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X. L. Xu, Y. Fang, T. C. Lee, D. Almeida, S. Jhanwar, D. H. Abramson, D. Cobrinik; A Cone Precursor Phenotype Distinguishes Human Retinoblastoma From Mouse Retinoblastoma Models. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2012. doi: https://doi.org/.
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The origin of retinoblastoma has been unclear in part because diverse retinal cell types are detected in retinoblastoma tumors. As a step towards identifying the cell of origin, we characterized the neoplastic cells in retinoblastoma tumors and defined the Rb expression pattern in the developing retina. We also compared the phenotype of human retinoblastomas to that of mouse retinoblastoma models.
Cell type-specific markers were evaluated in 40 retinoblastomas and 2 tumors from Rb1-/-,p130-/- chimeric mice. The neoplastic status of human tumor cells was assessed by Rb immunostaining and RB1 fluorescence in situ hybridization. Retinal cell markers were evaluated in serial orthotopic xenografts, and Rb expression was assessed in developing mouse and human retinas.
In 40 retinoblastomas, >95% of cells expressed markers of red/green cones, including Crx, RXRγ, cone arrestin, TRβ2, and L/M opsin. Among >10 tumors analyzed, cells that expressed other retinal markers (GFAP, Nestin, Pax6, Nrl, Rhodopsin, Chx10) also expressed Rb protein and were thus non-neoplastic. In tumors with a deleted RB1 locus, cells that lacked cone markers retained both wild type RB1 alleles and were likewise non-neoplastic. Moreover, cells expressing markers of cones but not other cells were propagated in serial xenografts, and Rb was prominently expressed in TRβ2+ L/M cone precursors in the developing human retina. In contrast, mouse retinal tumors expressed markers of amacrine or horizontal cells, including Pax6 and syntaxin, and mouse TRβ2+ cone precursors did not prominently express Rb protein (Figure).
The cone phenotype of neoplastic retinoblastoma cells and the prominent Rb expression in human cone precursors suggest an origin of retinoblastoma from post-mitotic cone precursors. The distinct features of mouse retinal tumors are consistent with an origin from a distinct cell type.
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