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The search for the retinoblastoma cell of origin

Nature Reviews Cancer volume 5, pages 91–101 (2005)Cite this article

Key Points

  • Identifying the cell of origin can uncover the initiating and subsequent genetic changes that occur as cells progress from preneoplastic lesions to tumours.

  • Retinoblastoma is a good tumour model for identifying the cell of origin, because retinal development is well understood and the initiating genetic lesion (loss of RB) is well characterized.

  • Models of retinoblastoma differ depending on when RB is thought to act and on the response of the cell of origin to RB loss.

  • Additional mutations, beyond RB disruption, must occur for retinoblastoma to develop. These could occur in genes that regulate programmes of cell death or cell differentiation. New mouse models support the latter possibility.

  • Improved animal models could help to identify the retinoblastoma cell of origin, and explain why retinal cells are especially susceptible to transformation following RB disruption.

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.

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Figure 1: Retinal development.
Figure 2: The mature retina.
Figure 3: Proliferation during retinal development.
Figure 4: Progenitor and precursor cell of origin models of retinoblastoma.
Figure 5: Function of post-RB mutations in retinoblastoma.

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Acknowledgements

Funding for work on RB in the authors' laboratories is supported by grants from the National Institutes of Health, Research to Prevent Blindness, the National Science Foundation and the American Cancer Society (M.A.D.), and the Canadian Institutes of Health Research (R.B.). M.A.D. is a Pew Scholar in Biomedical Sciences.

Author information

Authors and Affiliations

  1. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Michael A. Dyer

  2. Toronto Western Research Institute, University Health Network,

    Rod Bremner

  3. Departments of Ophthalmology and Visual Science, Laboratory Medicine and Pathobiology, Vision Science Research Program, University of Toronto, Toronto, M5T 2S8, Ontario, Canada

    Rod Bremner

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  1. Michael A. Dyer
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Correspondence to Michael A. Dyer or Rod Bremner.

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The authors declare no competing financial interests.

Related links

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DATABASES

Entrez Gene

BRN3B

Btf3

CHX10

CRX

cyclin D1

cyclin D3

Edr

Eya2

Fgf15

Mbdt1

p27

p57

p107

p130

PAX6

PTC

RB

SHH

National Cancer Institute

medulloblastoma

neuroblastoma

retinoblastoma

FURTHER INFORMATION

Michael A. Dyer's home page

Retinoblastoma

Rod Bremner's home page

Glossary

ECTOPIC CELL DIVISION

Cell division that would not normally occur during development or in the adult retina. Ectopic cell division does not necessarily refer to cancer cell cycles.

SYNTAXIN

Nervous-system-specific proteins implicated in the docking of synaptic vesicles.

Cre RETROVIRAL SYSTEM

By using genetically engineered mice with genes containing LoxP sites, retroviral infection can lead to gene inactivation in individual retinal progenitor cells in vivo.

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Dyer, M., Bremner, R. The search for the retinoblastoma cell of origin. Nat Rev Cancer 5, 91–101 (2005). https://doi.org/10.1038/nrc1545

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