The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Jerry A. Shields - One of the best experts on this subject based on the ideXlab platform.
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Retinoblastoma frontiers with intravenous intra arterial periocular and intravitreal chemotherapy
Eye, 2013Co-Authors: Carol L. Shields, Enzo Fulco, Juan D Arias, Carolina Alarcon, Marco Pellegrini, Pukhraj Rishi, Swathi Kaliki, Carlos Bianciotto, Jerry A. ShieldsAbstract:In this report, we explore Retinoblastoma diagnostic accuracy and review chemotherapy alternatives for Retinoblastoma using intravenous, intra-arterial, periocular, and intravitreal routes. A review of 2775 patients referred for management of Retinoblastoma, disclosed 78% with confirmed Retinoblastoma and 22% with simulating lesions, termed pseudoRetinoblastomas. Children ≤2 years old showed leading pseudoRetinoblastomas of persistent fetal vasculature, Coats disease, and vitreous haemorrhage, whereas those >5 years showed simulators of Coats, toxocariasis, and familial exudative vitreoretinopathy. The diagnosis of Retinoblastoma should be established before planning therapeutic strategy. Chemotherapy strategy depends on tumour laterality and stage of disease. If bilateral Retinoblastoma, intravenous chemotherapy (IVC) is important as first-line therapy for control of intraocular disease, prevention of metastasis, and reduction in prevalence of pinealoblastoma and long-term second malignant neoplasms. Bilateral groups D and E Retinoblastoma receive additional subtenon's carboplatin boost for improved local control. If unilateral disease is present, then intra-arterial chemotherapy (IAC) is often considered. IAC can be salvage therapy following chemoreduction failure. Unilateral Retinoblastoma of groups D and E are managed with enucleation or globe-conserving IVC and/or IAC. Intravitreal chemotherapy is cautiously reserved for recurrent vitreous seeds following other therapies. In conclusion, the strategy for Retinoblastoma management with chemotherapy depends on tumour laterality and stage of disease. Bilateral Retinoblastoma is most often managed with IVC and unilateral Retinoblastoma with IAC, but if advanced stage, combination IVC plus IAC or enucleation.
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Autofluorescence of treated Retinoblastoma
Journal of Aapos, 2011Co-Authors: Aparna Ramasubramanian, Carol L. Shields, Phoebe L. Mellen, Shamir Haji, Sarah A. Harmon, Geeta K. Vemuganti, Jerry A. ShieldsAbstract:Purpose To describe the autofluorescent features of Retinoblastomas after treatment. Methods Standard fundus photography and autofluorescence (AF) photography (580 nm excitation, 695 nm barrier filter) were performed on 88 tumors of 61 patients. Clinical features were correlated with autofluorescent features. Results The mean patient age at AF was 10.3 years. Of the 88 tumors, 5 (6%) were untreated, and 83 (94%) were treated. The untreated Retinoblastomas showed hyperautofluorescence (hyperAF) at the site of calcification in all 5 cases (100%). The treated Retinoblastomas showed intrinsic calcification in 54 cases (65%) and bright hyperAF at the site of calcification was detected in all cases. Of the 60 tumors with noncalcified remnant, the noncalcified portion was mildly hyperAF in 20 (33%), isoautofluorescence in 31 (52%), and mildly hypoautofluorescence (hypoAF) in 9 (15%). Surrounding retinal pigment epithelium hyperplasia appeared moderately hypoAF in 58 of 58 eyes (100%). Retinal pigment epithelium atrophy appeared mildly hyperAF in 29 (37%), isoautofluorescence in 33 (42%), and mildly hypoAF in 16 (21%). Conclusions AF of Retinoblastoma generally shows bright hyperAF of the calcified portion and variable AF of the noncalcified portion. The AF of calcification in Retinoblastoma was confirmed by fluorescent microscopy of unstained sections of Retinoblastoma after enucleation.
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Retinoblastoma management advances in enucleation intravenous chemoreduction and intra arterial chemotherapy
Current Opinion in Ophthalmology, 2010Co-Authors: Carol L. Shields, Jerry A. ShieldsAbstract:To provide an update on current management of Retinoblastoma The current major treatment strategies for Retinoblastoma involve enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Enucleation is reserved for eyes with extensive Retinoblastoma, in which there is no hope for useful vision. Newer implants following enucleation allow excellent cosmetic and motility outcome. Intravenous chemoreduction has been popular for nearly two decades and continues to provide favorable tumor control for most eyes classified as groups A, B, or C and some D eyes, using the International Classification of Retinoblastoma. Using chemoreduction, there has been an apparent reduction in the incidence of pinealoblastoma in children with germline mutation Retinoblastoma. Intra-arterial chemotherapy involves single-agent injection into the ophthalmic artery under careful neurointerventional guidance. This recently popularized therapy can be useful for eyes that fail standard treatments or for some eyes as a primary treatment. Short-term results are favorable but longer follow-up is warranted. Progress has been made in the past few years in the management of Retinoblastoma with better enucleation implants, chemoreduction-prevention of pinealoblastoma and excellent tumor control, and we face the recently popularized modality of intra-arterial chemotherapy with caution and hope.
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Retinoblastoma in oculocutaneous albinism
Retinal Cases & Brief Reports, 2010Co-Authors: Fariba Ghassemi, Carol L. Shields, Ralph C Eagle, Cesare Pirondini, Jerry A. ShieldsAbstract:Purpose:To report a case of Retinoblastoma in a child with oculocutaneous albinism (OCA).Methods:A 24-month-old girl with classic features of OCA developed leukocoria in the left eye.Results:The patient was found to have an endophytic Retinoblastoma and an exophytic Retinoblastoma, with a total reti
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Malignant transformation of retinocytoma into Retinoblastoma.
Retinal Cases & Brief Reports, 2008Co-Authors: Yusuf Uysal, Carol L. Shields, Jerry A. Shields, Ralph C EagleAbstract:Purpose: To describe presumed malignant transformation of a single retinocytoma into Retinoblastoma in a child with multifocal retinocytomas. Methods: A 7-year-old boy presented with a white fundus lesion in the left eye. Ophthalmic evaluation showed one retinocytoma (spontaneously regressed Retinoblastoma/arrested Retinoblastoma) in each eye and one active endophytic Retinoblastoma in the left eye. The left eye was enucleated. Results: Histopathologic examination disclosed a small predominantly endophytic Retinoblastoma with extensive vitreous seeding in association with a basal focus of well differentiated tumor with photoreceptor differentiation, suggestive of retinocytoma. The findings were consistent with malignant transformation of retinocytoma into Retinoblastoma. Conclusion: Patients presumed to have retinocytoma at clinical evaluation should have lifelong follow-up for the remote possibility of malignant transformation.
Carol L. Shields - One of the best experts on this subject based on the ideXlab platform.
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Retinoblastoma frontiers with intravenous intra arterial periocular and intravitreal chemotherapy
Eye, 2013Co-Authors: Carol L. Shields, Enzo Fulco, Juan D Arias, Carolina Alarcon, Marco Pellegrini, Pukhraj Rishi, Swathi Kaliki, Carlos Bianciotto, Jerry A. ShieldsAbstract:In this report, we explore Retinoblastoma diagnostic accuracy and review chemotherapy alternatives for Retinoblastoma using intravenous, intra-arterial, periocular, and intravitreal routes. A review of 2775 patients referred for management of Retinoblastoma, disclosed 78% with confirmed Retinoblastoma and 22% with simulating lesions, termed pseudoRetinoblastomas. Children ≤2 years old showed leading pseudoRetinoblastomas of persistent fetal vasculature, Coats disease, and vitreous haemorrhage, whereas those >5 years showed simulators of Coats, toxocariasis, and familial exudative vitreoretinopathy. The diagnosis of Retinoblastoma should be established before planning therapeutic strategy. Chemotherapy strategy depends on tumour laterality and stage of disease. If bilateral Retinoblastoma, intravenous chemotherapy (IVC) is important as first-line therapy for control of intraocular disease, prevention of metastasis, and reduction in prevalence of pinealoblastoma and long-term second malignant neoplasms. Bilateral groups D and E Retinoblastoma receive additional subtenon's carboplatin boost for improved local control. If unilateral disease is present, then intra-arterial chemotherapy (IAC) is often considered. IAC can be salvage therapy following chemoreduction failure. Unilateral Retinoblastoma of groups D and E are managed with enucleation or globe-conserving IVC and/or IAC. Intravitreal chemotherapy is cautiously reserved for recurrent vitreous seeds following other therapies. In conclusion, the strategy for Retinoblastoma management with chemotherapy depends on tumour laterality and stage of disease. Bilateral Retinoblastoma is most often managed with IVC and unilateral Retinoblastoma with IAC, but if advanced stage, combination IVC plus IAC or enucleation.
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Autofluorescence of treated Retinoblastoma
Journal of Aapos, 2011Co-Authors: Aparna Ramasubramanian, Carol L. Shields, Phoebe L. Mellen, Shamir Haji, Sarah A. Harmon, Geeta K. Vemuganti, Jerry A. ShieldsAbstract:Purpose To describe the autofluorescent features of Retinoblastomas after treatment. Methods Standard fundus photography and autofluorescence (AF) photography (580 nm excitation, 695 nm barrier filter) were performed on 88 tumors of 61 patients. Clinical features were correlated with autofluorescent features. Results The mean patient age at AF was 10.3 years. Of the 88 tumors, 5 (6%) were untreated, and 83 (94%) were treated. The untreated Retinoblastomas showed hyperautofluorescence (hyperAF) at the site of calcification in all 5 cases (100%). The treated Retinoblastomas showed intrinsic calcification in 54 cases (65%) and bright hyperAF at the site of calcification was detected in all cases. Of the 60 tumors with noncalcified remnant, the noncalcified portion was mildly hyperAF in 20 (33%), isoautofluorescence in 31 (52%), and mildly hypoautofluorescence (hypoAF) in 9 (15%). Surrounding retinal pigment epithelium hyperplasia appeared moderately hypoAF in 58 of 58 eyes (100%). Retinal pigment epithelium atrophy appeared mildly hyperAF in 29 (37%), isoautofluorescence in 33 (42%), and mildly hypoAF in 16 (21%). Conclusions AF of Retinoblastoma generally shows bright hyperAF of the calcified portion and variable AF of the noncalcified portion. The AF of calcification in Retinoblastoma was confirmed by fluorescent microscopy of unstained sections of Retinoblastoma after enucleation.
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Retinoblastoma management advances in enucleation intravenous chemoreduction and intra arterial chemotherapy
Current Opinion in Ophthalmology, 2010Co-Authors: Carol L. Shields, Jerry A. ShieldsAbstract:To provide an update on current management of Retinoblastoma The current major treatment strategies for Retinoblastoma involve enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Enucleation is reserved for eyes with extensive Retinoblastoma, in which there is no hope for useful vision. Newer implants following enucleation allow excellent cosmetic and motility outcome. Intravenous chemoreduction has been popular for nearly two decades and continues to provide favorable tumor control for most eyes classified as groups A, B, or C and some D eyes, using the International Classification of Retinoblastoma. Using chemoreduction, there has been an apparent reduction in the incidence of pinealoblastoma in children with germline mutation Retinoblastoma. Intra-arterial chemotherapy involves single-agent injection into the ophthalmic artery under careful neurointerventional guidance. This recently popularized therapy can be useful for eyes that fail standard treatments or for some eyes as a primary treatment. Short-term results are favorable but longer follow-up is warranted. Progress has been made in the past few years in the management of Retinoblastoma with better enucleation implants, chemoreduction-prevention of pinealoblastoma and excellent tumor control, and we face the recently popularized modality of intra-arterial chemotherapy with caution and hope.
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Retinoblastoma in oculocutaneous albinism
Retinal Cases & Brief Reports, 2010Co-Authors: Fariba Ghassemi, Carol L. Shields, Ralph C Eagle, Cesare Pirondini, Jerry A. ShieldsAbstract:Purpose:To report a case of Retinoblastoma in a child with oculocutaneous albinism (OCA).Methods:A 24-month-old girl with classic features of OCA developed leukocoria in the left eye.Results:The patient was found to have an endophytic Retinoblastoma and an exophytic Retinoblastoma, with a total reti
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Malignant transformation of retinocytoma into Retinoblastoma.
Retinal Cases & Brief Reports, 2008Co-Authors: Yusuf Uysal, Carol L. Shields, Jerry A. Shields, Ralph C EagleAbstract:Purpose: To describe presumed malignant transformation of a single retinocytoma into Retinoblastoma in a child with multifocal retinocytomas. Methods: A 7-year-old boy presented with a white fundus lesion in the left eye. Ophthalmic evaluation showed one retinocytoma (spontaneously regressed Retinoblastoma/arrested Retinoblastoma) in each eye and one active endophytic Retinoblastoma in the left eye. The left eye was enucleated. Results: Histopathologic examination disclosed a small predominantly endophytic Retinoblastoma with extensive vitreous seeding in association with a basal focus of well differentiated tumor with photoreceptor differentiation, suggestive of retinocytoma. The findings were consistent with malignant transformation of retinocytoma into Retinoblastoma. Conclusion: Patients presumed to have retinocytoma at clinical evaluation should have lifelong follow-up for the remote possibility of malignant transformation.
David H Abramson - One of the best experts on this subject based on the ideXlab platform.
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rb suppresses human cone precursor derived Retinoblastoma tumours
Nature, 2014Co-Authors: Xiaoliang L Xu, Suresh C Jhanwar, David H Abramson, Hardeep Singh, Lu Wang, Donglai Qi, Bradford K Poulos, David CobrinikAbstract:The nature of the retinal cell-type-specific circuitry that predisposes to Retinoblastoma is demonstrated, in which a program that is unique to post-mitotic human cone precursors sensitizes to the oncogenic effects of Retinoblastoma (Rb) protein depletion; hence, the loss of Rb collaborates with the molecular framework of cone precursors to initiate tumorigenesis. Inactivation of both alleles of the Retinoblastoma (RB) gene generally leads to the formation of Retinoblastomas, but rarely to other tumour types. David Cobrinik and colleagues now provide an explanation for this in a study that identifies the human retinal cell-of-origin from which Retinoblastomas arise. They find that of the various human retinal cell types, cone precursor cells are uniquely sensitive to transformation upon loss of RB. This is due to the cone precursor cell-specific molecular framework, for example, the high expression levels of MDM2 and MYCN which can collaborate with RB loss. These principles may more generally explain why certain initiating oncogenic mutations tend to be associated with specific cancer types. 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 cancers1,2,3,4,5, germline RB1 mutations predispose to Retinoblastoma far more strongly than to other malignancies6. 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 unclear7,8. 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.
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Retinoblastoma has properties of a cone precursor tumor and depends upon cone specific mdm2 signaling
Cell, 2009Co-Authors: Xiaoliang L Xu, Yuqiang Fang, Douglas Forrest, Cheryl Y Gregoryevans, Dena Almeida, Suresh C Jhanwar, David H Abramson, David CobrinikAbstract:Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses Retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that Retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that Retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured Retinoblastoma cells. Interestingly, Retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ, as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of Retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.
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risk of soft tissue sarcomas by individual subtype in survivors of hereditary Retinoblastoma
Journal of the National Cancer Institute, 2007Co-Authors: Ruth A Kleinerman, David H Abramson, Robert E Tarone, Johanna M Seddon, Margaret A Tucker, Joseph F FraumeniAbstract:Background Survivors of hereditary Retinoblastoma have an increased risk for second malignancies, especially soft tissue sarcomas. However, the risks of individual histologic subtypes of soft tissue sarcomas have not been evaluated. Methods We estimated the risk for six subtypes of soft tissue sarcomas (fibrosarcoma, liposarcoma, histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and others) in a cohort of 963 one-year survivors of hereditary Retinoblastoma among patients diagnosed at two US institutions from 1914 through 1984. We calculated standardized incidence ratios (SIRs) for specific subtypes of soft tissue sarcomas by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results database. We also calculated the cumulative risk for all soft tissue sarcomas combined. Results We observed 69 soft tissue sarcomas in 68 patients with hereditary Retinoblastoma. Risks were elevated for soft tissue sarcomas overall (SIR = 184, 95% confidence interval [Cl] = 143 to 233) and for individual subtypes. Leiomyosarcoma was the most frequent subtype (SIR = 390, 95% Cl = 247 to 585), with 78% of leiomyosarcomas diagnosed 30 or more years after the Retinoblastoma diagnosis (SIR = 435, 95% Cl = 258 to 687). Among patients treated with radiotherapy for Retinoblastoma, we found statistically significantly increased risks of soft tissue sarcomas in the field of radiation. Irradiated patients also had increased risks of soft tissue sarcomas, especially leiomyosarcomas, outside the field of radiation, and risks of soft tissue sarcomas were increased in nonirradiated patients as well, indicating a genetic predisposition to soft tissue sarcomas independent of radiation. The cumulative risk for any soft tissue sarcoma 50 years after radiotherapy for Retinoblastoma was 13.1% (95% Cl = 9.7% to 17.0%). Conclusion Long-term follow-up of a cohort of survivors of hereditary Retinoblastoma revealed a statistically significant excess of leiomyosarcoma and other soft tissue sarcomas that persists decades after the Retinoblastoma diagnosis. Retinoblastoma survivors should undergo regular medical surveillance for sarcomas in their adult years.
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cancer incidence after Retinoblastoma radiation dose and sarcoma risk
JAMA, 1997Co-Authors: Lennie F Wong, David H Abramson, John D Boice, Robert E Tarone, Ruth A Kleinerman, Marilyn Stovall, Marlene B Goldman, Johanna M Seddon, Nancy J Tarbell, Joseph F FraumeniAbstract:Context. —There is a substantial risk of a second cancer for persons with hereditary Retinoblastoma, which is enhanced by radiotherapy. Objective. —To examine long-term risk of new primary cancers in survivors of childhood Retinoblastoma and quantify the role of radiotherapy in sarcoma development. Design. —Cohort incidence study of patients with Retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. Setting/Participants. —A total of 1604 patients with Retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. Results. —Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary Retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (±SE) of a second cancer at 50 years after diagnosis was 51.0% (±6.2%) for hereditary Retinoblastoma, and 5.0% (±3.0%) for nonhereditary Retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary Retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater ( P Conclusions.— Genetic predisposition has a substantial impact on risk of subsequent cancers in Retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.
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mortality from second tumors among long term survivors of Retinoblastoma
Journal of the National Cancer Institute, 1993Co-Authors: Frederick P Li, David H Abramson, Lennie F Wong, Marlene B Goldman, Johanna M Seddon, Nancy J Tarbell, Robert M Ellsworth, John D BoiceAbstract:Background: Children diagnosed with Retinoblastoma, a rare cancer of the eye, tend to develop and die of second primary cancers in childhood and adolescence, but few investigations have followed patients into adulthood. Retinoblastoma is frequently caused by inherited mutations of the RB1 tumor suppressor gene. Most patients with germline (hereditary) mutations have bilateral disease. Purpose: We sought to quantify the mortality from second malignancies among long-term survivors of Retinoblastoma and to identify factors that predispose to these deaths. Methods: A retrospective cohort study examined mortality among 1603 patients enrolled at 1 year after diagnosis of Retinoblastoma during the period 1914-1984
David Cobrinik - One of the best experts on this subject based on the ideXlab platform.
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rb suppresses human cone precursor derived Retinoblastoma tumours
Nature, 2014Co-Authors: Xiaoliang L Xu, Suresh C Jhanwar, David H Abramson, Hardeep Singh, Lu Wang, Donglai Qi, Bradford K Poulos, David CobrinikAbstract:The nature of the retinal cell-type-specific circuitry that predisposes to Retinoblastoma is demonstrated, in which a program that is unique to post-mitotic human cone precursors sensitizes to the oncogenic effects of Retinoblastoma (Rb) protein depletion; hence, the loss of Rb collaborates with the molecular framework of cone precursors to initiate tumorigenesis. Inactivation of both alleles of the Retinoblastoma (RB) gene generally leads to the formation of Retinoblastomas, but rarely to other tumour types. David Cobrinik and colleagues now provide an explanation for this in a study that identifies the human retinal cell-of-origin from which Retinoblastomas arise. They find that of the various human retinal cell types, cone precursor cells are uniquely sensitive to transformation upon loss of RB. This is due to the cone precursor cell-specific molecular framework, for example, the high expression levels of MDM2 and MYCN which can collaborate with RB loss. These principles may more generally explain why certain initiating oncogenic mutations tend to be associated with specific cancer types. 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 cancers1,2,3,4,5, germline RB1 mutations predispose to Retinoblastoma far more strongly than to other malignancies6. 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 unclear7,8. 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.
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Retinoblastoma has properties of a cone precursor tumor and depends upon cone specific mdm2 signaling
Cell, 2009Co-Authors: Xiaoliang L Xu, Yuqiang Fang, Douglas Forrest, Cheryl Y Gregoryevans, Dena Almeida, Suresh C Jhanwar, David H Abramson, David CobrinikAbstract:Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses Retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that Retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that Retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured Retinoblastoma cells. Interestingly, Retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ, as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of Retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.
Xiaoliang L Xu - One of the best experts on this subject based on the ideXlab platform.
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rb suppresses human cone precursor derived Retinoblastoma tumours
Nature, 2014Co-Authors: Xiaoliang L Xu, Suresh C Jhanwar, David H Abramson, Hardeep Singh, Lu Wang, Donglai Qi, Bradford K Poulos, David CobrinikAbstract:The nature of the retinal cell-type-specific circuitry that predisposes to Retinoblastoma is demonstrated, in which a program that is unique to post-mitotic human cone precursors sensitizes to the oncogenic effects of Retinoblastoma (Rb) protein depletion; hence, the loss of Rb collaborates with the molecular framework of cone precursors to initiate tumorigenesis. Inactivation of both alleles of the Retinoblastoma (RB) gene generally leads to the formation of Retinoblastomas, but rarely to other tumour types. David Cobrinik and colleagues now provide an explanation for this in a study that identifies the human retinal cell-of-origin from which Retinoblastomas arise. They find that of the various human retinal cell types, cone precursor cells are uniquely sensitive to transformation upon loss of RB. This is due to the cone precursor cell-specific molecular framework, for example, the high expression levels of MDM2 and MYCN which can collaborate with RB loss. These principles may more generally explain why certain initiating oncogenic mutations tend to be associated with specific cancer types. 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 cancers1,2,3,4,5, germline RB1 mutations predispose to Retinoblastoma far more strongly than to other malignancies6. 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 unclear7,8. 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.
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Retinoblastoma has properties of a cone precursor tumor and depends upon cone specific mdm2 signaling
Cell, 2009Co-Authors: Xiaoliang L Xu, Yuqiang Fang, Douglas Forrest, Cheryl Y Gregoryevans, Dena Almeida, Suresh C Jhanwar, David H Abramson, David CobrinikAbstract:Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses Retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that Retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that Retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured Retinoblastoma cells. Interestingly, Retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ, as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of Retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.
