effect on cellular growth, melanogenesis, and dendricity, J Neurochem 74, 547–54 (2000).
Gillard BK, Clement R, Colucci-Guyon E, Babinet C, Schwarzmann G, Taki T, Kasama T, Marcus DM, Decreased synthesis of glycosphingolipids in cells lacking vimentin intermediate filaments, Exp Cell Res 242(2), 561–72 (1998).
Wikstrand CJ, Fredman P, Svennerholm L, Bigner DD, Detection of glioma-associated gangliosides GM2, GD2, GD3, 3'-isoLM1 and 3'6'-isoLD1 in central nervous system tumors in vitro and in Monoclonal anti-GD3 antibodies 725 vivo using epitope-defined monoclonal antibodies, Prog Brain Res 101, 213–23 (1994).
Masserini M, Palestini P, Pitto M, Glycolipid-enriched caveolae and caveolae-like domains in the nervous system, J Neurochem 73, 1–11 (1999).
IUPAC-IUB, Commission on Biochemical Nomenclature (CBN): The nomenclature of lipids, Lipids 12, 455–68 (1977).
Svennerholm L, Chromatographic separation of human brain gangliosides, J Neurochem 10, 613–23 (1963).
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Hedberg, K.M., Dellheden, B., Wikstrand, C.J. et al. Monoclonal anti-GD3 antibodies selectively inhibit the proliferation of human malignant glioma cells in vitro. Glycoconj J 17, 717–726 (2000). https://doi.org/10.1023/A:1011026823362
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DOI: https://doi.org/10.1023/A:1011026823362