Publication Date:
2014-09-26
Description:
Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear. Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232224/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232224/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Xiaoliang L -- Singh, Hardeep P -- Wang, Lu -- Qi, Dong-Lai -- Poulos, Bradford K -- Abramson, David H -- Jhanwar, Suresh C -- Cobrinik, David -- 1R01CA137124/CA/NCI NIH HHS/ -- R01 CA137124/CA/NCI NIH HHS/ -- England -- Nature. 2014 Oct 16;514(7522):385-8. doi: 10.1038/nature13813. Epub 2014 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA [2] Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. ; 1] The Vision Center, Division of Ophthalmology, Department of Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA [2] The Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. ; Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. ; Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. ; 1] Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA [2] Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. ; 1] The Vision Center, Division of Ophthalmology, Department of Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA [2] The Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA [3] USC Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, 1450 San Pablo Street, Los Angeles, California 90033, USA [4] Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake Avenue, Los Angeles, California 90033, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25252974" target="_blank"〉PubMed〈/a〉
Keywords:
Cell Transformation, Neoplastic
;
E2F Transcription Factors/metabolism
;
Gene Expression Regulation, Neoplastic
;
Genes, Retinoblastoma/genetics
;
Heterografts
;
Humans
;
Nuclear Proteins/metabolism
;
Oncogene Proteins/metabolism
;
Organ Specificity
;
Proto-Oncogene Proteins c-mdm2/metabolism
;
Retinal Cone Photoreceptor Cells/*metabolism/*pathology
;
Retinoblastoma/genetics/*metabolism/*pathology
;
Retinoblastoma Protein/deficiency/genetics/*metabolism
;
Retinoblastoma-Like Protein p107/metabolism
;
Retinoblastoma-Like Protein p130/deficiency/metabolism
;
S-Phase Kinase-Associated Proteins/metabolism
;
Stem Cells/metabolism/pathology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
