Photoreceptor differentiation of retinoblastoma: An electron microscopic study of 29 retinoblastomas

Tajima, Yasuo; Munakata, Shigeru; Ishida, Yasuo; Nakajima, Tohru; Sugano, Isamu; Nagao, Kōichi; Minoda, K; Kondō, Yōichirō

doi:10.1111/j.1440-1827.1994.tb01681.x

Cited by 12 publications

(12 citation statements)

References 9 publications

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“…3A), showed rosette-like structures resembling those in human retinoblastoma (Fig. 3B,C) (Tajima et al 1994), but had the nuclear morphology of the inner nuclear layer (Fig. 3C,D).…”

Section: Tumorigenesis In Rbp130-deficient Chimerasmentioning

confidence: 99%

“…Based on immunohistochemical analyses and morphological characteristics, human retinoblastoma was hypothesized to originate from photoreceptor cells in the outer nuclear layer (Bogenmann et al 1988;Tajima et al 1994). However, analyses of early, small retinoblastomas pointed to an inner nuclear layer origin, although they showed Flexner-Wintersteiner rosettes (Gallie et al 1999).…”

Section: Retinoblastoma Originmentioning

confidence: 99%

See 1 more Smart Citation

Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130

Dannenberg

Schuijff²,

Dekker³

et al. 2004

Genes Dev.

129

150

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The retinoblastoma gene family consists of three genes: RB, p107, and p130. While loss of pRB causes retinoblastoma in humans and pituitary gland tumors in mice, tumorigenesis in other tissues may be suppressed by p107 and p130. To test this hypothesis, we have generated chimeric mice from embryonic stem cells carrying compound loss-of-function mutations in the Rb gene family. We found that Rb/p107-and Rb/p130-deficient mice were highly cancer prone. We conclude that in a variety of tissues tumor development by loss of pRB is suppressed by its homologs p107 and p130. The redundancy of the retinoblastoma proteins in vivo is reflected by the behavior of Rb-family-defective mouse embryonic fibroblasts in vitro.[Keywords: Retinoblastoma; cancer; mouse model; pocket proteins] Supplemental material is available at http://www.genesdev.org. Inactivation of the retinoblastoma suppressor pRB has been found in many human cancers, including hereditary retinoblastoma and sporadic breast, bladder, prostate, and small cell lung carcinoma (Friend et al. 1986(Friend et al. , 1987Harbour et al. 1988;Lee et al. 1988;T'Ang et al. 1988;Bookstein et al. 1990). pRB controls the G 1 /S transition of the cell cycle by modulating the activity of E2F transcription factors. Hypophosphorylated pRB binds to E2Fs and forms complexes harboring chromatin remodeling proteins like histone deacetylases, SWI/SNF and histone methyltransferases, which actively repress genes that are essential for cell cycle regulation, DNA replication, DNA repair, G 2 /M checkpoints and differentiation (Harbour and Dean 2000;Muller et al. 2001;Ishida et al. 2001;Kalma et al. 2001;Rayman et al. 2002;Ren et al. 2002). Upon sequential phosphorylation by Cyclin D/CDK4 and Cyclin E/CDK2 kinases, pRB undergoes a conformational change leading to the release of E2Fs. Ink4A function has been found in melanoma, pancreatic, and bladder carcinomas, amplification of Cyclin D1 in breast, oesophagus, and head-andneck cancer, and CDK4 amplification or mutational activation in melanoma (for review, see Sherr 1996).RB is a member of the retinoblastoma gene family that encodes the so-called pocket proteins pRB, p107, and p130 (Ewen et al. 1991;Hannon et al. 1993;Li et al. 1993;Chow and Dean 1996). All three can repress transcription from E2F-responsive promoters (Zamanian and La 1993;Bremner et al. 1995;Starostik et al. 1996) and are regulated by cell-cycle dependent phosphorylation. (Graña et al. 1998;Lundberg and Weinberg 1998;Canhoto et al. 2000;Hansen et al. 2001). Over-expression of each of the pocket proteins results in growth suppression, although not every (tumor) cell type is equally sensitive to each family member (Zhu et al. 1993;Claudio et al. 1994;Beijersbergen et al. 1995). Whereas pRB predominantly binds E2F1, E2F2, and E2F3, p107 and p130 specifically bind E2F4 and E2F5 (Dyson 1998;Trimarchi and Lees 2002) and each of these complexes appears at different stages of the cell cycle: p130/E2F4 is mainly found in G 0 , pRB/E2F in G 0 and G 1 , and p107/E2F in S-phase (Dyson ...

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“…3A), showed rosette-like structures resembling those in human retinoblastoma (Fig. 3B,C) (Tajima et al 1994), but had the nuclear morphology of the inner nuclear layer (Fig. 3C,D).…”

Section: Tumorigenesis In Rbp130-deficient Chimerasmentioning

confidence: 99%

Section: Retinoblastoma Originmentioning

confidence: 99%

Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130

Dannenberg

Schuijff²,

Dekker³

et al. 2004

Genes Dev.

129

150

View full text Add to dashboard Cite

show abstract

“…Both intrinsic properties of progenitor cells and responses to extrinsic cues dictate retinal cell fate (Cepko et al 1996;Marquardt and Gruss 2002). Retinoblastomas have been proposed to derive from a primitive neuroectodermal cell (Kyritsis et al 1984), and evidence of photoreceptor differentiation has been described in some tumors (Bogenmann et al 1988;Vrabec et al 1989;Tajima et al 1994). However, the cell of origin of retinoblastomas has been controversial, and there has been limited examination of markers specific to neuronal retinal cell types other than photoreceptors in human tumor material.…”

mentioning

confidence: 99%

Cell type-specific effects of Rb deletion in the murine retina

MacPherson

Sage²,

Kim³

et al. 2004

Genes Dev.

217

256

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Certain cells of the human retina are extremely sensitive to loss of function of the retinoblastoma tumor suppressor gene RB. Retinoblastomas develop early in life and at high frequency in individuals heterozygous for a germ-line RB mutation, and sporadic retinoblastomas invariably have somatic mutation in the RB gene. In contrast, retinoblastomas do not develop in Rb +/− mice. Although retinoblastoma is thought to have developmental origins, the function of Rb in retinal development has not been fully characterized. Here we studied the role of Rb in normal retinal development and in retinoblastoma using conditional Rb mutations in the mouse. In late embryogenesis, Rb-deficient retinas exhibited ectopic S-phase and high levels of p53-independent apoptosis, particularly in the differentiating retinal ganglion cell layer. During postnatal retinal development, loss of Rb led to more widespread retinal apoptosis, and adults showed loss of photoreceptors and bipolar cells. Conditional Rb mutation in the retina did not result in retinoblastoma formation even in a p53-mutant background. However, on a p107-or p130-deficient background, Rb mutation in the retina caused retinal dysplasia or retinoblastoma.[Keywords: Retinoblastoma; p130; p107; p53; apoptosis] Supplemental material is available at http://www.genesdev.org. The RB gene was the first known tumor suppressor gene identified (Friend et al. 1986;Fung et al. 1987;Lee et al. 1987). In humans, inheritance of a mutant allele of RB leads to retinoblastoma at about a 90% frequency, with loss of the remaining wild-type allele thought to be a rate-limiting step in tumorigenesis. RB is also mutated in sporadic cancers of the brain, breast, bladder, lung, and bone (Horowitz et al. 1990). Moreover, mutation of some component of the "RB pathway," such as loss of p16INK4a or amplification of upstream RB regulators cyclin D or CDK4/6 is thought to occur in the majority of human cancers. Germ-line RB +/− humans are at some increased risk for tumors other than retinoblastoma, such as osteosarcomas (Eng et al. 1993); however, no tissue is as exquisitely sensitive to RB loss as the retina. The reason for this tissue sensitivity is unknown.The product of the RB gene, pRB, is a nuclear phosphoprotein that is an important regulator of the cell cycle (Weinberg 1995). pRB forms complexes with members of the E2F family of transcription factors to repress transcription of genes important for S-phase entry and progression. Interaction of pRB with chromatin remodeling enzymes such as HDAC appears to contribute to gene repression. Phosphorylation of pRB by cyclin-dependent kinases leads to dissociation of pRB from E2Fs and release of pRB-mediated repression. In addition to regulating S-phase entry, RB also regulates apoptosis and terminal differentiation and has been implicated in still other cellular processes (Lipinski and Jacks 1999;DiCiommo et al. 2000;Classon and Harlow 2002;Chau and Wang 2003).In contrast to most human tumors, retinoblastomas usually arise during the first few years o...

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“…13 Well-differentiated tumors may have photoreceptor differentiation characterized by rosettes with luminal projections of club-shaped bodies (fleurettes) filled with elongate mitochrondria. 16 Among some of the ocular masses in this report, there were similar projections of mitochondria-filled cytoplasm into rosette lumens that could be interpreted as primitive fleurettes (Figs. 2, 4).…”

Section: Discussionmentioning

confidence: 96%

“…4,16 As the ocular tumors were largely within the vitreous chamber with little or no remaining normal retinal structures, a retinal origin (retinoblastoma) seemed likely. Retinoblastomas can arise from any of the nucleated retinal layers.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Embryonal Tumors in Fish

2009

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This article describes 11 cases of neuronal embryonal neoplasia in captive adult teleost fish. Neoplasms were located within 1 or both eyes of 8 fish and the skin of 3 other fish. Ocular neoplasms most often presented as unilateral or bilateral exophthalmia. Seven ocular and 1 cutaneous mass were composed of small triangular (carrot-shaped) neoplastic cells with FlexnerWintersteiner-type rosette formation. Mass location and histologic and ultrastructural features were suggestive of retinoblastomas. One ocular mass was composed of ribbons and rosettes of neoplastic cells with multiple areas of neuronal differentiation and was diagnosed as a teratoid medulloepithelioma. A cutaneous mass from an electric eel (Electrophorus electricus) consisted of rosettes and streams of elongate neoplastic cells. The epidermal electroreceptor (ampullary) organ was considered as an origin. Although distant metastases were not observed, neoplasms were generally locally aggressive with postexcision recurrence. There was occasional spread to or de novo occurrence within the contralateral eye.Keywords eye, fish, medulloepithelioma, primitive neuroepithelial neoplasms, retinoblastoma, skin A number of neoplastic disorders have been reported in fish. Some well-documented neoplasms include viral-induced dermal sarcomas in walleyes and aflatoxin-associated hepatocellular adenomas and carcinomas in rainbow trout as well as a variety of sporadic tumors in numerous species. 1,2,12 This report details spontaneous ocular and cutaneous tumors in multiple fresh and marine teleost species with features characteristic of neuronal embryonal tumors.Neuronal embryonal tumors arise from neuroectodermal progenitor cells within subependymal matrix layers and have morphology and aggressive behavior in common.10 Tumor types include medulloepitheliomas, neuroblastomas, retinoblastomas, ependymoblastomas, and primitive neuroectodermal tumors (PNETs). PNETs are derived from pluripotent germinal neuroepithelial cells and may be further classified on the basis of anatomic location as medulloblastomas, cerebral PNETs, or peripheral neuroectodermal tumors. Note that classification schemes may differ because the cell origin of these tumors is often not well understood.In humans, neuronal embryonal tumors often arise within the first decade of life. Chromosomal deletions and/or MYCN gene amplification have been noted in affected children and may play a role in pathogenesis in humans.3 Retinoblastomas predominantly occur following inactivation of both RB1 (retinoblastoma susceptibility protein) tumor suppressor gene alleles. 13 Materials and MethodsMedical records, archived tissues, and histologic sections were evaluated as collected between 2001 and 2009 from 11 adult fish of 11 different species (Table 1) and housed at one of two facilities. Tissues taken at necropsy consisted of whole or representative sections of all major organs, including skin or body wall and bone. Smaller fish were fixed whole in formalin and bisected along the median plane for histo...

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Photoreceptor differentiation of retinoblastoma: An electron microscopic study of 29 retinoblastomas

Cited by 12 publications

References 9 publications

Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130

Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130

Cell type-specific effects of Rb deletion in the murine retina

Neuronal Embryonal Tumors in Fish

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