Modeling of Human Uveal Melanoma in Zebrafish Xenograft Embryos

Ent, Wietske van der; Burrello, Claudia; Teunisse, Amina F.A.S.; Ksander, Bruce R.; Velden, Pieter A. van der; Jager, Martine J.; Jochemsen, Aart G.; Snaar-Jagalska, B. Ewa

doi:10.1167/iovs.14-15202

Cited by 77 publications

(66 citation statements)

References 42 publications

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“…Human xenograft models of UM have been established in immune-deficient mice [363] and rats [364], rabbits [365], and zebrafish [366]. Established primary uveal melanoma cell lines have been injected into the anterior or posterior chamber and into the ciliary body or choroid.…”

Section: Animal Modelsmentioning

confidence: 99%

The biology of uveal melanoma

Amaro

Gangemi

Piaggio

et al. 2017

Cancer Metastasis Rev

186

193

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Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.

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Section: Animal Modelsmentioning

confidence: 99%

The biology of uveal melanoma

Amaro

Gangemi

Piaggio

et al. 2017

Cancer Metastasis Rev

186

193

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“…Migration of metastatic melanoma cells harvested from lymph nodes (MeWo cells) was decreased by dasatinib-mediated inhibition of homeobox C11 (HOXC11) protein interactions with Src [136]. Dasatinib treatment of uveal melanoma cells injected into zebrafish models has also demonstrated potent anti-migratory effects [137]. Mice inoculated with B16-ovalbumin overexpressing (B16-OVA) cells showed decreased extrapulmonary metastases when treated with high doses of dasatanib, but lung metastases were not inhibited [138].…”

Section: Effects Of Small Molecule Inhibitors On Emt In Melanomamentioning

confidence: 99%

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

et al. 2017

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Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others. Downstream effectors of these pathways induce expression of EMT transcription factors including Snail, Slug, Twist, and Zeb that promote repression of epithelial and induction of mesenchymal character. Emerging research has demonstrated that a variety of small molecule inhibitors as well as phytochemicals can influence the progression of EMT and may even reverse the process, inducing re-expression of epithelial markers. Phytochemicals are of particular interest as supplementary treatment options because of their relatively low toxicities and anti-EMT properties. Modulation of EMT signaling pathways using synthetic small molecules and phytochemicals is a potential therapeutic strategy for reducing the aggressive progression of metastatic melanoma. In this review, we discuss the emerging pathways and transcription factor targets that regulate EMT and evaluate potential synthetic small molecules and naturally occurring compounds that may reduce metastatic melanoma progression.

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“…For an optimal visualization, the transgenic zebrafish line Tg(fli1:EGFP) expressing a green fluorescent vasculature was used [22] . One of the models used yolk sac implantation and has recently been described extensively [17] . The technique is as follows: before implantation, eggs were kept at 28 ° C and manually dechorionated at 1 day post-fertilization (dpf).…”

Section: Setting Up a Um Model In Zebrafishmentioning

confidence: 99%

“…We used the yolk sac model to determine the effect of drugs on migration and proliferation [17] . We tested the effect of crizotinib, a multitarget tyrosine kinase inhibitor, to evaluate c-Met inhibition.…”

Section: Effect Of Crizotinib On Um Xenograftsmentioning

confidence: 99%

“…We have recently reported that the zebrafish UM model that we developed can be used efficiently to test the efficiency of new anti-UM drugs [17] . However, one can inject tumor cells into zebrafish through several routes, which may lead to different types of tumor growth; those different phenotypes will be discussed in the following section.…”

Section: Introductionmentioning

confidence: 99%

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Embryonic Zebrafish: Different Phenotypes after Injection of Human Uveal Melanoma Cells

et al. 2015

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Although murine xenograft models for human uveal melanoma (UM) are available, they are of limited utility for screening large compound libraries for the discovery of new drugs. We need new preclinical models which can efficiently evaluate drugs that can treat UM metastases. The zebrafish embryonic model is ideal for drug screening purposes because it allows the investigation of potential antitumor properties of drugs within 1 week. The optical transparency of the zebrafish provides unique possibilities for live imaging of fluorescence-labelled cancer cells and their behavior. In addition, the adaptive immune response, which is responsible for the rejection of transplanted material, is not yet present in the early stages of fish development, and systemic immunosuppression is therefore not required to allow growth of tumor cells. We studied the behavior of UM cells following injection into zebrafish embryos and observed different phenotypes. We also analyzed cell migration, proliferation, formation of micrometastasis and interaction with the host microenvironment. Significant differences were noted between cell lines: cells derived from metastases showed more migration and proliferation than cells derived from the primary tumors. The addition of the c-Met inhibitor crizotinib to the water in which the larvae were kept reduced the migration and proliferation of UM cells expressing c-Met. This indicates the applicability of the zebrafish xenografts for testing novel inhibitory compounds and provides a fast and sensitive in vivo vertebrate model for preclinical drug screening to combat UM.

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Modeling of Human Uveal Melanoma in Zebrafish Xenograft Embryos

Abstract: We established a zebrafish xenograft model of human uveal melanoma with demonstrated applicability for screening large libraries of compounds in drug discovery studies.

Cited by 77 publications

References 42 publications

The biology of uveal melanoma

The biology of uveal melanoma

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

Embryonic Zebrafish: Different Phenotypes after Injection of Human Uveal Melanoma Cells

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