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Developmental stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors
- Source :
- Proceedings of the National Academy of Sciences. 115
- Publication Year :
- 2018
- Publisher :
- Proceedings of the National Academy of Sciences, 2018.
-
Abstract
- Most retinoblastomas initiate in response to the inactivation of the RB1 gene and loss of functional RB protein. The tumors may form with few additional genomic changes and develop after a premalignant retinoma phase. Despite this seemingly straightforward etiology, mouse models have not recapitulated the genetic, cellular, and stage-specific features of human retinoblastoma genesis. For example, whereas human retinoblastomas appear to derive from cone photoreceptor precursors, current mouse models develop tumors that derive from other retinal cell types. To investigate the basis of the human cone-specific oncogenesis, we compared developmental stage-specific cone precursor responses to RB loss in human and murine retina cultures and in cone-specific Rb1-knockout mice. We report that RB-depleted maturing (ARR3(+)) but not immature (ARR3(−)) human cone precursors enter the cell cycle, proliferate, and form retinoblastoma-like lesions with Flexner–Wintersteiner rosettes, then form low or nonproliferative premalignant retinoma-like lesions with fleurettes and p16(INK4A) and p130 expression, and finally form highly proliferative retinoblastoma-like masses. In contrast, in murine retina, only RB-depleted immature (Arr3(−)) cone precursors entered the cell cycle, and they failed to progress from S to M phase. Moreover, whereas intrinsically highly expressed MDM2 and MYCN contribute to RB-depleted maturing (ARR3(+)) human cone precursor proliferation, ectopic MDM2 and Mycn promoted only immature (Arr3(−)) murine cone precursor cell-cycle entry. These findings demonstrate that developmental stage-specific as well as species- and cell type-specific features sensitize to RB1 inactivation and reveal the human cone precursors’ capacity to model retinoblastoma initiation, proliferation, premalignant arrest, and tumor growth.
- Subjects :
- 0301 basic medicine
Retinal Neoplasms
Cell
medicine.disease_cause
Retinoblastoma Protein
S Phase
Mice
03 medical and health sciences
0302 clinical medicine
Species Specificity
medicine
Animals
Humans
Mice, Knockout
Retina
Multidisciplinary
biology
Retinoblastoma
Cell cycle
medicine.disease
Cone (formal languages)
eye diseases
Cell biology
030104 developmental biology
medicine.anatomical_structure
PNAS Plus
Retinal Cone Photoreceptor Cells
030221 ophthalmology & optometry
ARR3
biology.protein
Mdm2
sense organs
Carcinogenesis
Cell Division
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 115
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....b8a206be49b4162c534e814ff4967b8b