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1.
EMBO J ; 40(22): e107264, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34494680

RESUMEN

Emerging evidence suggests that intracellular molecules and organelles transfer between cells during embryonic development, tissue homeostasis and disease. We and others recently showed that transplanted and host photoreceptors engage in bidirectional transfer of intracellular material in the recipient retina, a process termed material transfer (MT). We used cell transplantation, advanced tissue imaging approaches, genetic and pharmacologic interventions and primary cell culture to characterize and elucidate the mechanism of MT. We show that MT correlates with donor cell persistence and the accumulation of donor-derived proteins, mitochondria and transcripts in acceptor cells in vivo. MT requires cell contact in vitro and is associated with the formation of stable microtubule-containing protrusions, termed photoreceptor nanotubes (Ph NTs), that connect donor and host cells in vivo and in vitro. Ph NTs mediate GFP transfer between connected cells in vitro. Furthermore, interfering with Ph NT outgrowth by targeting Rho GTPase-dependent actin remodelling inhibits MT in vivo. Collectively, our observations provide evidence for horizontal exchange of intracellular material via nanotube-like connections between neurons in vivo.


Asunto(s)
Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/ultraestructura , Retina/citología , Actinas/metabolismo , Animales , Transporte Biológico , Supervivencia Celular , Vesículas Extracelulares , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Retina/fisiología , Retinoblastoma/metabolismo , Retinoblastoma/patología , Transducina/metabolismo , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismo
2.
Am J Pathol ; 194(9): 1780-1798, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38879085

RESUMEN

Retinoblastoma (RB) is an intraocular malignancy initiated by loss of RB1 function and/or dysregulation of MYCN oncogene. RB is primarily treated with chemotherapy; however, systemic toxicity and long-term adverse effects remain a significant challenge necessitating the identification of specific molecular targets. Aurora kinase A (AURKA), a critical cell cycle regulator, contributes to cancer pathogenesis, especially in RB1-deficient and MYCN-dysregulated tumors. The current immunohistochemistry study in patient specimens (n = 67) indicated that AURKA is overexpressed in RB, and this elevated expression correlates with one or more histopathologic high-risk factors, such as tumor involvement of the optic nerve, choroid, sclera, and/or anterior segment. More specifically, AURKA is ubiquitously expressed in most advanced-stage RB tumors that show a suboptimal response to chemotherapy. shRNA-mediated depletion/pharmacologic inhibition studies in cell lines, patient-derived cells, in vivo xenografts, and enucleated patient specimens confirmed that RB cells are highly sensitive to a lack of functional AURKA. In addition, AURKA and N-myc proto-oncogene protein (MYCN) associate with each other to regulate their levels in RB cells. Overall, these results demonstrate a previously unknown up-regulation of AURKA in RB, facilitated by its crosstalk with MYCN. The elevated levels of this kinase may indicate unfavorable prognosis in tumors refractory to chemotherapy. This study provides a rationale and confirms that therapeutic targeting of elevated AURKA in RB could be a potential treatment approach.


Asunto(s)
Aurora Quinasa A , Proto-Oncogenes Mas , Neoplasias de la Retina , Retinoblastoma , Preescolar , Femenino , Humanos , Masculino , Aurora Quinasa A/metabolismo , Aurora Quinasa A/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Terapia Molecular Dirigida , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Neoplasias de la Retina/patología , Neoplasias de la Retina/metabolismo , Neoplasias de la Retina/genética , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/patología , Retinoblastoma/metabolismo , Retinoblastoma/genética , Factores de Riesgo , Animales , Embrión de Pollo
3.
Crit Rev Immunol ; 44(3): 89-98, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38421707

RESUMEN

The methyltransferase 14, N6-adenosine-methyltransferase subunit (METTL14) and Cyclin-dependent kinase inhibitor 2A (CDKN2A) have been identified as involved in the regulation of various cancer progression, while their mechanism and regulatory effect in retinoblastoma (RB) is still unclear. Cell colony formation, CCK-8 as well as Western blotting were used to evaluate the proliferation, apoptosis as well as p53 protein level of RB cell line. The METTL14 and CDKN2A levels were detected by qRT-PCR or Western blotting when METTL14 was up-regulated or CDKN2A was down-regulated. MeRIP and Pearson analysis were performed to confirm the regulatory relationship between METTL14 among CDKN2A. We found that the levels of CDKN2A and METTL14 were abundant in RB samples, as well as RB cells. METTL14 enhances N6-methyladenosine (m6A) modification of CDKN2A to upregulate its mRNA and protein levels. The proliferation of RB cells can be inhibited by silencing CDKN2A, which promotes apoptosis and p53 protein level. Furthermore, high-expression of METTL14 eliminated the anti-tumor effect of CDKN2A silencing in RB progression in vitro. CDKN2A is mediated by METTL14-m6A modified and restrains p53 pathway activation to accelerate the malignancy of RB. This points to the METTL14-m6A-CDKN2A-p53 pathway axis as a possible prospective target for the future RB treatment.


Asunto(s)
Adenina/análogos & derivados , Neoplasias de la Retina , Retinoblastoma , Humanos , Retinoblastoma/genética , Proteína p53 Supresora de Tumor/genética , Adenosina , Metiltransferasas/genética , Neoplasias de la Retina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética
4.
Nature ; 569(7756): 423-427, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31043741

RESUMEN

Mutations in the retinoblastoma (RB) tumour suppressor pathway are a hallmark of cancer and a prevalent feature of lung adenocarcinoma1-3. Although RB was the first tumour suppressor to be identified, the molecular and cellular basis that underlies selection for persistent RB loss in cancer remains unclear4-6. Methods that reactivate the RB pathway using inhibitors of cyclin-dependent kinases CDK4 and CDK6 are effective in some cancer types and are currently under evaluation for the treatment of lung adenocarcinoma7-9. Whether RB pathway reactivation will have therapeutic effects and whether targeting CDK4 and CDK6 is sufficient to reactivate RB pathway activity in lung cancer remains unknown. Here we model RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS-driven tumours in mice. We show that RB loss enables cancer cells to bypass two distinct barriers during tumour progression. First, RB loss abrogates the requirement for amplification of the MAPK signal during malignant progression. We identify CDK2-dependent phosphorylation of RB as an effector of MAPK signalling and critical mediator of resistance to inhibition of CDK4 and CDK6. Second, RB inactivation deregulates the expression of cell-state-determining factors, facilitates lineage infidelity and accelerates the acquisition of metastatic competency. By contrast, reactivation of RB reprograms advanced tumours towards a less metastatic cell state, but is nevertheless unable to halt cancer cell proliferation and tumour growth due to adaptive rewiring of MAPK pathway signalling, which restores a CDK-dependent suppression of RB. Our study demonstrates the power of reversible gene perturbation approaches to identify molecular mechanisms of tumour progression, causal relationships between genes and the tumour suppressive programs that they control and critical determinants of successful cancer therapy.


Asunto(s)
Linaje de la Célula , Progresión de la Enfermedad , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia , Retinoblastoma/metabolismo , Células 3T3 , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Linaje de la Célula/genética , Quinasa 2 Dependiente de la Ciclina/deficiencia , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Metástasis de la Neoplasia/genética , Retinoblastoma/genética
5.
Proc Natl Acad Sci U S A ; 119(28): e2200721119, 2022 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-35867756

RESUMEN

Most retinoblastomas develop from maturing cone precursors in response to biallelic RB1 loss and are dependent on cone maturation-related signaling. Additionally, ∼2% lack RB1 mutations but have MYCN amplification (MYCNA), N-Myc protein overexpression, and more rapid and invasive growth, yet the MYCNA retinoblastoma cell of origin and basis for its responses to deregulated N-Myc are unknown. Here, using explanted cultured retinae, we show that ectopic N-Myc induces cell cycle entry in cells expressing markers of several retinal types yet induces continuous proliferation and tumorigenesis only in cone precursors. Unlike the response to RB1 loss, both immature cone arrestin-negative (ARR3-) and maturing ARR3+ cone precursors proliferate, and maturing cone precursors rapidly dedifferentiate, losing ARR3 as well as L/M-opsin expression. N-Myc-overexpressing retinal cells also lose cell lineage constraints, occasionally coexpressing the cone-specific RXRγ with the rod-specific NRL or amacrine-specific AP2α and widely coexpressing RXRγ with the progenitor and Müller cell-specific SOX9 and retinal ganglion cell-specific BRN3 and GAP43. Mechanistically, N-Myc induced Cyclin D2 and CDK4 overexpression, pRB phosphorylation, and SOX9-dependent proliferation without a retinoma-like stage that characterizes pRB-deficient retinoblastoma, despite continuous p16INK4A expression. Orthotopic xenografts of N-Myc-overexpressing retinal cells formed tumors with retinal cell marker expression similar to those in MYCN-transduced retinae and MYCNA retinoblastomas in patients. These findings demonstrate the MYCNA retinoblastoma origin from immature and lineage-deconstrained cone precursors, reveal their opportunistic use of an undifferentiated retinal progenitor cell feature, and illustrate that different cancer-initiating mutations cooperate with distinct developmental stage-specific cell signaling circuitries to drive retinoblastoma tumorigenesis.


Asunto(s)
Carcinogénesis , Proteína Proto-Oncogénica N-Myc , Células Fotorreceptoras Retinianas Conos , Neoplasias de la Retina , Retinoblastoma , Carcinogénesis/genética , Ciclo Celular , Humanos , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Células Fotorreceptoras Retinianas Conos/patología , Neoplasias de la Retina/metabolismo , Neoplasias de la Retina/patología , Retinoblastoma/metabolismo , Retinoblastoma/patología
6.
Proc Natl Acad Sci U S A ; 119(16): e2117857119, 2022 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-35412907

RESUMEN

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC­derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a­regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.


Asunto(s)
Neoplasias Óseas , Carcinogénesis , Factor de Transcripción E2F3 , Regulación Neoplásica de la Expresión Génica , Células Madre Pluripotentes Inducidas , Osteosarcoma , Proteínas de Unión a Retinoblastoma , Empalmosomas , Ubiquitina-Proteína Ligasas , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Carcinogénesis/genética , Factor de Transcripción E2F3/genética , Factor de Transcripción E2F3/metabolismo , Genes de Retinoblastoma , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Osteosarcoma/genética , Osteosarcoma/patología , Neoplasias de la Retina/genética , Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Empalmosomas/genética , Empalmosomas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
7.
Glia ; 72(5): 872-884, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38258347

RESUMEN

RB1 deficiency leads to retinoblastoma (Rb), the most prevalent intraocular malignancy. Tumor-associated macrophages (TAMs) are related to local inflammation disorder, particularly by increasing cytokines and immune escape. Microglia, the unique resident macrophages for retinal homeostasis, are the most important immune cells of Rb. However, whether RB1 deficiency affects microglial function remain unknown. In this study, microglia were successfully differentiated from Rb patient- derived human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs), and then we investigated the function of RB1 in microglia by live imaging phagocytosis assay, immunofluorescence, RNA-seq, qRT-PCR, ELISA and retina organoids/microglia co-culturing. RB1 was abundantly expressed in microglia and predominantly located in the nucleus. We then examined the phagocytosis ability and secretion function of iMGs in vitro. We found that RB1 deficiency did not affect the expression of microglia-specific markers or the phagocytic abilities of these cells by live-imaging. Upon LPS stimulation, RB1-deficient microglia displayed enhanced innate immune responses, as evidenced by activated MAPK signaling pathway and elevated expression of IL-6 and TNF-α at both mRNA and protein levels, compared to wildtype microglia. Furthermore, retinal structure disruption was observed when retinal organoids were co-cultured with RB1-deficient microglia, highlighting the potential contribution of microglia to Rb development and potential therapeutic strategies for retinoblastoma.


Asunto(s)
Células Madre Pluripotentes Inducidas , Neoplasias de la Retina , Retinoblastoma , Humanos , Retinoblastoma/genética , Retinoblastoma/metabolismo , Retinoblastoma/patología , Microglía/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Retina , Neoplasias de la Retina/genética , Neoplasias de la Retina/metabolismo , Neoplasias de la Retina/patología
8.
Br J Cancer ; 131(3): 491-497, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38871807

RESUMEN

BACKGROUND: Retinoblastoma is the most common intra-ocular malignancy in children and frequently presents in very young patients who commonly require intravenous carboplatin. Delivering this is challenging due to a lack of uniform dosing recommendations, rapid changes in physiological function and the risk of side-effects. METHODS: We conducted a retrospective review of neonates and infants in the UK with retinoblastoma, who have undergone carboplatin therapeutic drug monitoring (TDM). We report on the pharmacokinetic, treatment efficacy and toxicity data. RESULTS: In total, 29 patients (median age 5 weeks at treatment onset) underwent a total of 74 TDM guided cycles of chemotherapy, involving real time sampling and dose adjustment. An additional 13 patients underwent TDM sampling to modify doses between cycles. Without the adoption of TDM guided dosing, carboplatin exposures would have been ≥20% outside the target AUC in 38/78 (49%) of treatment cycles. Excellent responses and a reassuringly low incidence of toxicities were observed following dose adjustment, despite the young patient age and the implementation of dose increases in the majority of cases. CONCLUSIONS: Real time TDM is safe, effective and deliverable for neonates and infants receiving carboplatin for retinoblastoma and should be considered standard of care up to the age of 6 months.


Asunto(s)
Carboplatino , Monitoreo de Drogas , Neoplasias de la Retina , Retinoblastoma , Humanos , Retinoblastoma/tratamiento farmacológico , Carboplatino/administración & dosificación , Lactante , Recién Nacido , Monitoreo de Drogas/métodos , Reino Unido , Femenino , Estudios Retrospectivos , Masculino , Neoplasias de la Retina/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Resultado del Tratamiento
9.
Oncologist ; 29(2): e275-e281, 2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-37874925

RESUMEN

BACKGROUND: Retinoblastoma is the most common intraocular malignant tumor occurring among children, with an incidence rate of 1/15 000. This study built a joinpoint regression model to assess the incidence trend of retinoblastoma from 2004 to 2015 and constructed a nomogram to predict the overall survival (OS) in children. MATERIALS AND METHODS: Patients less than 19 years diagnosed with retinoblastoma from 2004 to 2015 were selected from the SEER database. Joinpoint regression analysis (version 4.9.0.0) was performed to evaluate the trends in retinoblastoma incidence rates from 2004 to 2015. Cox Regression Analysis was applied to investigate prognostic risk factors that influence OS. RESULTS: Joinpoint regression revealed that retinoblastoma incidence exhibited no significant increase or decrease from 2004 to 2015. As per the multiple Cox regression, tumor size, laterality, and residence (rural-urban continuum code) were correlated with OS and were used to construct a nomogram. The nomogram exhibited a good C-index of 0.71 (95% CI, 0.63 to 0.79), and the calibration curve for survival probability demonstrated that the predictions corresponded well with actual observations. CONCLUSIONS AND RELEVANCE: A prognostic nomogram integrating the risk factors for retinoblastoma was constructed to provide comparatively accurate individual survival predictions. If validated, this type of assessment could be used to guide therapy in patients with retinoblastoma.


Asunto(s)
Neoplasias de la Retina , Retinoblastoma , Niño , Humanos , Pronóstico , Nomogramas , Incidencia , Retinoblastoma/epidemiología , Neoplasias de la Retina/epidemiología , Programa de VERF
10.
Cancer Immunol Immunother ; 73(1): 19, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38240863

RESUMEN

BACKGROUND: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. METHODS: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. RESULTS: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. CONCLUSION: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neoplasias de la Retina , Retinoblastoma , Humanos , Retinoblastoma/terapia , Trasplante Autólogo , Recurrencia Local de Neoplasia , Inmunoterapia , Gangliósidos , Antígenos B7
11.
Mol Carcinog ; 63(5): 926-937, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38380957

RESUMEN

Early treatment of retinoblastoma (RB) has significantly improved clinical outcomes. N6-methyladenosine (m6A) methylation is crucial for cancer progression. Thus, we investigated the role of FTO-dependent demethylation in RB and its underlying mechanisms. The biological behavior of RB cells was analyzed using cell counting kit-8, colony formation analysis, transwell assay, flow cytometry, and western blot analysis. m6A modification was evaluated using methylated RNA immunoprecipitation and dual-luciferase reporter assays, and E2F3 stability was assessed using Actinomycin D. The roles of FTO and E2F3 were also elucidated in vivo. These results indicated that FTO was highly expressed in RB cells with low m6A levels. FTO knockdown inhibited RB cell growth, migration, invasion, and epithelial-mesenchymal transition and arrested the cell cycle at the G0/G1 phase. Mechanistically, FTO interference promoted m6A methylation of E2F3, which was recognized by YTHDF2, thereby reducing mRNA stability. E2F3 overexpression partially rescued the effects of FTO knockdown on biological behavior. Moreover, FTO knockdown reduced tumor weight, tumor volume, ki67 expression, and tumor cell infiltration by mediating E2F3. Taken together, FTO silencing inhibited the malignant processes of RB by suppressing E2F3 in an m6A-YTHD2-dependent manner. These findings suggest that FTO is a novel therapeutic target for RB.


Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Factor de Transcripción E2F3 , Neoplasias de la Retina , Retinoblastoma , Humanos , Adenosina , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Ciclo Celular , Factor de Transcripción E2F3/genética , Factor de Transcripción E2F3/metabolismo , Retinoblastoma/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
12.
J Hum Genet ; 69(9): 467-474, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38956221

RESUMEN

Retinoblastoma (RB) is a childhood retinal neoplasm and commonly treated with cytotoxic chemotherapeutic agents. However, these therapeutic approaches often lead to diverse adverse effects. A precise molecular therapy will alleviate these side effects and offer better treatment outcomes. Over the years, kinases have become potential drug targets in cancer therapy. Hence, we aimed to investigate genetic alterations of putative kinase drug targets in RB. Targeted exome sequencing was performed on 35 RB tumors with paired blood samples using a gene panel consisting of 29 FDA-approved kinase genes. Single nucleotide variants were analyzed for pathogenicity using an in-house pipeline and copy number variations (CNVs) were detected by a depth of coverage and CNVPanelizer. The correlation between genetic changes and clinicopathological features was assessed using GraphPad Prism. Three somatic mutations, two in ERBB4 and one in EGFR were identified. Two of these mutations (ERBB4 c.C3836A & EGFR c.A1196T) were not reported earlier. CNV analysis revealed recurrent gains of ALK, MAP2K2, SRC, STK11, and FGFR3 as well as frequent losses of ATM, PI3KCA and ERBB4. Notably, nonresponsive tumors had a higher incidence of amplifications in clinically actionable genes such as ALK. Moreover, ALK gain and ATM loss were strongly correlated with optic nerve head invasion. In conclusion, our study revealed genetic alterations of druggable kinases in RB, providing preliminary insights for the exploration of kinase-targeted therapy in RB.


Asunto(s)
Variaciones en el Número de Copia de ADN , Terapia Molecular Dirigida , Mutación , Retinoblastoma , Humanos , Retinoblastoma/genética , Retinoblastoma/tratamiento farmacológico , Retinoblastoma/patología , Masculino , Femenino , Preescolar , Lactante , Niño , Neoplasias de la Retina/genética , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/patología , Receptor ErbB-4/genética , Secuenciación del Exoma , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB
13.
Ophthalmology ; 131(4): 468-477, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37839559

RESUMEN

PURPOSE: To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. DESIGN: Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. PARTICIPANTS: A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. INTERVENTIONS: Chemotherapy, radiotherapy, enucleation, and orbital exenteration. MAIN OUTCOME MEASURES: Enucleation and death. RESULTS: Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1-261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 [16%]), cT2 (n = 951 [34%]), cT3 (n = 1136 [41%]), cT4 (n = 267 [10%]), N1 (n = 48 [2%]), and M1 (n = 129 [6%]) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively. CONCLUSIONS: At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Asunto(s)
Neoplasias de la Retina , Retinoblastoma , Niño , Humanos , Masculino , Femenino , Lactante , Preescolar , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiología , Retinoblastoma/terapia , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/epidemiología , Neoplasias de la Retina/terapia , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Asia/epidemiología , Estudios Retrospectivos , Enucleación del Ojo
14.
Ophthalmology ; 131(10): 1215-1224, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38703794

RESUMEN

PURPOSE: To study the long-term efficacy of intravitreal topotecan (IVT) for vitreous seeds in eyes with retinoblastoma and risk factors for their recurrence. DESIGN: Retrospective, non-comparative, interventional study. PARTICIPANTS: Ninety-one eyes of 90 patients with retinoblastoma treated between January 2013 and April 2019. METHODS: Patients with recurrent or refractory vitreous seeds after completion of intravenous or intra-arterial chemotherapy were treated with IVT (30 µg/0.15 ml) by the safety-enhanced technique. The injection was repeated every 4 weeks until the regression of seeds. Patients with a minimum follow-up of 12 months were included in the analysis. MAIN OUTCOME MEASURES: Primary outcome measures were vitreous seed regression and eye salvage. Secondary outcomes were risk factors for vitreous seed recurrence after treatment with IVT, vision salvage, and complications of IVT. RESULTS: The median age of the patients was 18 months, with most having group D (n = 58 [64%]) and group E (n = 26 [29%]) retinoblastoma. Vitreous seeds were refractory in 46 eyes (51%) and recurrent in 45 eyes (49%). A total of 317 IVT injections were administered, with the median being 3 injections. The median number of IVT injections required was 2.5 injections for dust, 3 injections for sphere, and 5 injections for cloud morphologic features. Recurrence of vitreous seeds after IVT was seen in 17 eyes (19%) at a mean follow-up of 7.9 months. At a mean follow-up 34 months, vitreous seed regression was achieved in 88 eyes (97%) and eye salvage was achieved in 77 eyes (85%). Older age (P = 0.018) and recurrence of retinal tumor (15/17 eyes; P < 0.01) significantly increased the risk of vitreous seed recurrence. Cataract was the most common complication seen in 17 eyes (9%). CONCLUSIONS: Intravitreal topotecan at an every 3- to 4-week regimen is effective against both refractory and recurrent vitreous seeds. The vitreous seed morphologic features correspond to the number of injections required for regression. Increasing age and recurrence of retinal tumor increase the risk of vitreous seed recurrence after treatment with IVT. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Asunto(s)
Inyecciones Intravítreas , Siembra Neoplásica , Neoplasias de la Retina , Retinoblastoma , Inhibidores de Topoisomerasa I , Topotecan , Cuerpo Vítreo , Humanos , Retinoblastoma/tratamiento farmacológico , Topotecan/administración & dosificación , Estudios Retrospectivos , Masculino , Neoplasias de la Retina/tratamiento farmacológico , Lactante , Femenino , Cuerpo Vítreo/efectos de los fármacos , Preescolar , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/uso terapéutico , Estudios de Seguimiento , Recurrencia Local de Neoplasia/tratamiento farmacológico , Niño , Factores de Riesgo , Agudeza Visual/fisiología
15.
BMC Cancer ; 24(1): 287, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38438837

RESUMEN

BACKGROUND: Management guidelines and corresponding survival data for patients with recurrent retinoblastoma (RB) are lacking. This study aimed to summarize the clinical characteristics of patients with recurrent RB and analyze their survival outcomes. METHODS: We retrospectively analyzed 68 patients with recurrent RB who underwent treatment in our institution from January 2016 to December 2020. Patients were grouped according to location of recurrence: intraocular, orbital, and distant metastasis. RESULTS: The male:female ratio was 1.3:1 and the median age at recurrence was 37.5 months (range, 30.3-62.8). The number of patients in the intraocular recurrence, orbital recurrence, and metastasis groups was 13 (19.1%), 23 (33.8%), and 32 (47.1%), respectively. Thirty patients died, 36 were alive at last follow-up, and two were lost to follow-up. Eye enucleation was performed in 94.1% of patients. Five-year overall survival in patients with intraocular recurrence, orbital recurrence, and metastasis was 84.6%, 69.6%, and 31.3%, respectively (P = 0.001). Most deaths occurred within 2 years of recurrence. Presence of high-risk pathological factors, central nervous system invasion, and absence of combination therapy were independent predictors of worse 5-year overall survival. CONCLUSION: The rate of eye preservation in survivors of recurrent RB was very low. Although 5-year overall survival in patients who underwent treatment for intraocular and orbital recurrence was high, it was low in those with metastasis. RB patients may need lifelong follow-up for recurrence and secondary malignancy.


Asunto(s)
Neoplasias de la Retina , Retinoblastoma , Humanos , Femenino , Masculino , Preescolar , Retinoblastoma/cirugía , Estudios Retrospectivos , Análisis de Supervivencia , Sistema Nervioso Central , Neoplasias de la Retina/cirugía
16.
Exp Eye Res ; 240: 109798, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38246332

RESUMEN

Retinoblastoma (RB) is a rare ocular cancer seen in children that counts for approximately 3% of all childhood cancers. It is found that mutation in RB1, a tumour Suppressor Gene on chromosome 13 as the cause of malignancy. Retinoblastoma protein is the target for ceramide to cause apoptosis. We studied lipidomics of two RB cell lines, one aggressive cell line (NCC-RbC-51) derived from a metastatic site and one non aggressive cell line (WERI-Rb1) in comparison with a control cell line (MIO-M1). Lipid profiles of all the cell lines were studied using high resolution mass spectrometer coupled to high performance liquid chromatography. Data acquired from all the three cell lines in positive mode were analyzed to identify differentially expressed metabolites. Several phospholipids and lysophospholipids were found to be dysregulated. We observed upregulation of hexosyl ceramides, and down regulation of dihydroceramides and higher order sphingoglycolipids hinting at a hindered sphingolipid biosynthesis. The results obtained from liquid chromatography-mass spectrometry are validated by using qPCR and it was observed that genes involved in ceramide biosynthesis pathway are getting down regulated.


Asunto(s)
Neoplasias de la Retina , Retinoblastoma , Niño , Humanos , Retinoblastoma/patología , Esfingolípidos/metabolismo , Cromatografía Líquida con Espectrometría de Masas , Ceramidas/metabolismo , Neoplasias de la Retina/genética , Neoplasias de la Retina/patología
17.
Exp Eye Res ; 247: 110040, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39134132

RESUMEN

Retinoblastoma (RB) is the most common intraocular malignancy among children and presents a certain mortality risk, especially in low- and middle-income countries. Clarifying the molecular mechanisms underlying the onset and progression of retinoblastoma is vital for devising effective cancer treatment approaches. PRMT1, a major type I PRMT, plays significant roles in cancer development. However, its expression and role in retinoblastoma are still unclear. Our research revealed a marked increase in PRMT1 levels in both retinoblastoma tissues and Y79 cells. The overexpression of PRMT1 in Y79 cells promoted their growth and cell cycle progression. Conversely, the suppression of PRMT1 hindered the growth of Y79 cells and impeded cell cycle progression. Mechanistically, PRMT1 mediated the growth of Y79 retinoblastoma cells by targeting the p53/p21/CDC2/Cyclin B pathway. Additionally, the ability of PRMT1 knockdown to suppress cell proliferation was also observed in vivo. Overall, PRMT1 could function as a potential target for therapeutic treatment in individuals with retinoblastoma.


Asunto(s)
Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Proteína-Arginina N-Metiltransferasas , Proteínas Represoras , Neoplasias de la Retina , Retinoblastoma , Proteína p53 Supresora de Tumor , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Retinoblastoma/patología , Retinoblastoma/metabolismo , Retinoblastoma/genética , Humanos , Proliferación Celular/fisiología , Neoplasias de la Retina/patología , Neoplasias de la Retina/metabolismo , Neoplasias de la Retina/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Proteína Quinasa CDC2/metabolismo , Proteína Quinasa CDC2/genética , Regulación Neoplásica de la Expresión Génica , Animales , Ratones , Western Blotting , Ciclo Celular/fisiología , Transducción de Señal/fisiología , Células Tumorales Cultivadas , Línea Celular Tumoral , Ratones Desnudos
18.
Hum Genomics ; 17(1): 82, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37658463

RESUMEN

This review presents current knowledge on the molecular biology of retinoblastoma (RB). Retinoblastoma is an intraocular tumor with hereditary and sporadic forms. 8,000 new cases of this ocular malignancy of the developing retina are diagnosed each year worldwide. The major gene responsible for retinoblastoma is RB1, and it harbors a large spectrum of pathogenic variants. Tumorigenesis begins with mutations that cause RB1 biallelic inactivation preventing the production of functional pRB proteins. Depending on the type of mutation the penetrance of RB is different. However, in small percent of tumors additional genes may be required, such as MYCN, BCOR and CREBBP. Additionally, epigenetic changes contribute to the progression of retinoblastoma as well. Besides its role in the cell cycle, pRB plays many additional roles, it regulates the nucleosome structure, participates in apoptosis, DNA replication, cellular senescence, differentiation, DNA repair and angiogenesis. Notably, pRB has an important role as a modulator of chromatin remodeling. In recent years high-throughput techniques are becoming essential for credible biomarker identification and patient management improvement. In spite of remarkable advances in retinoblastoma therapy, primarily in high-income countries, our understanding of retinoblastoma and its specific genetics still needs further clarification in order to predict the course of this disease and improve therapy. One such approach is the tumor free DNA that can be obtained from the anterior segment of the eye and be useful in diagnostics and prognostics.


Asunto(s)
Oftalmología , Neoplasias de la Retina , Retinoblastoma , Humanos , Retinoblastoma/genética , Retina , Apoptosis , Neoplasias de la Retina/genética
19.
Mol Cell Biochem ; 479(4): 1011-1022, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37273040

RESUMEN

Retinoblastoma (RB) is an intraocular malignancy that is most common in children and rare in adults. Addressing novel biomarkers and therapeutic targets for RB to modulate tumor progression has become a challenge. The aim of the present study was to investigate the function of long non-coding RNAs (LncRNAs) LOXL1-AS1 in RB cell proliferation and metastasis. It was found that LOXL1-AS1 was overexpressed in RB tissues and cells. In order to evaluate cell viability and colony formation potential, the knockdown of LOXL1-AS1 has been established. Knockdown of LOXL1-AS1 was also inhibited cells migration and invasion. In addition, the proportion of cells in the G2/M phase of the sh-LOXL1-AS1 group increased significantly, and the proportion of cells in the sh-NC group decreased significantly. In the xenograft model of RB, the tumors in the sh-LOXL1-AS1 group grow slowly compared to the sh-NC group. Western blot analysis revealed that LOXL1-AS1 can regulate the progression of RB cells through MAPK signaling pathway in vitro and in vivo. These results indicated that LncRNA LOXL1-AS1 promotes proliferation, invasion and inhibits apoptosis of retinoblastoma by regulating MAPK signaling pathway, and might be expected to be a novel basis for clinical diagnosis and treatment.


Asunto(s)
ARN Largo no Codificante , Neoplasias de la Retina , Retinoblastoma , Humanos , Aminoácido Oxidorreductasas/genética , Aminoácido Oxidorreductasas/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Retina/genética , Retinoblastoma/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal
20.
Anticancer Drugs ; 35(7): 615-622, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38742728

RESUMEN

Chemotherapy remains the main approach conserving vision during the treatment of retinoblastoma, the most prevalent eye cancer in children. Unfortunately, the development of chemoresistance stands as the primary reason for treatment failure. Within this study, we showed that prolonged exposure to vincristine led to heightened expression of JAK1 and JAK2 in retinoblastoma cells, while the other members of the JAK family exhibited no such changes. Employing a genetic intervention, we demonstrated the efficacy of depleting either JAK1 or JAK2 in countering vincristine-resistant retinoblastoma cells. In addition, the dual depletion of both JAK1 and JAK2 produced a more potent inhibitory outcome compared to the depletion of either gene alone. We further demonstrated that ruxolitinib, a small molecular inhibitor of JAK1/2, effectively reduced viability and colony formation in vincristine-resistant retinoblastoma cells. It also acts synergistically with vincristine in retinoblastoma cells regardless of inherent cellular and genetic heterogeneity. The effectiveness of ruxolitinib as standalone treatment against chemoresistant retinoblastoma, as well as its combination with vincristine, was validated in multiple retinoblastoma mouse models. Importantly, mice exhibited favorable tolerance to ruxolitinib administration. We confirmed that the underlying mechanism of ruxolitinib's action in chemoresistant retinoblastoma cells is the inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Our study reveals that the underlying mechanism driving ruxolitinib's impact on chemoresistant retinoblastoma cells is the inhibition of JAK/STAT signaling. This study reveals the contribution of JAK1/2 to the development of chemoresistance in retinoblastoma and underscores the effectiveness of targeting JAK1/2 as a strategy to sensitize retinoblastoma to chemotherapy.


Asunto(s)
Resistencia a Antineoplásicos , Janus Quinasa 1 , Nitrilos , Pirazoles , Pirimidinas , Retinoblastoma , Vincristina , Retinoblastoma/tratamiento farmacológico , Retinoblastoma/patología , Nitrilos/farmacología , Pirimidinas/farmacología , Animales , Vincristina/farmacología , Pirazoles/farmacología , Humanos , Ratones , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/patología , Sinergismo Farmacológico , Proliferación Celular/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología
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