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M.A. Dyer, N. Laurie, S. Donovan; Retinoblastoma Does Not Arise From an Intrinsically Death Resistant Cell . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4859.
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© ARVO (1962-2015); The Authors (2016-present)
The initiating genetic lesion in retinoblastoma is loss of the RB1 gene and disruption of the Rb pathway. Recent studies on mouse retinoblastoma have led to the hypothesis that retinoblastoma arises from an intrinsically death resistant cell during retinal development.
The purpose of this research project is to test whether retinoblastoma cells progress down a fast–track of tumorigenesis because they bypass the Arf–Mdm2–p53 tumor surveillance pathway as is widely believed.
We performed a series of molecular genetic experiments in developing mouse retinae, mouse retinoblastomas, primary human fetal retinae and human retinoblastomas to test each step in the Arf–Mdm2–p53 tumor surveillance pathway in retinoblastoma tumorigenesis. These studies include in vivo retroviral experiments using Cre–expressing retroviruses, square wave electroporation, FISH and immunostaining of 49 primary human retinoblastoma samples, and a variety of molecular and cellular analyses.
We report here that the Arf–Mdm2–p53 tumor surveillance pathway is activated following disruption of the Rb pathway in the developing retina, leading to apoptosis and cell cycle exit. Using BAC–CGH, microarray analysis and FISH analysis of primary human retinoblastomas we identified a novel genetic amplification that disrupts the Arf–Mdm2–p53 h pathway in 60–70% of human retinoblastomas. Using biochemical and molecular approaches we directly demonstrated that increased expression of this gene is sufficient to promote the clonal survival and expansion of human retinal progenitor cells lacking Rb and mouse retinal progenitor cells lacking Rb and p107. This effect was p53 dependent and reversible by a small molecule inhibitor of the interaction between this protein and p53.
These data demonstrate that the p53 pathway is inactivated in retinoblastoma and this cancer does not originate from an intrinsically death resistant cell as previously believed. In addition, our data provide for the first time, a specific target for chemotherapy to treat children with retinoblastoma.
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