Abstract
Glycosphingolipid abnormalities have long been implicated in tumour malignancy and metastasis. Gangliosides are a family of sialic acid-containing glycosphingolipids that modulate cell–cell and cell–matrix interactions. Histology and ganglioside composition were examined in a natural brain tumour of the VM mouse strain. The tumour is distinguished from other metastatic tumour models because it arose spontaneously and metastasizes to several organs including brain and spinal cord after subcutaneous inoculation of tumour tissue in the flank. By electron microscopy, the tumour consisted of cells (15 to 20 μm in diameter) that had slightly indented nuclei and scant cytoplasm. The presence of smooth membranes with an absence of junctional complexes was a characteristic ultrastructural feature. No positive immunostaining was found for glial or neuronal markers. The total ganglioside sialic acid content of the subcutaneously grown tumour was low (12.6 ± 0.9 μg per 100 mg dry wt n = 6 separate tumours) and about 70% of this was in the form of N-glycolylneuraminic acid. In contrast, the ganglioside content of the cultured VM tumour cells was high (248.4 ± 4.4 μg n = 3) and consisted almost exclusively of N-acetylneuraminic acid. The ganglioside pattern of the tumour grown subcutaneously was complex, while GM3, GM2, GM1, and GD1a were the major gangliosides in the cultured tumour cells. This tumour will be a useful natural model for evaluating the role of gangliosides and other glycolipids in tumour cell invasion and metastasis. © 2001 Cancer Research Campaign www.bjcancer.com
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References
Ando S and Yu RK (1977) Isolation and characterization of a novel trisialoganglioside, GT1a, from human brain. J Biol Chem 252: 6247–6250
Ando S and Yu RK (1979) Isolation and characterization of two isomers of brain tetrasialogangliosides. J Biol Chem 254: 12224–12229
Bai H and Seyfried TN (1997) Influence of ganglioside GM3 and high density lipoprotein (HDL) on the cohesion of mouse brain tumor cells. J Lipid Res 38: 160–172
Bosmann HB, Bieber GF, Brown AE, Case KR, Gersten DM, Kimmerer TW and Lione A (1973) Biochemical parameters correlated with tumour cell implantation. Nature 246: 487–489
Brunson KW, Beattie G and Nicolsin GL (1978) Selection and altered properties of brain-colonising metastatic melanoma. Nature 272: 543–545
Coffman RL and Weissman IL (1981) B220: a B cell-specific member of the T200 glycoprotein family. Nature 289: 681–683
Conley FK (1984) Metastatic brain tumor model in mice that mimics the neoplastic cascade in humans. Neurosurgery 14: 187–192
Cotterchio M and Seyfried TN (1994) Serum gangliosides in mice with metastatic and non-metastatic brain tumors. J Lipid Res 35: 10–14
Coulombe J and Pelletier G (1993) Gangliosides and organ-specific metastatic colonization. Int J Cancer 53: 104–109
Deng W, Li R and Ladisch S (2000) Influence of cellular ganglioside depletion on tumor formation. J Natl Cancer Inst 92: 912–917
Duffy PE (1983). Astrocytes: Normal, Reactive, and Neoplastic, Raven Press: New York
Ecsedy JA, Yohe HC, Bergeron AJ and Seyfried TN (1998) Tumour-infiltrating macrophages contribute to the glycosphinglipid composition of brain tumours. J Lipid Res 39: 2218–2227
El-Abbadi M and Seyfried TN (1994) Influence of growth environment on the ganglioside composition of an experimental mouse brain tumor. Mol Chem Neuropathol 21: 273–285
Eng LF (1985) Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes. J Neuroimmunol 8: 203–214
Fang LH, Lucero M, Kazarian T, Wei Q, Luo FY and Valentino LA (1997) Effects of neuroblastoma tumor gangliosides on platelet adhesion to collagen. Clin Exp Metastasis 15: 33–40
Flavin HJ, Wieraszko A and Seyfried TN (1991) Enhanced aspartate release from hippocampal slices of epileptic (El) mice. J Neurochem 56: 1007–1011
Fraser H (1971) Astrocytomas in an inbred mouse strain. J Pathol 103: 266–270
Fraser H (1986) Brain tumours in mice, with particular reference to astrocytoma. Food Chem Toxicol 24: 105–111
Fredman P (1988) Gangliosides in human malignant gliomas. New Trends in Ganglioside research: Neurochemical and Neurogenerative Aspects, Ledeen RW, Hogan EL, Tettamanti G, Yates A, Yu RK (eds). pp. 151–161, Liviana, Padova
Fredman P, Wikstrand CJ, Mansson JE, Reifenberger G, Bigner SH, Rasheed A, Svennerholm L and Bigner DD (1996) In vivo growth conditions suppress the expression of ganglioside GM2 and favour that of lacto series gangliosides in the human glioma D-54MG cell line. Glycoconj J 13: 391–399
Hakomori S (1996) Tumor malignancy defined by aberrant glycosylation and sphingo (glyco) lipid metabolism. Cancer Res 56: 5309–5318
Kahn HJ, Marks A, Thom H and Baumal R (1983) Role of antibody to S100 protein in diagnostic pathology. Am-J-Clin-Pathol 79: 341–347
Kanda S, Cochran AJ, Lee WR, Morton DL and Irie RF (1992) Variations in the ganglioside profile of uveal melanoma correlate with cytologic heterogeneity. Int J Cancer 52: 682–687
Kim U, Baumler A, Carruthers C and Bielat K (1975) Immunological escape mechanism in spontaneously metastasizing mammary tumors. Proc Natl Acad Sci USA 72: 1012–1016
Kloppel TM, Morre DJ and Jacobsen LB (1979) Ganglioside patterns of metastatic and non-metastatic transplantable hepatocellular carcinomas of the rat. J Supramol Struct 11: 485–492
Ladisch S, Kitada S and Hays EF (1987) Gangliosides shed by tumor cells enhance tumor formation in mice. J Clin Invest 79: 1879–1882
Laferte S, Fukuda MN, Fukuda M, Dell A and Dennis JW (1987) Glycosphingolipids of lectin-resistant mutants of the highly metastatic mouse tumor cell line, MDAY-D2. Cancer Res 47: 150–159
Li Y-T, King MJ and Li SC (1980) Enzymatic degradation of gangliosides. Adv Exp Med Biol 125: 93–104
Manfredi MG, Lim S, Claffey KP and Seyfried TN (1999) Gangliosides influence angiogenesis in an experimental mouse brain tumor. Cancer Res 59: 5392–5397
Merritt WD, Morre DJ, Doak RL and Keenan TW (1980) Gangliosides of liver tumors induced by N-2 fluorenylacetamide III. Galactosyl and sialyl transferases in single carcinomas and nodules. Cancer Biochem Biophys 4: 183–194
Morgan KT, Frith CH, Swenberg JA, McGrath JT, Zulch KJ and Crowder DM (1984) A morphologic classification of brain tumors found in several strains of mice. J Natl Cancer Inst 72: 151–160
Muthing J, Portner A and Jager V (1992) Ganglioside alterations in YAC-1 cells cultivated in serum-supplemented and serum-free growth medium. Glycoconj J 9: 265–273
Nicolson GL (1984) Cell surface molecules and tumor metastasis. Regulation of metastatic phenotypic diversity. Exp Cell Res 150: 3–22
Niederkorn JY, Mellon J, Pidherney M, Mayhew E and Anand R (1993) Effect of anti-ganglioside antibodies on the metastatic spread of intraocular melanomas in a nude mouse model of human uveal melanoma. Curr Eye Res 12: 347–358
Pedersen PH, Rucklidge GJ, Mork SJ, Terzis AJ, Engebraaten O, Lund Johansen M, Backlund EO, Laerum OD and Bjerkvig R (1994) Leptomeningeal tissue: a barrier against brain tumor cell invasion. J Natl Cancer Inst 86: 1593–1599
Pilkington GJ, Darling JL, Lantos PL and Thomas DG (1985) Tumorigenicity of cell lines (VMDk) derived from a spontaneous murine astrocytoma. Histology, fine structure and immunocytochemistry of tumours. J Neurol Sci 71: 145–164
Powers JM, Liu Y, Moser AB and Moser HW (1992) The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 51: 630–643
Ruggieri S, Mugnai G, Mannini A, Calorini L, Fallani A, Barletta E, Mannori G and Cecconi O (1999) Lipid characteristics in metastatic cells. Clin Exp Metastasis 17: 271–276
Said JW, Hargreaves HK and Pinkus GS (1979) Non-Hodgkin’s lymphomas: an ultrastructural study correlating morphology with immunologic cell type. Cancer 44: 504–528
Sanchez Madrid F, Simon P, Thompson S and Springer TA (1983) Mapping of antigenic and functional epitopes on the alpha- and beta-subunits of two related mouse glycoproteins involved in cell interactions, LFA-1 and Mac-1. J Exp Med 158: 586–602
Schackert G, Simmons RD, Buzbee TM, Hume DA and Fidler IJ (1988) Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier. J Natl Cancer Inst 80: 1027–1034
Schlaepfer WW (1987) Neurofilaments: structure, metabolism and implications in disease. J Neuropathol Exp Neurol 46: 117–129
Serano RD, Pegram CN and Bigner DD (1980) Tumorigenic cell culture lines from a spontaneous VM/Dk murine astrocytoma (SMA). Acta Neuropathol Berl 51: 53–64
Seyfried TN (2001) Perspectives on brain tumor formation involving macrophages, glia, and neural stem cells. Persp Biol Med 44: 263–282
Seyfried TN, Glaser GH and Yu RK (1978) Cerebral, cerebellar, and brain stem gangliosides in mice susceptible to audiogenic seizures. J Neurochem 31: 21–27
Seyfried TN, Yu RK, Saito M and Albert M (1987) Ganglioside composition of an experimental mouse brain tumor. Cancer Res 47: 3538–3542
Seyfried TN, El-Abbadi M and Roy ML (1992) Ganglioside distribution in murine neural tumors. Mol Chem Neuropathol 17: 147–167
Seyfried TN, El-Abbadi M, Ecsedy JA, Bai HW and Yohe H (1996) Influence of host cell infiltration on the glycolipid content of mouse brain tumors. J Neurochem 66: 2026–2033
Seyfried TN, El-Abbadi M, Ecsedy JA, Griffin ME and Yohe HC (1998) Ganglioside composition of a mouse brain tumor grown in the severe combined immunodeficiency (SCID) mouse. Mol Chem Neuropathol 33: 27–37
Shapiro WR (1986) Therapy of adult malignant brain tumors: what have the clinical trials taught us?. Semin Oncol 13: 38–45
Skipski VP, Carter SP, Terebus-Kekish OI, Podlaski FJJ, Peterson RH and Stock CC (1981) Ganglioside profiles of metastases and of metastasizing and nonmetastasizing rat primary mammary carcinomas. J Natl Cancer Inst 67: 1251–1258
Sternberger LA (1979). Immunocytochemistry, Wiley: New York
Sung CC, Pearl DK, Coons SW, Scheithauer BW, Johnson PC and Yates AJ (1994) Gangliosides as diagnostic markers of human astrocytomas and primitive neuroectodermal tumors. Cancer 74: 3010–3022
Sung CC, Pearl DK, Coons SW, Scheithauer BW, Johnson PC, Zheng M and Yates AJ (1995) Correlation of ganglioside patterns of primary brain tumors with survival. Cancer 75: 851–859
Swenberg JA (1982) Neoplasms of the nervous system. The Mouse in Biomedical Research, Foster HI, Small JD, Fox JG (eds). IV: 529–527, Academic Press: New York
Vinores SA, Bonnin JM, Rubinstein LJ and Marangos PJ (1984) Immunohistochemical demonstration of neuron-specific enolase in neoplasms of the CNS and other tissues. Arch Pathol Lab Med 108: 536–540
Vural G, Hagmar B and Walaas L (1996) Extracranial metastasis of glioblastoma multiforme diagnosed by fine-needle aspiration: a report of two cases and a review of the literature. Diagn Cytopathol 15: 60–65
Wikstrand CJ, Fredman P, McLendon RR, Svennerholm L and Bigner DD (1994) Altered expression of ganglioside phenotypes of human gliomas in vivo and in vitro. Mol Chem Neuropathol 21: 129–138
Yates AJ (1988) Glycolipids and gliomas. A review. Neurochem Pathol 8: 157–180
Yogeeswaran G (1983) Cell surface glycolipids and glycoproteins in malignant transformation. Adv Cancer Res 38: 289–344
Yogeeswaran G and Salk PL (1981) Metastatic potential is positively correlated with cell surface sialylation of cultured murine tumor cell lines. Science 212: 1514–1516
Yu RK and Ledeen RW (1970) Gas–liquid chromatographic assay of lipid-bound sialic acids: measurement of gangliosides in brain of several species. J Lipid Res 11: 506–516
Zebda N, Pedron S, Rebbaa A, Portoukalian J and Berthier Vergnes O (1995) Deficiency of ganglioside biosynthesis in metastatic human melanoma cells: relevance of CMP-NeuAc:LacCer alpha 2–3 sialyltransferase (GM3 synthase). FEBS Lett 362: 161–164
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El-Abbadi, M., Seyfried, T., Yates, A. et al. Ganglioside composition and histology of a spontaneous metastatic brain tumour in the VM mouse. Br J Cancer 85, 285–292 (2001). https://doi.org/10.1054/bjoc.2001.1909
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DOI: https://doi.org/10.1054/bjoc.2001.1909
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