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Migration Pathways of Human Glioblastoma Cells Xenografted into the Immunosuppressed Rat Brain

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Abstract

Diffuse invasion of the brain by tumor cells is a hallmark of human glioblastomas and a major cause for the poor prognosis of these tumors. This phenomenon is only partially reproduced by rodent models of gliomas that display a very high rate of proliferation and limited cell migration. We have analyzed the development of human glioblastoma cells (GL15) xenografted into the brain of immunosuppressed rats, in order to define the characteristics of tumor cell invasion. As identified by the specific immunolabeling of the tumor cells for the human HLA-ABC antigen, GL15 tumors reproduced the three types of intraparenchymal invasion observed in patients. First, a majority of multipolar tumor cells intermingled rapidly and profusely with host neural cells in the margin of the injection site. This progressively enlarging area was principally responsible for the tumor growth over time. Second, in the gray matter, columns of thin bipolar tumor cells aligned along capillary walls. Third, in the white matter, elongated bipolar isolated tumor cells were observed scattered between axonal fibers. The maximum migration distances along white matter fibers remained significantly higher than the maximum migration distances along blood vessels, up to two months after injection. Development of the tumor was associated with a significant increase of vascularization in the area of tumor spread. Xenografting of human GL15 glioblastoma cells into the immunosuppressed rat brain allowed to differentiate between the three classical types of invasion identified in the clinic, to quantify precisely the distances of migration, and to evaluate cell morphology for each of these routes. The present results support the existence of host/tumor cells interactions with specific characteristics for each type of invasion.

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References

  1. Black PM: Brain tumors. Part 1. N Engl J Med 324: 1471–1476, 1991

    Google Scholar 

  2. Black PM: Brain tumors. Part 2. N Engl J Med 324: 1555–1564, 1991

    Google Scholar 

  3. Giese A, Westphal M: Glioma invasion in the central nervous system. Neurosurgery 39: 235–252, 1996

    Google Scholar 

  4. Pilkington GJ: Tumour cell migration in the central nervous system. Brain Pathol 4: 157–166, 1994

    Google Scholar 

  5. Daumas-Duport C, Scheithauer BW, Kelly PJ: A histologic and cytologic method for the spatial definition of gliomas. Mayo Clin Proc 62: 435–449, 1987

    Google Scholar 

  6. Kleihues P, Soylemezoglu F, Schauble B, Scheithauer BW, Burger PC: Histopathology, classification, and grading of gliomas. Glia 15: 211–221, 1995

    Google Scholar 

  7. Pilkington GJ, Bjerkvig R, De Ridder L, Kaaijk P: In vitro and in vivo models for the study of brain tumor invasion. Anticancer Res 17: 4107–4109, 1997

    Google Scholar 

  8. Peterson DL, Sheridan PJ, Brown WE: Animal models for brain tumors: historical perspectives and future directions. J Neurosurg 80: 865–876, 1994

    Google Scholar 

  9. Barth RF: Rat brain tumor models in experimental neurooncology: The 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 Gliomas. J Neuro-Oncol 36: 91–102, 1998

    Google Scholar 

  10. Bernstein JJ, Goldberg WJ, Laws ER: Immunohistochemistry of human malignant astrocytoma cells xenografted to rat brain: Apolipoprotein E. Neurosurgery 24: 541–546, 1989

    Google Scholar 

  11. Bernstein JJ, Goldberg WJ, Laws ER: Human malignant astrocytoma xenografts migrate in rat brain: a model for central nervous system cancer research. J Neurosci Res 22: 134–143, 1989

    Google Scholar 

  12. Pedersen PH, Marienhagen K, Mork S, Bjerkvig R: Migratory pattern of fetal rat brain cells and human glioma cells in the adult rat brain. Cancer Res 53: 5158–5165, 1993

    Google Scholar 

  13. Pedersen PH, Edvardsen K, Garcia-Cabrera I, Mahesparan R, Thorsen J, Mathisen B, Rosenblum ML, Bjerkvig R: Migratory patterns of lac-Z transfected human glioma cells in the rat brain. Int J Cancer 62: 767–771, 1995

    Google Scholar 

  14. Finkelstein SD, Black P, Nowak TP, Hand CM, Christensen S, Finch PW: Histological characteristics and expression of acidic and basic fibroblast growth factor genes in intracerebral xenogeneic transplants of human glioma cells. Neurosurgery 34: 136–143, 1994

    Google Scholar 

  15. Scherer HJ: The forms of growth in gliomas and their practical significance. Brain 63: 1–35, 1940

    Google Scholar 

  16. Gladson CL: The extracellular matrix of gliomas: Modulation of cell function. J Neuropathol Exp Neurol 58: 1029–1040, 1999

    Google Scholar 

  17. Bocchini V, Casalone R, Collini P, Rebel G, Lo Curto F: Changes in glial fibrillary acidic protein and karyotype during culturing of two cell lines established from human glioblastoma multiforme. Cell Tiss Res 265: 73–81, 1991

    Google Scholar 

  18. Bocchini V, Beccari T, Arcuri C, Bruyere L, Fages C, Tardy M: Glial fibrillary acidic protein and its encoding mRNA exhibit mosaic expression in a glioblastoma multiform cell line of clonal origin. Int J Dev Neurosci 11: 485–492, 1993

    Google Scholar 

  19. Arcuri C, Bocchini V, Guerrieri P, Fages C, Tardy M: PKA and PKC activation induces opposite glial fibrillary acidic protein (GFAP) expression and morphology changes in a glioblastoma multiform cell line of clonal origin. J Neurosci Res 40: 622–631, 1995

    Google Scholar 

  20. Geny C, Naimi-Sadaoui S, Jeny R, Belkadi AM, Juliano SL, Peschanski M: Long-term delayed vascularization of human neural transplants to the rat brain. J Neurosci 14: 7553–7562, 1994

    Google Scholar 

  21. Belien JA, Somi S, de Jong JS, van Diest PJ, Baak JP: Fully automated microvessel counting and hot spot selection by image processing of whole tumour section in invasive breast cancer. J Clin Pathol 52: 184–192, 1999

    Google Scholar 

  22. Benda P, Lightbody J, Sato G, Levine L, Sweet W: Differentiated rat glial cell strain in tissue culture. Science 161: 370–371, 1968

    Google Scholar 

  23. Weizsaecker M, Deen DF, Rosenblum ML, Hoshino T, Gutin PH, Barker M: The 9L rat brain tumor: description and application of an animal model. J Neurol 224: 183–192, 1981

    Google Scholar 

  24. San-Galli F, Vrignaud P, Robert J, Coindre JM, Cohadon F: Assessment of the experimental model of transplanted C6 glioblastoma in Wistar rats. J Neuro-Oncol l7: 299–304, 1989

    Google Scholar 

  25. Albert FK, Forsting M, Sartor K, Adams HP, Kunze S: Early post operative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34: 45–61, 1994

    Google Scholar 

  26. Choucair AK, Levin VA, Gutin PH, Davis RL, Silver P, Edwards MS, Wilson CB: Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg 65: 654–658, 1986

    Google Scholar 

  27. De Crevoisier R, Pierga JY, Dendale R, Feuvret L, Noel G, Simon JM, Mazeron JJ: Radiothérapie des glioblastomes. Cancer Radiother 1: 194–207, 1997

    Google Scholar 

  28. Lee SW, Fraass BA, Marsh LH, Herbort K, Gebarski SS, Martel MK, Radany EH, Lichter AS, Sandler HM: Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 43: 79–88, 1999

    Google Scholar 

  29. Vajkoczy P, Menger MD, Goldbrunner R, Ge S, Fong TAT, Vollmar B, Schilling L, Ullrich A, Hirth KP, Tonn JC, Schmiedek P, Rempel SA: Targeting angiogenesis inhibits tumor infiltration and expression of the pro-invasive protein Spark. Int J Cancer 87: 261–268, 2000

    Google Scholar 

  30. Silbergeld DL, Chicoine MR: Isolation and characterization of human malignant glioma cells from histologically normal brain. J Neurosurg 86: 525–531, 1997

    Google Scholar 

  31. Chicoine MR, Silbergeld DL: Invading C6 glioma cells maintaining tumorigeniciy. J Neurosurg 83: 665–671, 1995

    Google Scholar 

  32. Quinonero J, Colin C, Villarroya H, Collins P, Jacque C: Migration pathways, differentiation and survival of macroglial cells from a xenograft implanted into the thalamus of newborn mice. Int J Devl Neurosci 11: 545–554, 1993

    Google Scholar 

  33. Emmett CJ, Lawrence JM, Raisman G, Seeley PJ: Cultured epithelioid astrocytes migrate after transplantation into the adult rat brain. J Comp Neurol 310: 330–341, 1991

    Google Scholar 

  34. Jacque C, Quinonero J, Collins PV, Villarroya H, Suard I: Comparative migration and development of astroglial and oligodendroglial cell populations from a brain xenograft. J Neurosci 12: 3098–3106, 1992

    Google Scholar 

  35. Okoye GS, Powell EM, Geller HM: Migration of A7 immortalized astrocytic cells grafted into the adult rat stiatum. J Comp Neurol 362: 524–534, 1995

    Google Scholar 

  36. Friedlander DR, Zagzag D, Shiff B, Cohen H, Allen JC, Kelly PJ, Grumet M: Migration of brain tumor cells on extracellular matrix protein in vitro correlates with tumor type and grade and involves αv and β1 integrins. Cancer Res 56: 1939–1947, 1996

    Google Scholar 

  37. Rutka JT, Apodaca G, Stern R, Rosenblum M: The extracellular matrix of the central and peripheral nervous systems: structure and function. J Neurosurg 69: 155–170, 1988

    Google Scholar 

  38. Bignami A, Hosley M, Dahl D: Hyaluronic acid and hyaluronic acid-biding proteins in brain extracellular matrix. Anat Embryol 188: 419–433, 1993

    Google Scholar 

  39. Aspberg A, Miura R, Bourdoulous S, Shimonaka M, Heinegard D, Schachner M, Ruoslahti E, Yamaguchi Y: The C-type lectin domain of lecticans, a family of aggregating chondroitin sulfate proteoglycans, bind tenascin-R by protein–protein interactions independent of carbohydrate moiety. Proc Natl Acad Sci USA 94: 10116–10121, 1997

    Google Scholar 

  40. Maleski M, Hockfield S: Glial cells assemble hyaluronanbased pericellular matrices in vitro. Glia 20: 193–202, 1997

    Google Scholar 

  41. Giese A, Loo MA, Rief MD, Tran N, Berens ME: Substrates for astrocytoma invasion. Neurosurgery 37: 294–302, 1995

    Google Scholar 

  42. Giese A, Kluwe L, Laube B, Meissner H, Berens ME, Westphal M: Migration of human glioma cells on myelin. Neurosurgery 38: 755–764, 1996

    Google Scholar 

  43. Bjerkvig R, Lund-Johansen M, Edvardsen K: Tumor cell invasion and angiogenesis in the central nervous system. Curr Opin Oncol 9: 223–229, 1997

    Google Scholar 

  44. Wolburg H, Risau W: Formation of the blood–brain barrier. In: Kettenmann H, Ranson BR (eds) Neuroglia. Oxford, New York, 1995, pp 763–776

    Google Scholar 

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Authors and Affiliations

  1. Faculté de Médecine, INSERM Unité 421, IM3, France

    J.S. Guillamo, F. Lisovoski, C. Christov, C. Le Guérinel, M. Peschanski & T. Lefrançois

  2. Service de Neurochirurgie, Hôpital Henri Mondor, Créteil, France

    C. Le Guérinel

  3. Service de Neurologie Déjerine, CHU Côte de Nacre, Caen

    G.L. Defer

  4. Laboratoire de Neurobiologie, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France

    T. Lefrançois

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  1. J.S. Guillamo
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Guillamo, J., Lisovoski, F., Christov, C. et al. Migration Pathways of Human Glioblastoma Cells Xenografted into the Immunosuppressed Rat Brain. J Neurooncol 52, 205–215 (2001). https://doi.org/10.1023/A:1010620420241

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