Retinoblastoma Cell of Origin

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THE SEARCH FOR THE RETINOBLASTOMA CELL OF ORIGIN

Michael A. Dyer* and Rod Bremner ‡

Abstract | The cellular effects of the genetic defects associated with tumorigenesis are context dependent. To better understand the reasons that different cell types require distinct combinations of mutations to form tumours, it is essential to identify and characterize a tumour’s ‘cell of origin’. Retinoblastoma, a rare childhood cancer of the retina that is caused by RB inactivation, is a good model in which to search for a tumour cell of origin, because retinal development is well understood and the initiating genetic lesion is well characterized. Identifying the cell of origin for this tumour would advance our understanding of how cellular context affects the requirement of specific mutations for cancer initiation and progression.

Since the first tumour-suppressor gene was identified in 1986 (REF. 1), significant advances have been made in our understanding of the genetic basis of neoplasia. One interesting discovery was that genetic defects that transform cells in one setting are harmless in another. For example, loss of function of the hedgehog signalling pathway through mutations in Patched (PTC) can lead to an increased incidence of medulloblastoma, which is derived from granule-cell progenitors during cerebellar development2–4. It is not surprising that the hedgehog signalling pathway is mutated in medulloblastoma, because sonic hedgehog (SHH), which is secreted by the Purkinje cells in the developing cerebellum, is required for the proliferation of normal granule progenitor cells5. SHH signalling through PTC is also essential for the proliferation and differentiation of normal retinal progenitor cells6,7, but the Ptc+/– mutations in mice that increase susceptibility to medulloblastoma do not increase the incidence of retinoblastoma2–4,8. Similarly, mutations that trigger retinoblastoma do not increase the formation of medulloblastoma1,9–13. How do the same...