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Establishment and Propagation of Human Retinoblastoma Tumors in Immune Deficient Mice
Published on: August 4, 2011
Murine bilateral retinoblastoma exhibiting rapid-onset, metastatic progression and N-myc gene amplification
David MacPherson1, Karina Conkrite, Mandy Tam
1Department of Embryology, Carnegie Institution, Baltimore, MD 21218, USA. macpherson@ciwemb.edu
Abstract:
Human retinoblastoma is a pediatric cancer initiated by RB gene mutations in the developing retina. We have examined the origins and progression of retinoblastoma in mouse models of the disease. Retina-specific inactivation of Rb on a p130-/- genetic background led to bilateral retinoblastoma with rapid kinetics, whereas on a p107-/- background Rb mutation caused predominantly unilateral tumors that arose with delayed kinetics and incomplete penetrance. In both models, retinoblastomas arose from cells at the extreme periphery of the murine retina. Furthermore, late retinoblastomas progressed to invade the brain and metastasized to the cervical lymph nodes. Metastatic tumors lacking Rb and p130 exhibited chromosomal changes revealed by representational oligonucleotide microarray analysis including high-level amplification of the N-myc oncogene. N-myc was found amplified in three of 16 metastatic retinoblastomas lacking Rb and p130 as well as in retinoblastomas lacking Rb and p107. N-myc amplification ranged from 6- to 400-fold and correlated with high N-myc-expression levels. These murine models closely resemble human retinoblastoma in their progression and secondary genetic changes, making them ideal tools for further dissection of steps to tumorigenesis and for testing novel therapies.
Insights
Mouse models reveal retinoblastoma (RB) originates in the retina
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Human retinoblastoma is a pediatric cancer caused by RB gene mutations.
- Understanding retinoblastoma's origins and progression is crucial for developing therapies.
Purpose of the Study:
- To investigate retinoblastoma development using genetically engineered mouse models.
- To analyze the role of Rb, p130, and p107 in retinoblastoma tumorigenesis.
- To identify secondary genetic changes associated with tumor progression and metastasis.
Main Methods:
- Retina-specific Rb inactivation in mouse models with different genetic backgrounds (p130-/- and p107-/-).
- Monitoring tumor development, kinetics, and penetrance.
- Representational oligonucleotide microarray analysis (ROMA) to detect chromosomal abnormalities.
- N-myc expression analysis in metastatic tumors.
Main Results:
- Rb inactivation led to bilateral retinoblastoma in p130-/- mice (rapid kinetics) and unilateral tumors in p107-/- mice (delayed kinetics, incomplete penetrance).
- Tumors originated from the peripheral retina and could invade the brain and metastasize.
- N-myc oncogene amplification (6- to 400-fold) was observed in metastatic retinoblastomas lacking Rb and p130, correlating with high N-myc expression.
Conclusions:
- Murine models accurately mimic human retinoblastoma progression and secondary genetic alterations.
- N-myc amplification is a significant secondary genetic change in advanced retinoblastoma.
- These models are valuable for studying tumorigenesis and testing new therapeutic strategies.
