The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model

BMC Cancer

Celina Garcia⁴  Luiz Gustavo Dubois⁴  Anna Lenice Xavier⁴  Luiz Henrique Geraldo⁴  Anna Carolina Carvalho da Fonseca⁴  Ana Helena Correia²  Fernanda Meirelles¹  Grasiella Ventura⁴  Luciana Romão³  Nathalie Henriques Silva Canedo²  Jorge Marcondes de Souza²  João Ricardo Lacerda de Menezes⁴  Vivaldo Moura-Neto⁴  Fernanda Tovar-Moll¹  Flavia Regina Souza Lima⁴ 

[1] National Center of Structural Biology and Bioimaging (CENABIO), 22281-100 Rio de Janeiro, Brazil

[2] Serviço de Anatomia Patológica/Serviço de Neurocirurgia – Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

[3] Universidade Federal do Rio de Janeiro/Macaé, 27930-560 Macaé, Brazil

[4] Instituto de Ciências Biomédicas, CCS – Bloco F, Universidade Federal do Rio de Janeiro, 21949-590 Rio de Janeiro, Brazil

关键词: Reactive gliosis;    Angiogenesis;    Microglia;    Glioblastoma;   

Others  :  1117929
DOI  :  10.1186/1471-2407-14-923

 received in 2014-07-23, accepted in 2014-11-26,  发布年份 2014

【 摘 要 】

Background

Glioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice.

Methods

Xenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses.

Results

Our data show that two weeks after injection, the produced tumor presents histopathological characteristics recommended by World Health Organization for the diagnosis of GBM in humans. The tumor was able to produce reactive gliosis in the adjacent parenchyma, angiogenesis, an intense recruitment of macrophage and microglial cells, and presence of necrosis regions. Besides, MRI showed that tumor mass had enhanced contrast, suggesting a blood–brain barrier disruption.

Conclusions

This study demonstrated that the xenografted tumor in mouse brain parenchyma develops in a very similar manner to those found in patients affected by GBM and can be used to better understand the biology of GBM as well as testing potential therapies.

【 授权许可】

   
2014 Garcia et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA: Malignant glioma: genetics and biology of a grave matter. Genes Dev 2001, 15(11):23.
• [2]Charles NA, Holland E, Gilbertson R, Glass R, Kettenmann H: The brain tumor microenvironment. Glia 2011, 59(8):11.
• [3]Dolecek TA, Propp JM, Stroup NE, Kruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 2012, 14(Suppl. 5):49.
• [4]Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007, 114(2):13.
• [5]Weller M: Novel diagnostic and therapeutic approaches to malignant glioma. Swiss Med Wkly 2011, 141:w13210.
• [6]Hedlund A, Ahrén M, Gustafsson H, Abrikossova N, Warntjes M, Jönsson JI, Uvdal K, Engström M: Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement. Int J Nanomedicine 2011, 6:8.
• [7]Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R: Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010, 468(7325):5.
• [8]Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V: Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010, 468(7325):5.
• [9]Huse JT, Holland EC: Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer 2010, 10(5):13.
• [10]Woodworth DC, Pope WB, Liau LM, Kim HJ, Lai A, Nghiemphu PL, Cloughesy TF, Ellingson BM: Nonlinear distortion correction of diffusion MR images improves quantitative DTI measurements in glioblastoma. J Neurooncol 2013, 116(3):8.
• [11]Graeber MB, Scheithauer BW, Kreutzberg GW: Microglia in brain tumors. Glia 2002, 40(2):8.
• [12]Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, Sawaya R, Heimberger AB: Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol 2010, 12(11):13.
• [13]Alves TR, Lima FR, Kahn SA, Lobo D, Dubois LG, Soletti R, Borges H, Neto VM: Glioblastoma cells: a heterogeneous and fatal tumor interacting with the parenchyma. Life Sci 2011, 89(15–16):8.
• [14]Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002, 3(11):8.
• [15]Lima FR, Kahn SA, Soletti RC, Biasoli D, Alves T, da Fonseca AC, Garcia C, Romão L, Brito J, Holanda-Afonso R, Faria J, Borges H, Moura-Neto V: Glioblastoma: therapeutic challenges, what lies ahead. Biochim Biophys Acta 2012, 1826(2):12.
• [16]Moore SJ, Leung CL, Norton HK, Cochran JR: Engineering agatoxin, a cystine-knot peptide from spider venom, as a molecular probe for in vivo tumor imaging. PLoS One 2013, 8(4):e60498.
• [17]Hambardzumyan D, Parada LF, Holland EC, Charest A: Genetic modeling of gliomas in mice: new tools to tackle old problems. Glia 2011, 59(8):14.
• [18]Faria J, Romão L, Martins S, Alves T, Mendes FA, de Faria GP, Hollanda R, Takiya C, Chimelli L, Morandi V, de Souza JM, Abreu JG, Moura Neto V: Interactive properties of human glioblastoma cells with brain neurons in culture and neuronal modulation of glial laminin organization. Differentiation 2006, 74:11.
• [19]Diniz LP, Alves-Leon SV, Tortelli V, Vargas Lopes C, Setti-Perdigão P, Stipursky J, Kahn SA, Romão LF, de Miranda J, Alves-Leon SV, de Souza JM, Castro NG, Panizzutti R, Gomes FC: Astrocyte-induced synaptogenesis is mediated by transforming growth factor β signaling through modulation of D-serine levels in cerebral cortex neurons. J Biol Chem 2012, 287(49):13.
• [20]Kleihues P, Sobin LH: World Health Organization classification of tumors. Cancer 2000, 88(12):2887.
• [21]Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD: IDH1 and IDH2 Mutations in Gliomas. N Engl J Med 2009, 360(8):765-773.
• [22]Zhang Z, Trautmann K, Artelt M, Burnet M, Schluesener HJ: Bone morphogenetic protein-6 is expressed early by activated astrocytes in lesions of rat traumatic brain injury. Neuroscience 2006, 138(1):7.
• [23]Rolls A, Shechter R, Schwartz M: The bright side of the glial scar in CNS repair. Nat Rev Neurosci 2009, 10(3):7.
• [24]Dvorak HF, Weaver VM, Tlsty TD, Bergers G: Tumor microenvironment and progression. J Surg Oncol 2011, 103(6):7.
• [25]Fonseca AC, Badie B: Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies. Clin Dev Immunol 2013, 2013:5.
• [26]Habberstad AH, Lind-Landström T, Sundstrøm S, Torp SH: Primary human glioblastomas - prognostic value of clinical and histopathological parameters. Clin Neuropathol 2012, 31(5):8.
• [27]Yi L, Zhou C, Wang B, Chen T, Xu M, Xu L, Feng H: Implantation of GL261 neurospheres into C57/BL6 mice: a more reliable syngeneic graft model for research on glioma-initiating cells. Int J Oncol 2013, 43(2):12.
• [28]Doblas S, He T, Saunders D, Hoyle J, Smith N, Pye Q, Lerner M, Jensen RL, Towner RA: In vivo characterization of several rodent glioma models by 1H MRS. NMR Biomed 2012, 25(4):11.
• [29]Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA: Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006, 9(5):13.
• [30]Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA: CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013, 19(10):9.
• [31]Radaelli E, Ceruti R, Patton V, Russo M, Degrassi A, Croci V, Caprera F, Stortini G, Scanziani E, Pesenti E, Alzani R: Immunohistopathological and neuroimaging characterization of murine orthotopic xenograft models of glioblastoma multiforme recapitulating the most salient features of human disease. Histol Histopathol 2009, 24(7):13.
• [32]Brehar FM, Ciurea AV, Chivu M, Zarnescu O, Radulescu R, Dragu D: The development of xenograft glioblastoma implants in nude mice brain. J Med Life 2008, 1(3):12.
• [33]Russell PS, Chase CM, Madsen JC, Hirohashi T, Cornell LD, Sproule TJ, Colvin RB, Roopenian DC: Coronary artery disease from isolated non-H2-determined incompatibilities in transplanted mouse hearts. Transplantation 2011, 91(8):6.
• [34]Varlet P, Soni D, Miquel C, Roux FX, Meder JF, Chneiweiss H, Daumas-Duport C: New variants of malignant glioneuronal tumors: a clinicopathological study of 40 cases. Neurosurgery 2004, 55(6):16.
• [35]Suematsu S, Watanabe T: Generation of a synthetic lymphoid tissue-like organoid in mice. Nat Biotechnol 2004, 22(12):7.
• [36]Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R: Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 2005, 174(40):13.
• [37]Shultz LD, Ishikawa F, Greiner DL: Humanized mice in translational biomedical research. Nat Rev Immunol 2007, 7(2):13.
• [38]Bajénoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN: Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 2006, 25(6):12.
• [39]Ichimura K, Pearson D, Kocialkowski S, Bäcklund LM, Chan R, Jones DT, Collins VP: IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 2009, 11(4):8.
• [40]Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN: Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol 2009, 68(12):7.
• [41]Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT: Angiogenesis in brain tumours. Nat Rev Neurosci 2007, 8(8):13.
• [42]Das S, Marsden PA: Angiogenesis in glioblastoma. N Engl J Med 2013, 369(16):4.
• [43]Markovic DS, Glass R, Synowitz M, Rooijen NV, Kettenmann H: Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol 2005, 64(9):9.
• [44]Huysentruyt LC, Akgoc Z, Seyfried TN: Hypothesis: are neoplastic macrophages/microglia present in glioblastoma multiforme? ASN Neuro 2011, 3(4):1759-0914.
• [45]Voskoglou-Nomikos T, Pater J, Seymour L: Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin Cancer Res 2003, 9:13.
• [46]Sausville EA, Burger A: Contributions of human tumor xenografts to anticancer drug development. Cancer Res 2006, 66(7):5.
• [47]Rodrigues JC, Zhang GG, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Dietz AB, Forsyth PA, Yong VW, Parney IF: Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol 2010, 12(4):15.
• [48]Fulop GM, Phillips R: The scid mutation in mice causes a general defect in DNA repair. Nature 1990, 347(6292):4.
• [49]Biedermann KA, Sun J, Giaccia AJ, Tosto LM, Brown JM: Scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc Natl Acad Sci U S A 1991, 88:4.
• [50]Ishii-Ohba H, Kobayashi S, Nishimura M, Shimada Y, Tsuji H, Sado T, Ogiu T: Existence of a threshold-like dose for gamma-ray induction of thymic lymphomas and no susceptibility to radiation-induced solid tumors in SCID mice. Mutat Res 2007, 619(1–2):10.
• [51]Kahn SA, Biasoli D, Garcia C, Geraldo LH, Pontes B, Sobrinho M, Frauches AC, Romão L, Soletti RC, Assunção Fdos S, Tovar-Moll F, de Souza JM, Lima FR, Anderluh G, Moura-Neto V: Equinatoxin II potentiates temozolomide- and etoposide-induced glioblastoma cell death. Curr Top Med Chem 2013, 12(19):12.