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Changes in retinoblastoma cell adhesion associated with optic nerve invasion.

ABSTRACT: In the 1970s, several human retinoblastoma cell lines were developed from cultures of primary tumors. As the human retinoblastoma cell lines were established in culture, growth properties and changes in cell adhesion were described. Those changes correlated with the ability of the human retinoblastoma cell lines to invade the optic nerve and metastasize in orthotopic xenograft studies. However, the mechanisms that underlie these changes were not determined. We used the recently developed knockout mouse models of retinoblastoma to begin to characterize the molecular, cellular, and genetic changes associated with retinoblastoma tumor progression and optic nerve invasion. Here we report the isolation and characterization of the first mouse retinoblastoma cell lines with targeted deletions of the Rb family. Our detailed analysis of these cells as they were propagated in culture from the primary tumor shows that changes in cadherin-mediated cell adhesion are associated with retinoblastoma invasion of the optic nerve prior to metastasis. In addition, the same changes in cadherin-mediated cell adhesion correlate with the invasive properties of the human retinoblastoma cell lines isolated decades ago, providing a molecular mechanism for these earlier observations. Most importantly, our studies are in agreement with genetic studies on human retinoblastomas, suggesting that changes in this pathway are involved in tumor progression.

SUBMITTER: Laurie N

PROVIDER: S-EPMC2786692 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Changes in retinoblastoma cell adhesion associated with optic nerve invasion.

Laurie Nikia N Mohan Adithi A McEvoy Justina J Reed Damon D Zhang Jiakun J Schweers Brett B Ajioka Itsuki I Valentine Virginia V Johnson Dianna D Ellison David D Dyer Michael A MA

Molecular and cellular biology 20090928 23

In the 1970s, several human retinoblastoma cell lines were developed from cultures of primary tumors. As the human retinoblastoma cell lines were established in culture, growth properties and changes in cell adhesion were described. Those changes correlated with the ability of the human retinoblastoma cell lines to invade the optic nerve and metastasize in orthotopic xenograft studies. However, the mechanisms that underlie these changes were not determined. We used the recently developed knockou ...[more]

PMID: 19786571

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Project description:ObjectivesAs described recently, intravenously injected gadolinium-based contrast agent (GBCA) penetrates into the anterior eye chamber (AC) and is drained from the retina to the distal optic nerve (ON) along perivascular spaces, which serves retinal homeostasis and was termed the orbital glymphatic system (GS). Independently, AC enhancement predicted ON infiltration, a major risk factor for advanced retinoblastoma (RB), in a small RB patient cohort. We aimed to review the supposed imaging biomarker for ON infiltration in a large RB cohort and with respect to the recently described orbital GS.MethodsThis IRB-approved retrospective single-center study encompassed 539 orbital MRIs performed with an orbital coil and with the children under general anesthesia. Differences of signal intensity ratios (∆SIRs) of the AC to the lens were determined between non-contrast and GBCA-enhanced T1-weighted images and were correlated with histopathologic presence of ON infiltration.Results∆SIR of the RB eye was an independent, significant predictor for ON invasion in multivariate analysis with adjustment for tumor size (p < 0.05) and increased with infiltration level.ConclusionsGBCA enhancement of the AC predicts ON infiltration. This might be caused by impairment of the orbital glymphatic system, which is supposed to clear toxic metabolites from the retina to the postlaminar ON. In RB with ON infiltration, this efflux path is likely to be inhibited, which is supposed to result in disturbed retinal homeostasis, release of vascular endothelial growth factor, and iris neovascularization, which increases penetration of GBCA into the AC.Key points• Infiltration of the optic nerve can be predicted by anterior chamber enhancement after intravenous MRI contrast agent administration. • Increased anterior chamber enhancement in retinoblastoma with optic nerve infiltration might result from dysfunction of the orbital glymphatic system with disturbance of retinal homeostasis and consecutive iris neovascularization.

Project description:BackgroundPrognosis for pediatric metastatic Retinoblastoma (Rb) is poor and current therapies are limited by high systemic toxicity rates and insufficient therapeutic efficacy for metastatic Rb. Tumor dissemination to the brain is promoted by the heterogeneous adhesive and invasive properties of Rb cells within the tumor. In this study we evaluate, for the first time, the expression, and roles of the ELTD1 and GPR125 adhesion G protein-coupled receptors (GPCRs) in Rb cell migration, viability and invasion.MethodsWe characterized the RNA expression of adhesion-GPCRs in 64 Rb tumors compared to 11 fetal retinas using the database from the Childhood Solid Tumor Network from St Jude Children's Research Hospital. The role of ELTD1 and GPR125 in Rb were investigated ex vivo by microarray analysis, in vitro by cell viability, Western blot and migration assays, in addition to imaging of the subcellular localization of the GPCRs. To elucidate their role in vivo we utilized siRNA technology in an established Rb orthotopic xenograft murine model.ResultsOur investigation demonstrates, for the first time, that ELTD1 but not GPR125, is significantly increased in Rb tumors compared to fetal retinas. We utilized established the Rb cell lines Y79 and Weri-Rb-1, which represent an aggressive, metastatic, and non-metastatic phenotype, respectively, for the in vitro analyses. The studies demonstrated that ELTD1 is enriched in Weri-Rb-1 cells, while GPR125 is enriched in Y79 cells. The measured differences extended to their subcellular localization as ELTD1 labeling displayed punctate clusters in cell-to-cell adhesion sites of Weri-Rb-1 cells, while GPR125 displayed a polarized distribution in Y79 cells. Lastly, we demonstrated the lack of both adhesion receptors does not affect Rb cell viability, yet inhibition of ELTD1 decreases Y79 cell migration in vitro and invasion in vivo.ConclusionTaken together, our data suggest that ELTD1, is a potential target to prevent extraocular Rb. The results within establish ELTD1 as a potential therapeutic target for metastatic Rb.

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Changes in retinoblastoma cell adhesion associated with optic nerve invasion.

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Changes in retinoblastoma cell adhesion associated with optic nerve invasion.

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