Retinoblastoma (RB), the most common ocular cancer in young children, forms in response to mutations in the RB1 gene and the loss of functional RB protein. RB affects one in every 20,000 children in the United States around the age of five.

 Despite the seemingly straightforward etiology of RB, mouse models have not been able to mimic the genetic, cellular and stage-specific features of human RB genesis. Prior studies suggest that RBs arise from cone photoreceptor precursors; not so in mouse models, which yield tumors deriving from other retinal cell types and lacking human RB features.

A team of researchers from California recently found that in cultured human retinas, RBs arise from RB-depleted cone precursors that are in a specific maturation state and form premalignant retinomas prior to RB lesions. In contrast, comparable mouse cells of a similar maturation state that are supplemented with human cone precursor-specific tumor-enabling proteins failed to proliferate.

To investigate the basis of the human tumor formation, the researchers compared cone precursor responses with RB loss in human and murine retinas. They discovered that maturing but not immature human cone precursors enter the cell cycle, proliferate and form RB-like lesions. In mice, however,  only immature cone precursors entered the cell cycle, and they failed to progress.

The study concludes that human species-specific developmental features underlie RB genesis and may challenge the production of accurate RB models and, as a consequence, the ability to provide early treatment to prevent tumor formation in genetically predisposed children.