Angiogenesis and cell proliferation in human craniopharyngioma xenografts in nude mice

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Craniopharyngioma is one of the most common congenital tumors of the sellar and suprasellar regions and accounts for between 4 and 6% of all intracranial tumors. Its oncogenesis and biological behavior have not been well studied, and neither a cell line nor an animal model have been established. To better understand the tumor and improve its clinical management, the authors investigated the angiogenesis and cellular proliferation in subcutaneous craniopharyngioma xenografts obtained by implanting human tumor cells into athymic nude mice.


Human craniopharyngioma cells obtained from surgical specimens were subcutaneously implanted into BALB/c-nu/nu nude mice to establish a preliminary animal model of a transplanted tumor. Immunohistochemical staining with streptavidin–peroxidase complex was used to identify the cell phenotype and to evaluate the angiogenesis and proliferation in the xenografts. Expression of cytokeratin, minichromosome maintenance deficient 6 (MCM6) protein, and endothelial cell marker CD34 on the xenograft sections were assayed quantitatively by computer-assisted microscopy.

Twenty-seven surviving subcutaneous xenografts were obtained in 15 nude mice. The total implantation success rate was 28.12% (adamantine epithelioma [AE], 37.50%; squamous papillary tumor [SPT], 18.75%). Formation of capillaries and cell proliferation were observed in all of these xenografts. Microvessel density and degree of MCM6 immunostaining were positively correlated in the surviving grafts (r = 0.410, p < 0.05), but there was no significant difference in these variables between the AE and SPT groups (p > 0.05).


A preliminary animal model of human craniopharyngioma was established in the nude mouse by heterotopic implantation. Surviving xenografts maintained their vascularization and proliferation activities until harvesting at 12 weeks.

Abbreviations used in this paper:AE = adamantine epithelioma; CK = cytokeratin; MCM6 = minichromosome maintenance deficient 6; MVD = microvessel density; SPT = squamous papillary tumor.

Article Information

Address reprint requests to: Chao You, M.D., Ph.D., Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China. email:

© AANS, except where prohibited by US copyright law.



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    Photomicrographs demonstrating cellular proliferation in xenografts.Upper: Active proliferation is visible in AE xeno-graft cells. The actively proliferating nuclei were intensely immunostained with anti-MCM6 in cell nests; staining was relatively infrequent in the stellate reticulum.Lower: Proliferation in SPT xenograft cells. Most of the cells that were intensely immunostained with anti-MCM6 were dispersed in squamous epithelial layers. The nuclear reaction product of MCM6 was sparsely expressed in loose connective tissue. Immunoperoxidase, original magnifications × 325(upper) and × 400(lower).

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    Photomicrographs showing xenograft vascularization.Upper: Microvessels labeled by CD24 are visible in a section from an AE xenograft. Angiogenesis was evident in the stroma near enamel epithelial layers.Lower: Two capillaries stained by CD34 are visible in this section from the center of an SPT xenograft. Immunoperoxidase, original magnification × 400.



Bullard DEBigner DD: Heterotransplantation of human craniopharyngiomas in athymic “nude” mice. Neurosurgery 4:3083141979


Bunin GRSurawicz TSWitman PAPreston-Martin SDavis FBruner JM: The descriptive epidemiology of craniopharyngioma. J Neurosurg 89:5475511998


Caldarelli Mdi Rocco CPapacci FColosimo C Jr: Management of recurrent craniopharyngioma. Acta Neurochir (Wien) 140:4474541998


Demirag FÜnsal EYilmaz AÇag lar A: Prognostic significance of vascular endothelial growth factor, tumor necrosis, and mitotic activity index in malignant pleural mesothelioma. Chest 128:338233872005


De Vile CJGrant DBKendall BENeville BGRStanhope RWatkins KE: Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted?. J Neurosurg 85:73811996


Dusik-Sharpe J: Kerry’s story: the challenges of facing a recurrent craniopharyngioma. Axon 26:8122004


El-Assal ONYamanoi ASoda YYamaguchi MIgarashi MYamamoto A: Clinical significance of microvessel density and vascular endothelial growth factor expression in hepato-cellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology 27:155415621998


Goldberg GMEshbaugh DE: Squamous cell nests of the pituitary gland as related to the origin of craniopharyngiomas. A study of their presence in newborns and infants to age four. Arch Pathol 70:2932991960


Goldrath AWBogatzki LYBevan MJ: Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med 192:5575642000


Grobben BDe Deyn PPSlegers H: Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res 310:2572702002


Gutmann DHBaker SJGiovannini MGarbow JWeiss W: Mouse models of human cancer consortium symposium on nervous system tumors. Cancer Res 63:300130042003


Holland EC: Brain tumor animal models: importance and progress. Curr Opin Oncol 13:1431472001


Honegger JRenner CFahlbusch RAdams EF: Progesterone receptor gene expression in craniopharyngiomas and evidence for biological activity. Neurosurgery 41:135913641997


Huang PTaghian AAllam AFreeman JDuffy MSuit H: The effect of whole-body irradiation of nude mice on the tumor transplantability and control probability of a human soft tissue sarcoma xenograft. Radiat Res 145:3373421996


Jiang RLiu ZZhu C: [Culture of craniopharyngioma cell in vitro and supression effect of Belomycin on the tumor.]. Chin J Neurosurg 17:29312001. (Chn)


Li SQ[Craniopharyngioma]. inXu QWJiang YP: (eds)[Clinical Craniocerebral Disease.] TianjinScience & Technology Press2003. 278286(Chn)


Matsuo MYonemitsu NZaitsu MIshii KHamasaki YFukuyama K: Expression of prostaglandin H synthase-2 in human brain tumors. Acta Neuropathol 102:1811872001


Méndez JStillman B: Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. Mol Cell Biol 20:860286122000


Mennel HD: Significance of experimental models in neurooncology. Neurosurg Rev 3:1291371980


Müller HLKaatsch PWarmuth-Metz MFlentje MSörenson N: [Childhood craniopharyngioma: current concepts in diagnostics and therapy.]. Monatsschr Kinderheilkd 151:105610632003. (Ger)


Nelson GABastian FOSchlitt MWhite RL: Malignant transformation in craniopharyngioma. Neurosurgery 22:4274291988


Peterson DLSheridan PJBrown WE Jr: Animal models for brain tumors: historical perspectives and future directions. J Neurosurg 80:8658761994


Plate KH: Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:3133201999


Raghavan RDickey WT JrMargraf LRWhite CL IIICoimbra CHynan LS: Proliferative activity in craniopharyngiomas: clinicopathological correlations in adults and children. Surg Neurol 54:2412482000


Rice JM: Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models. Toxicol Appl Pharmacol 199:1751912004


Rickert CHPaulus W: Lack of chromosomal imbalances in adamantinomatous and papillary craniopharyngioma. J Neurol Neurosurg Psychiatry 74:2602612003


Sachs DH: The immunologic response to xenografts. ILAR J 37:16221995


Schrader CJanssen DKlapper WSiebmann JUMeusers PBrittinger G: Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma. Br J Cancer 93:9399452005


Schwed GMay NPechersky YCalvi BR: Drosophila mini-chromosome maintenance 6 is required for chorion gene amplification and genomic replication. Mol Biol Cell 13:6076202002


Sekine SShibata TKokubu AMorishita YNoguchi MNakanishi Y: Craniopharyngiomas of adamantinomatous type harbor β-catenin gene mutations. Am J Pathol 161:199720012002


Stripp DCMaity AJanss AJBelasco JBTochner ZAGoldwein JW: Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults. Int J Radiat Oncol Biol Phys 58:7147202004


Sweet WHCraniopharyngiomas: a summary of data. inSchmidek HH: (ed) ed 4LondonElsevier2002. Vol 1:477486


Taghian AHuang P: The nude and SCID mice as a tumor model in experimental cancer biology. Cancer J 8:52581995


Takahashi YTucker SLKitadai YKoura ANBucana CDCleary KR: Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 132:5415461997


Tavangar SMLarijani BMahta ASeyed SMAMehrazine MBandarian F: Craniopharyngioma: a clinicopathological study of 141 cases. Endocr Pathol 15:3393442004


Van Effenterre RBoch AL: Craniopharyngioma in adults and children: a study of 122 surgical cases. J Neurosurg 97:3112002


Vidal SKovacs KLloyd RVMeyer FBScheithauer BW: Angiogenesis in patients with craniopharyngiomas: correlation with treatment and outcome. Cancer 94:7387452002


Vyramuthu NBenton TF: The management of craniopharyngioma. Clin Radiol 34:6296321983


Weidner N: Intratumor microvessel density as a prognostic factor in cancer. Am J Pathol 147:9191995


Xin WRubin MAMcKeever PE: Differential expression of cytokeratins 8 and 20 distinguishes craniopharyngioma from Rathke cleft cyst. Arch Pathol Lab Med 126:117411782002




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