Special Issue "Zebrafish: The Key for Cancer Treatment"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Clinical Genomics in Genetic Diseases and Cancer".

Deadline for manuscript submissions: closed (31 August 2017)

Special Issue Editor

Guest Editor
Prof. Laura Sánchez

Department of Genetics, University of Santiago de Compostela, Campus de Lugo, Avda/ Carvallo Calero s/n, CP - 27002 Lugo, SPAIN
Website | E-Mail
Phone: +34 982 822 428

Special Issue Information

Dear Colleagues,

Zebrafish has been used since the early 1970s in Oregon as a model organism for vertebrate development and gene function. Over the past few years, zebrafish has emerged as a cancer model that complements the murine system. This model was discovered in cancer research with cancer currently being the second cause of death worldwide. It has been increasingly used in subsequent years due to the exponential growth of cancer, especially in developed countries. By virtue of its experimental swiftness, low cost maintenance and high-throughput advantages against the murine model, the zebrafish has had a high impact on research.

Covering areas ranging from biochemistry or genetics, to toxicology or xenotransplantation, zebrafish is a useful tool to discover some of the most important underlying mechanisms of cancer proliferation, migration and metastasis. Using this small fish, researchers from all over the world are able to gather information in a very efficient way to fight against this heterogeneous disease.

In this Special Issue, we would like to invite submissions of original research or review articles on any topic related to “Zebrafish: The Key for Cancer Treatment”. We thereby hope to gather knowledge to find critical steps for cancer treatment using this model organism. We look forward to receiving your contributions.

Dr. Laura Sánchez
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • zebrafish
  • cancer
  • model organism
  • xenograft
  • screening
  • high throughput

Published Papers (5 papers)

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Research

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Open AccessArticle The Plasticizer Bisphenol A Perturbs the Hepatic Epigenome: A Systems Level Analysis of the miRNome
Genes 2017, 8(10), 269; doi:10.3390/genes8100269
Received: 31 July 2017 / Revised: 18 September 2017 / Accepted: 4 October 2017 / Published: 13 October 2017
PDF Full-text (5415 KB) | Supplementary Files
Abstract
Ubiquitous exposure to bisphenol A (BPA), an endocrine disruptor (ED), has raised concerns for both human and ecosystem health. Epigenetic factors, including microRNAs (miRNAs), are key regulators of gene expression during cancer. The effect of BPA exposure on the zebrafish epigenome remains poorly
[...] Read more.
Ubiquitous exposure to bisphenol A (BPA), an endocrine disruptor (ED), has raised concerns for both human and ecosystem health. Epigenetic factors, including microRNAs (miRNAs), are key regulators of gene expression during cancer. The effect of BPA exposure on the zebrafish epigenome remains poorly characterized. Zebrafish represents an excellent model to study cancer as the organism develops a disease that resembles human cancer. Using zebrafish as a systems toxicology model, we hypothesized that chronic BPA-exposure impacts the miRNome in adult zebrafish and establishes an epigenome more susceptible to cancer development. After a 3 week exposure to 100 nM BPA, RNA from the liver was extracted to perform high throughput mRNA and miRNA sequencing. Differential expression (DE) analyses comparing BPA-exposed to control specimens were performed using established bioinformatics pipelines. In the BPA-exposed liver, 6188 mRNAs and 15 miRNAs were differently expressed (q ≤ 0.1). By analyzing human orthologs of the DE zebrafish genes, signatures associated with non-alcoholic fatty liver disease (NAFLD), oxidative phosphorylation, mitochondrial dysfunction and cell cycle were uncovered. Chronic exposure to BPA has a significant impact on the liver miRNome and transcriptome in adult zebrafish with the potential to cause adverse health outcomes including cancer. Full article
(This article belongs to the Special Issue Zebrafish: The Key for Cancer Treatment)
Open AccessArticle RECQ1 Helicase Silencing Decreases the Tumour Growth Rate of U87 Glioblastoma Cell Xenografts in Zebrafish Embryos
Genes 2017, 8(9), 222; doi:10.3390/genes8090222
Received: 14 July 2017 / Revised: 18 August 2017 / Accepted: 5 September 2017 / Published: 6 September 2017
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Abstract
RECQ1 helicase has multiple roles in DNA replication, including restoration of the replication fork and DNA repair, and plays an important role in tumour progression. Its expression is highly elevated in glioblastoma as compared to healthy brain tissue. We studied the effects of
[...] Read more.
RECQ1 helicase has multiple roles in DNA replication, including restoration of the replication fork and DNA repair, and plays an important role in tumour progression. Its expression is highly elevated in glioblastoma as compared to healthy brain tissue. We studied the effects of small hairpin RNA (shRNA)-induced silencing of RECQ1 helicase on the increase in cell number and the invasion of U87 glioblastoma cells. RECQ1 silencing reduced the rate of increase in the number of U87 cells by 30%. This corresponded with a 40% reduction of the percentage of cells in the G2 phase of the cell cycle, and an accumulation of cells in the G1 phase. These effects were confirmed in vivo, in the brain of zebrafish (Danio rerio) embryos, by implanting DsRed-labelled RECQ1 helicase-silenced and control U87 cells. The growth of resulting tumours was quantified by monitoring the increase in xenograft fluorescence intensity during a three-day period with fluorescence microscopy. The reduced rate of tumour growth, by approximately 30% in RECQ1 helicase-silenced cells, was in line with in vitro measurements of the increase in cell number upon RECQ1 helicase silencing. However, RECQ1 helicase silencing did not affect invasive behaviour of U87 cells in the zebrafish brain. This is the first in vivo confirmation that RECQ1 helicase is a promising molecular target in the treatment of glioblastoma. Full article
(This article belongs to the Special Issue Zebrafish: The Key for Cancer Treatment)
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Review

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Open AccessReview Zebrafish in Translational Cancer Research: Insight into Leukemia, Melanoma, Glioma and Endocrine Tumor Biology
Genes 2017, 8(9), 236; doi:10.3390/genes8090236
Received: 14 August 2017 / Revised: 8 September 2017 / Accepted: 14 September 2017 / Published: 20 September 2017
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Abstract
Over the past 15 years, zebrafish have emerged as a powerful tool for studying human cancers. Transgenic techniques have been employed to model different types of tumors, including leukemia, melanoma, glioblastoma and endocrine tumors. These models present histopathological and molecular conservation with their
[...] Read more.
Over the past 15 years, zebrafish have emerged as a powerful tool for studying human cancers. Transgenic techniques have been employed to model different types of tumors, including leukemia, melanoma, glioblastoma and endocrine tumors. These models present histopathological and molecular conservation with their human cancer counterparts and have been fundamental for understanding mechanisms of tumor initiation and progression. Moreover, xenotransplantation of human cancer cells in embryos or adult zebrafish offers the advantage of studying the behavior of human cancer cells in a live organism. Chemical-genetic screens using zebrafish embryos have uncovered novel druggable pathways and new therapeutic strategies, some of which are now tested in clinical trials. In this review, we will report on recent advances in using zebrafish as a model in cancer studies—with specific focus on four cancer types—where zebrafish has contributed to novel discoveries or approaches to novel therapies. Full article
(This article belongs to the Special Issue Zebrafish: The Key for Cancer Treatment)
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Open AccessReview Emerging Estrogenic Pollutants in the Aquatic Environment and Breast Cancer
Genes 2017, 8(9), 229; doi:10.3390/genes8090229
Received: 19 July 2017 / Revised: 7 September 2017 / Accepted: 8 September 2017 / Published: 15 September 2017
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Abstract
The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways.
[...] Read more.
The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen-like compounds. Estrogen receptors alpha (ERα) and beta (ERβ) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERα-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen-like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens. Full article
(This article belongs to the Special Issue Zebrafish: The Key for Cancer Treatment)
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Open AccessReview Zebrafish Xenograft: An Evolutionary Experiment in Tumour Biology
Genes 2017, 8(9), 220; doi:10.3390/genes8090220
Received: 2 August 2017 / Revised: 27 August 2017 / Accepted: 29 August 2017 / Published: 5 September 2017
PDF Full-text (767 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Though the cancer research community has used mouse xenografts for decades more than zebrafish xenografts, zebrafish have much to offer: they are cheap, easy to work with, and the embryonic model is relatively easy to use in high-throughput assays. Zebrafish can be imaged
[...] Read more.
Though the cancer research community has used mouse xenografts for decades more than zebrafish xenografts, zebrafish have much to offer: they are cheap, easy to work with, and the embryonic model is relatively easy to use in high-throughput assays. Zebrafish can be imaged live, allowing us to observe cellular and molecular processes in vivo in real time. Opponents dismiss the zebrafish model due to the evolutionary distance between zebrafish and humans, as compared to mice, but proponents argue for the zebrafish xenograft’s superiority to cell culture systems and its advantages in imaging. This review places the zebrafish xenograft in the context of current views on cancer and gives an overview of how several aspects of this evolutionary disease can be addressed in the zebrafish model. Zebrafish are missing homologs of some human proteins and (of particular interest) several members of the matrix metalloproteinase (MMP) family of proteases, which are known for their importance in tumour biology. This review draws attention to the implicit evolutionary experiment taking place when the molecular ecology of the xenograft host is significantly different than that of the donor. Full article
(This article belongs to the Special Issue Zebrafish: The Key for Cancer Treatment)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Working Title: A versatile transgenic zebrafish recapitulates genetic, proteomic and histological features of Ewing sarcoma: New model for drug discovery.
Putative Authors: Wietske van der Ent1,2, Dana Ohana3 Peter J. Schoonheim1, Karoly Szuhai3, Herman P. Spaink1, Pancras C.W. Hogendoorn2, Magnus Palmblad3 , B. Ewa Snaar-Jagalska1*
Affiliations: 1Institute of Biology, Leiden University, Leiden, The Netherlands , 2Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands, 3Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
Abstract: Ewing sarcoma, a highly malignant bone and soft-tissue tumour, is characterized by a translocation between EWSR1 and a member of the ETS family, most commonly FLI1 or ERG. Despite knowledge of this key feature of Ewing sarcoma, so far no transgenic mouse models have been established that can accurately recapitulate this disease, as all attempts have led to embryonic death. The exact cell of origin for Ewing sarcoma is unknown, which confounds determination of a promoter suitable to drive EWSR1-ETS expression. Here, we have generated a zebrafish transgenic model for Ewing sarcoma where expression of GFP-tagged EWSR1-ERG protein is driven by a Gal4-responsive UAS promoter. By crossing Tg(14xUAS:GFP-EWSR1-ERG) fish with various transgenic driver lines expressing Gal4 via specific tissue-specific promoters, we observed that neuronal cells are more permissive of EWSR1-ERG expression than cells in the notochord or muscles of the fish. Histology shows that these transgenic cells have round nuclei and scant cytoplasm, bearing a resemblance to cell features of human EWS tumour biopsies. Using next generation sequencing and comparative LC-MS/MS  proteomics analysis on embryos with neuronally expressed EWSR1-ERG, we show regulation of various pathways known to be transcriptionally regulated in EWS, such as the downregulation of the Notch pathways, as well as other pathways which may be of interest. The zebrafish Tg(14xUAS:GFP-EWSR1-ERG) line provides a flexible method to investigate the effects of EWSR1-ERG expression in different background tissues and is a promising tool to study processes involved in Ewing sarcoma development and testing potential treatments.

Working Title: Finding novel cancer therapies using zebrafish.
Putative Authors: Aurora Idilli, Francesca Precazzini, Marina Mione and Viviana Anelli
Affiliations: Laboratory of Experimental Cancer Biology, Cibio, University of Trento, Via Sommarive 9, Trento, Italy
Abstract: Over the past 15 years, zebrafish has emerged as a powerful tool for studying human cancers. Transgenic techniques have been employed to model leukemia, rhabdomyosarcoma, melanoma and glioblastoma. These models present histopathological and molecular conservation with their human cancer counterparts and have been fundamental for understanding mechanisms of tumor initiation and progression. Moreover, xenotrasplantations of human cancer cells in embryos, juvenile or adults zebrafish offer the advantage of studying the behavior of human cancer cells in a live organism. Chemical-genetic screens using zebrafish embryos have uncovered novel drug pathways and new therapeutic strategies, some of which are now tested in clinical trials. 

Working Title: Emerging estrogenic pollutants in the aquatic environment and breast cancer.
Putative Authors: Sylvain Lecomte, Denis Habauzit, Farzad Pakdel*
Affiliations: Research Institute in Health, Environment and Occupation (Irset), Inserm U1085, Team TREC-Transcription, Environment and Cancer, University of Rennes 1, France
*Corresponding Author: Farzad PAKDEL (farzad.pakdel@univ-rennes1.fr)
Abstract: Over the past five decades, the number of industrial chemicals in the aquatic environment has considerably increased. Among these contaminants, endocrine disrupting chemicals (EDCs) represent a significant part. These kind of compounds interfere with normal hormonal processes through multiple molecular pathways. They represent therefore a potential risk for human and wildlife as they are suspected to be involved in the development of diseases such as reprotoxicity, metabolic disorders and cancers. Indeed, several studies have suggested that the increase of breast cancer in industrialized country are linked to EDCs, particularly estrogen-like compounds. In cell, estrogen receptors (ERs, ERalpha and ERbeta) are the main targets of these compounds. More than 70% of breast cancer cells express ERalpha and their growth is influenced by estrogenic compounds. It is therefore important to characterize the estrogenic potential in surface water and to identify the molecules responsible for the hormonal effect. This would give us the possibility to prevent their effects on the breast tissue. The aim of this review is to make an overview of the emerging environmental estrogen-like compounds in the environment, to sum up the studies that evidence their direct or indirect interactions with ERs and their potential involvement in breast cancer development. Finally, we also summarize the use of in vitro and in vivo methods and models such as zebrafish, in the identification and characterization of environmental estrogens.

Working Title: The zebrafish as a model for skin cancer: a new tool for drug development.
Putative Authors: Carlo Pincelli, Annalisa Saltari and Elisabetta Palazzo
Affiliations: School of Medicine, University of Modena and Reggio Emilia, Modena, Italy
Abstract: Danio rerio, commonly known as zebrafish, is considered a promising model for the study of the mechanisms underlying tumor development, treatment efficacy and drug resistance. Given the advantages in terms of low costs, high genetic homology to humans, easy handling and transparent body for live imaging, the zebrafish has been employed to study and reproduce a broad spectrum of human tumours, including melanoma and squamous cell carcinoma (SCC). The zebrafish models for cutaneous neoplasia have been generated with different strategies including injection of cancer cells, tumour induction through chemical carcinogens and genetic manipulation. Exciting data have been recently published in melanoma by using the innovative genome-engineering Crispr/Cas9 (clustered regularly interspaced short palindromic repeats) and TALENs (transcription activator-like effectors) technologies. In the last decades, the acquisition of new genetic and transcriptomic data has led to the identification of potential targets for the treatment of skin cancer prompting the need of in vivo models for toxicological tests on large scale. To this purpose, given its higher fecundity in comparison to mouse models, the zebrafish represents an ideal tool for high-throughput drug screening. The present review focuses on the applications of zebrafish for the study of melanoma and SCC and summarizes the main findings on skin cancer initiation, relapse and drug resistance. Moreover, it highlights the progress and future perspectives for its employment as an innovative platform for the screening of small molecules and compounds.

Working Title: Cross talk between TP53 and c-MYC in the pathophysiology of Diamond-Blackfan anemia: Evidence from RPL11-deficient in vivo and in vitro models.  
Putative Authors: Anirban Chakraborty1*, Tamayo Uechi2, Yukari Nakajima2, Hanna T. Gazda 3,4, Pierre-Emmanuel Gleizes5,6 and Naoya Kenmochi2*
Affiliations: 1Department of Biomedical Sciences, NU Centre for Science Education & Research, Nitte University, Mangalore-18, India
2Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan
3Division of Genetics and Program in Genomics, The Manton Center for Orphan Diseases Research, Children’s Hospital Boston, Boston, Massachusetts
4Harvard Medical School, Boston, Massachusetts 
5Laboratoire de Biologie Moléculaire Eucaryote, Université de Toulouse, UPS, F-31000 Toulouse, France
6CNRS, UMR 5099, F-31000 Toulouse, France
* Corresponding author
Abstract: The synthesis of ribosomes is a major metabolic activity in cells. Mutations in genes encoding ribosomal proteins have been identified in Diamond Blackfan anaemia; DBA, a rare genetic disorder that presents with a prominent phenotype involving the erythroid component of the hematopoietic lineage. Impaired ribosome biogenesis causes nucleolar stress that triggers a TP53-signaling pathway, which plays an important role in the pathophysiology of DBA. Several ribosomal proteins, particularly RPL11, take part in mediating this TP53 response.  However, RPL11 is one of the mutated RPs in DBA and previously, we showed that Rpl11 deficiency in zebrafish activates the Tp53 pathway. Interestingly, RPL11 also controls the transcriptional activity of c-MYC, an oncoprotein that positively regulates ribosome biogenesis. In this study, we explored the role of c-Myc in cellular and animal models to gain further insights into the mechanisms of Tp53 induction in response to RPL11 deficiency. c-Myc and several c-Myc target nucleolar proteins, including those that bind to MDM2 or modify p53, showed upregulation and increased localization in the head region of Rpl11-deficient zebrafish, where the morphological abnormalities and tp53 expression were more pronounced. Rpl11-deficient zebrafish also exhibited defects in ribosome biogenesis. However, co-inhibition of Tp53 did not alleviate the erythroid aplasia in these fish. Interestingly, in cells derived from peripheral blood of RPL11 mutated DBA patients, the ribosome biogenesis was defective but the expression level of c-Myc and its target nucleolar proteins was unchanged. The results of this study suggest a model in which increased synthesis of c-Myc target nucleolar proteins triggers a p53 response in RPL11 deficiency. Our results further demonstrate that this induction of Tp53 mediates only the morphological, but not the erythroid defects, associated with RPL11 deficiency.

Working Title: RecQ1 helicase silencing slows proliferation of U87 glioblastoma cells in the zebrafish embryonic brain.
Putative Authors: Katja Hrovat1, Miloš Vittori2, Tamara Lah Turnšek1
Affiliations: National Institute of Biology, Ljubljana, Slovenia
Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
Abstract: In this study, the proliferation of U87 cells in which the expression of RecQ1 helicase has been experimentally reduced is compared to the proliferation of sham-transfected U87 cells. In vitro measurments of cell proliferation are compared with in vivo measurments in the brain and yolk sac of zebrafish embryos during a three-day period. Decreased proliferation was observed in vitro as well as in the zebrafish brain, whereas U87 cells do not readily proliferate in the yolk sac, resulting in no visible effect of RecQ1 depletion. This is the first in vivo confirmation of RecQ1 as a potential therapeutic target in the treatment of glioblastoma.

Working Title: Co-implantation with glioblastoma stem-like cells influences the invasion of U87 glioblastoma cells in zebrafish embryos.
Putative Authors: Miloš Vittori1, Barbara Breznik2, Tamara Lah Turnšek2
Affiliations: Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia 
National Institute of Biology, Ljubljana, Slovenia 
Abstract: We assessed the proliferation and invasion of U87 cells and the CD133+ glioblastoma stem-like cell line NCH421k in the brain of zebrafish embryos. Our results demonstrate that the co-implantation of both cell types strongly affects the invasion of U87 cells, quantified by measurements of relative cell dispersion and the frequency of invading cells, whereas it does not affect the invasion of NCH421k cells. The two cell lines are inhomogeneously distributed in the tumours, with each cell type occupying a well defined region of the tumour. These results are compared with the behaviour of U87 cells when co-implanted with mesenchymal stem cells.

 

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