Downregulation of Nodal inhibits metastatic progression in retinoblastoma

Asnaghi, Laura; White, David T.; Yoon, Lynn; Price, Antoinette; Lee, Grace Y.; Sahoo, Arpan; Mumm, Jeff S.; Eberhart, Charles G.

doi:10.1186/s40478-019-0785-4

Cited by 8 publications

(4 citation statements)

References 34 publications

(50 reference statements)

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“…In 2019, Asnaghi et al published two articles [ 26 , 27 ], in which they analyzed the function of ACVR1C/ALK7, a type I receptor of the TGF-ß family and its ligands Nodal, Activin A/B and GDF3. They found a three-fold increase of the receptor ACVR1C in invasive retinoblastomas, which invaded the optic nerve compared to non-invasive tumors [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Downregulation of Nodal also showed a reduction in the epithelial-to-mesenchymal transition (EMT) markers ZEB1 and snail and a reduction in migration of cells in the transwell invasion assay. Further, they showed a 34% reduction in the so- called minimum bonding sphere (MBS) at 4 dpi, which represented the migration of Y79 cells injected in the zebrafish eye [ 27 ]. Both articles from Asnaghi et al analyzed the pathways that are involved in cell migration of Y79 and WERI-RB-1 cells and retinoblastoma tumors that migrate along the optic nerve in humans, but they do not show the migration route in the injected zebrafish either.…”

Section: Discussionmentioning

confidence: 99%

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Zebrafish as an Orthotopic Tumor Model for Retinoblastoma Mimicking Routes of Human Metastasis

Maricic

Schwermer

Schramm

et al. 2022

Cancers

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Background: Retinoblastoma (RB) is the most common eye cancer in children that has a high mortality rate when left untreated. Mouse models for retinoblastoma have been established but are time- and cost-intensive. The aim of this work was to evaluate an orthotopic transplantation model of retinoblastoma in zebrafish that also allows for tracking migratory routes and to explore advantages and disadvantages with respect to drug testing. Methods: Three fluorescence-labeled retinoblastoma cell lines (RB355, WERI-RB-1, Y79) were injected into the left eye of two-day-old zebrafish, while the un-injected right eye served as control. The migratory trajectories of injected retinoblastoma cells were observed until 8 days post injection (dpi), both in lateral and dorsal view, and measuring fluorescence intensity of injected cells was done for RB355 cells. Results: Time until the onset of migration and routes for all three retinoblastoma cell lines were comparable and resulted in migration into the brain and ventricles of the forebrain, midbrain and hindbrain. Involvement of the optic nerve was observed in 10% of injections with the RB355 cell line, 15% with Y79 cells and 5% with WERI-RB-1 cells. Fluorescence intensity of injected RB355 cells showed an initial increase until five dpi, but then decreased with high variability until the end of observation. Conclusion: The zebrafish eye is well suited for the analysis of migratory routes in retinoblastoma and closely mirrors patterns of retinoblastoma metastases in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Zebrafish as an Orthotopic Tumor Model for Retinoblastoma Mimicking Routes of Human Metastasis

Maricic

Schwermer

Schramm

et al. 2022

Cancers

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show abstract

“…In the most recent studies, the authors injected retinoblastoma cells intravitreally and observed how the cancer cells were able to disseminate outside the eye, and how spread was reduced when fish were treated with different inhibitors to block transcriptional pathways, potentially related to the development of the disease. These results may have translational value, opening the door to the discovery of new therapies for retinoblastoma [ 138 , 139 ]. Additionally, a novel orthotopic xenograft model for conjunctival melanoma has been recently established by retro-orbital injection, to mimic primary tumor spread and to test the possible repurposing of the anti-tumor ruthenium-based photosensitizer TLD1433 for retinoblastoma [ 124 ].…”

Section: Microenvironmentmentioning

confidence: 99%

Modeling Cancer Using Zebrafish Xenografts: Drawbacks for Mimicking the Human Microenvironment

Cabezas-Sáinz

Pensado‐López

Sáinz

et al. 2020

Cells

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The first steps towards establishing xenografts in zebrafish embryos were performed by Lee et al., 2005 and Haldi et al., 2006, paving the way for studying human cancers using this animal species. Since then, the xenograft technique has been improved in different ways, ranging from optimizing the best temperature for xenografted embryo incubation, testing different sites for injection of human tumor cells, and even developing tools to study how the host interacts with the injected cells. Nonetheless, a standard protocol for performing xenografts has not been adopted across laboratories, and further research on the temperature, microenvironment of the tumor or the cell–host interactions inside of the embryo during xenografting is still needed. As a consequence, current non-uniform conditions could be affecting experimental results in terms of cell proliferation, invasion, or metastasis; or even overestimating the effects of some chemotherapeutic drugs on xenografted cells. In this review, we highlight and raise awareness regarding the different aspects of xenografting that need to be improved in order to mimic, in a more efficient way, the human tumor microenvironment, resulting in more robust and accurate in vivo results.

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“…This form of cancer accounts for ∼3% of the pediatric cancer population. [ 1 ] Its progression is activated due to the mutation in the Rb gene, responsible for the transcription tumor suppressor Rb protein. [ 2 ] Rb tumors occur either as endophytic or exophytic tumors.…”

Section: Introductionmentioning

confidence: 99%

In vitro triple culture model of retinoblastoma for pre‐clinical investigations

Jahagirdar

Jain

Dandekar

2023

Biotechnology Journal

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Background: Retinoblastoma (Rb) is a rare cancer of the retina that occurs during early childhood. The disease is relatively rare but aggressive, accounting for ∼3% of childhood cancers. Treatment modalities encompass the administration of large doses of chemotherapeutic drugs, which result in multiple side-effects. Therefore, it is essential to have safe and effective newer therapies and suitable physiologically relevant, alternative-to-animal, in vitro cell culture-based models to enable rapid and efficient evaluation of potential therapies. Methodology:This investigation was focused on the development of a triple co-culture model comprising Rb, retinal epithelium, and choroid endothelial cells, using a protein coating cocktail, to recapitulate this ocular cancer under in vitro conditions. This resulting model was used for screening drug toxicity, based on the growth profile of Rb cells, using carboplatin as the model drug. Further, a combination of bevacizumab and carboplatin was evaluated using the developed model, to lower the concentration of carboplatin and thereby reduce its physiological side-effects. Major Results:The effect of drug treatment on the triple co-culture was assessed by increase in the apoptotic profile of Rb cells. Further, the barrier properties were found to be lower with a decrease in the angiogenetic signals that included expression of vimentin. Measurement of cytokine levels signified reduced inflammatory signals due to the combinatorial drug treatment. Conclusions:These findings validated that the triple co-culture Rb model was suitable for evaluating anti-Rb therapeutics and could thereby decrease the immense load on animal trials, which are the primary screens employed for evaluating retinal therapies. K E Y W O R D Sdisease model, pre-clinical drug testing, retinal cells, retinoblastoma, triple culture INTRODUCTIONRetinoblastoma (Rb) is a type of ocular cancer that is particularly prevalent in children up to 5 years of age. This form of cancer accounts for ∼3% of the pediatric cancer population. [1] Its progression is activated due to the mutation in the Rb gene, responsible for the transcription tumor suppressor Rb protein. [2] Rb tumors occur either as endophytic or exophytic tumors. Endophytic tumors arise in the inner retinal layer, whereas exophytic tumors develop in the outer retinal layer further extending the sub-retinal space beneath the retina. [3] The currently available treatment options for Rb can be classified as (1) focal therapy including cryotherapy, conventional laser photocoagulation, transpupillary thermotherapy, photodynamic therapy (in vitro study), and plaque radiotherapy; (2) external beam radiotherapy;(3) systemic chemotherapy; and (4) enucleation. Proper management of Rb, by tumor reduction, excision, and curbing the side effects of

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Downregulation of Nodal inhibits metastatic progression in retinoblastoma

Cited by 8 publications

References 34 publications

Zebrafish as an Orthotopic Tumor Model for Retinoblastoma Mimicking Routes of Human Metastasis

Zebrafish as an Orthotopic Tumor Model for Retinoblastoma Mimicking Routes of Human Metastasis

Modeling Cancer Using Zebrafish Xenografts: Drawbacks for Mimicking the Human Microenvironment

In vitro triple culture model of retinoblastoma for pre‐clinical investigations

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