Establishment of a novel retinoblastoma (Rb) nude mouse model by intravitreal injection of human Rb Y79 cells - comparison of in vivo analysis versus histological follow up.
Retinoblastoma (Rb) is the most frequent primary intraocular tumour in children and, if left untreated, can cause death. Preclinical animal models that mimic molecular, genetic, and cellular features of cancers are essential for studying cancer and searching for promising diagnosis and treatment modalities. There are several models described for Rb, but none of them fully meet our requirements. The aim of this study was to create a novel xenograft-nude mouse-model with broad application possibilities, which closely resembles the clinical observations of Rb patients and which could be used to investigate the development and spread of the tumour by using scanning laser ophthalmoscopy/optical coherence tomography (SLO/OCT) as well as histology methods. We injected human retinoblastoma Y79 cells intravitreally in both eyes of immune-deficient nude mice. The incidences of retinoblastoma as well as growth velocity were analysed 3, 6, 9 and 12 weeks after cell injection in vivo by SLO/OCT as well as ex vivo by electron microscopy (EM) and hematoxylin/eosin (HE) staining. Moreover, internal organs were histologically screened for potentially occurring metastases. Three weeks post-injection, animals developed a retinoblastoma, and after five weeks tumour growth resulted in swelling of the eyes in individual animals, showing a similar phenotype to that of untreated Rb patients at advanced stages of tumour-development. After 12 weeks, 67.5% of all analysed eyes (29 of 42) contained a retinoblastoma. At early stages of Rb development, the SLO/OCT analysis correlated with the histology results. If the tumours were too large, only histological investigations were feasible. The ultrastructural characteristics of the xenograft-tumours were very similar to those described for patient's tumours. In one mouse, brain metastases were observed. Our retinoblastoma mouse model closely resembles the human disease. SLO/OCT can be used for the detection of Rb at early stages of development and could be used for monitoring the success of future therapies.
Division of Experimental Vitreoretinal Surgery, Center for Ophthalmology, Eberhard Karls University Tuebingen, Tuebingen 72076, Germany.
Alexander V
AV
Tschulakow
Division of Experimental Vitreoretinal Surgery, Center for Ophthalmology, Eberhard Karls University Tuebingen, Tuebingen 72076, Germany.
Ulrich
U
Schraermeyer
Division of Radiobiology & Molecular Environmental Research, Department of Radiation Oncology, Eberhard Karls University Tuebingen Tuebingen 72076, Germany.
H Peter
HP
Rodemann
Division of Experimental Vitreoretinal Surgery, Center for Ophthalmology, Eberhard Karls University Tuebingen, Tuebingen 72076, Germany sylvie.julien@med.uni-tuebingen.de.
Sylvie
http://orcid.org/0000-0002-2322-511X
S
Julien-Schraermeyer
Histology; Mouse model; OCT; Retinoblastoma; SLO; Xenograft
J Ophthalmol. 2014;2014:829879
24734170
J AAPOS. 2011 Apr;15(2):167-72
21596295
Expert Opin Drug Discov. 2013 Apr;8(4):383-94
23427911
Nippon Ganka Gakkai Zasshi. 1982;86(4):418-25
7113830
Invest Ophthalmol. 1962 Dec;1:728-44
14012138
Br J Ophthalmol. 2009 Jan;93(1):21-3
18621794
Eur J Cancer. 2010 Feb;46(3):659-68
20031388
Cancer Res. 1977 Apr;37(4):1003-10
844036
PLoS One. 2012;7(6):e39626
22737248
J Hematol Oncol. 2015 May 29;8:59
26022250
Invest Ophthalmol Vis Sci. 1993 Nov;34(12 ):3336-46
8225869
Invest Ophthalmol Vis Sci. 2009 Dec;50(12):5888-95
19661229
Mol Vis. 2015 May 01;21:515-22
25999678
Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1979 Oct;211(4):279-87
317224
Invest Ophthalmol Vis Sci. 1977 Mar;16(3):256-9
844983
Curr Opin Ophthalmol. 2013 Nov;24(6):581-8
24100372
PLoS One. 2009 Oct 19;4(10):e7507
19838301
Arch Ophthalmol. 2009 Mar;127(3):282-90
19273791
J Pediatr Ophthalmol Strabismus. 2004 Nov-Dec;41(6):338-44
15609518
Ophthalmology. 1986 Aug;93(8):1010-5
3763145
Indian J Ophthalmol. 2015 Jul;63(7):586-93
26458476
Ophthalmologica. 1982;185(3):158-67
7133630
Am J Pathol. 2000 Oct;157(4):1405-12
11021842
Ophthalmology. 2004 Jun;111(6):1228-32
15177976
J AAPOS. 2011 Apr;15(2):125-6
21596291
J Natl Cancer Inst. 1974 Aug;53(2):347-60
4135597
Bull Cancer. 2014 Apr;101(4):380-7
24793631