Looking for the Most Suitable Orthotopic Retinoblastoma Mouse Model in Order to Characterize the Tumoral Development

Abstract

PURPOSE. Because retinoblastoma therapies have many adverse effects, new approaches must be developed and evaluated on animal models. We describe orthotopic xenograft models of retinoblastoma using different strains of mice, suitable for this purpose. METHODS.Human retinoblastoma tumors were established on immunodeficient mice by subcutaneous engraftment of tumors from enucleated eyes. The orthotopic model was obtained by subretinal injections of suspension cells into the right eye of immunodeficient (Swiss-nude, severe combined immunodeficiency [SCID]) and immunocompetent mice (C57BL/6N, B6Albino). In vivo tumor growth was monitored by fundus and spectral-domain optical coherence tomography (SD-OCT) imaging and compared with histology. RESULTS.Retinal and vitreal tumor growth was achieved both in immunocompetent and immunodeficient strains after the subretinal injection of tumor cells. The best tumor engraftment rate was obtained in the SCID mice (68.8%). No tumor growth was observed in the C57BL/6N strain. Chronic retinal detachment may occur in most strains after the subretinal injection, in particular the Swiss-nude strain, which exhibits retinal degeneration.CONCLUSIONS. The setting up of an orthotopic mouse model depends mainly on the choice of the engrafted cells (cell lines or patient-derived xenografts) but it can also depend on the xenografted mouse strain. Severe combined immunodeficiency mice (an immunodeficient strain) achieved the best tumor engraftment rate (68.8%). However, intraocular tumor growth was also satisfactory (50%) in the immunocompetent strain B6Albino, and this strain will allow to exploit the immune response after a tumor treatment. Both of these strains may therefore be recommended when setting up orthotopic retinoblastoma xenografts.

Retinoblastoma: Etiology, Modeling, and Treatment

“…Subcutaneous xenografts are maintained by serial passaging from one mouse to another [ 94 , 95 ]. Orthotopic implantation, in which tumor cells are injected directly into the anterior or vitreous cavity, has a high success rate of model establishment compared with subcutaneous xenografting [ 94 , 95 , 96 , 97 ]. Additionally, orthotopic models have demonstrated tumor invasion into the retina, subretinal space, ciliary body, choroid, and sclera as well as dissemination into the brain [ 97 ].…”

“…Xenograft models represent the advanced disease stage and better recapitulate human tumors; this is because the surgical samples are obtained from patients with advanced tumors and contain genetic lesions that occur in the disease. However, an appropriate mouse strain for setting up an orthotopic retinoblastoma model must be used to achieve the best engraftment rate and tumor growth [ 96 ]. Retinoblastoma organoids serve as a model for advanced tumors.…”

Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma

“…Pre‐clinical studies are mandatory to evaluate the effect of different chemotherapies but the translation to clinics must be investigated. A patient‐derived orthotopic xenograft murine model of Rb, as developed previously, might be useful for translational research testing new intravitreous therapies for vitreous seeds.…”

Retinoblastoma, the visible CNS tumor: A review

“…OCT has proven useful for xenografts: intravitreal xenografts could be monitored (Corson et al, ; Tschulakow, Schraermeyer, Rodemann, & Julien‐Schraermeyer, ) and subretinal xenografts could be rapidly assessed by a combination of OCT and funduscopy (Lemaitre et al, ). Of course, OCT assessment of morphology of xenografts is less clinically relevant than the morphology of tumors arising intraretinally as in genetic retinoblastoma models.…”