Zebrafish Xenografts for Drug Discovery and Personalized Medicine

Abstract

Cancer is the second leading cause of death in the world. Given that cancer is a highly individualized disease, predicting the best chemotherapeutic treatment for individual patients can be difficult. Ex vivo models such as mouse patientderived xenografts (PDX) and organoids are being developed to predict patient-specific chemosensitivity profiles before treatment in the clinic. Although promising, these models have significant disadvantages including long growth times that introduce genetic and epigenetic changes to the tumor. The zebrafish xenograft assay is ideal for personalized medicine. Imaging of the small, transparent fry is unparalleled among vertebrate organisms. In addition, the speed (5-7 days) and small patient tissue requirements (100-200 cells per animal) are unique features of the zebrafish xenograft model that enable patient-specific chemosensitivity analyses. Zebrafish Have Become a Leading Animal Model for Human Disease and Personalized MedicineFifty years ago, George Streisinger took a leap of faith. He chose a fish for his vertebrate genetic model organism (see Glossary). Many of his contemporaries believed that a fish would be too evolutionarily distant from mammals to have any relevance for human health, and that he would only learn about the genetics of fish [1]. We have since learned that zebrafish and humans have more in common than not. For example, zebrafish retain most of the same organs ('two eyes, mouth, brain, spinal cord, intestine, pancreas, liver, bile ducts, kidney, esophagus, heart, ear, nose, muscle, blood, bone, cartilage, and teeth') but notably lack lungs. Zebrafish would therefore be unsuitable for the development of lung disease models (although they would make an excellent lung cancer metastasis model) [2]. Publication of the complete zebrafish genome in 2013 showed that 70% of the genes in zebrafish have human orthologs, and cross-comparison of disease-related genes annotated in the Online Mendelian Inheritance in Man (OMIM) database reveals that 82% of those genes have at least one zebrafish ortholog [2,3]. HighlightsZebrafish xenografts are proven models of human cancer biology that provide rapid in vivo validation of anticancer drugs and drug targets.Zebrafish have emerged as unsurpassed models for imaging tumor metastasis.

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

“…The zebrafish model presents numerous advantages and has been used in several experimental approaches, including drug screenings and the generation of patient-derived zebrafish Avatars, using embryonic-larval stages or even adult zebrafish [30,31,33,[88][89][90][91]. The optical transparency and single-cell resolution allow for the evaluation of different readouts apart from the classically used tumor size analysis [32,91].…”

A Great Catch for Investigating Inborn Errors of Metabolism—Insights Obtained from Zebrafish

“…The impact made on IEM by the zebrafish model is evident. Even more, the influence zebrafish studies had in the last decades in a great variety of diseases and their relevance for human treatment has been highlighted in numerous publications [ 159 , 192 , 193 , 194 , 195 , 196 , 197 ]. It is to be expected that the role of zebrafish will continue to grow for rare metabolic disorders, especially with the prospect of drug screening and the effectiveness of CRISPR/Cas9 editing.…”

Alterações Genotóxicas, Citotóxicas E Mutagênicas: Um Conteúdo a Ser Ilustrado E Trabalhado No Ensino Médio

“…However, xenotransplantation in adult zebrafish allows a better analogy to human due to the tissue similarity between the mature tissues of zebrafish and the origin of xenograft. Currently, xenotransplantation in adult zebrafish is no longer compromised by the need to suppress the immune systems, through the use of techniques such as irradiation γ, treatment with dexamethasone and more recently a Casper line of transparent immunocompromised zebrafish, prkdc fb103/fb103 il2rga fb104/fb104 Casper-strain zebrafish (8,52,54,55). Zebrafish larvae and embryos may represent an interesting alternative to adult zebrafish because they allow the analysis of microtumor formation, tumour-induced angiogenesis and cell invasion.…”

“…The study of tumour angiogenesis is also possible, due to its vascular embryonic system. Techniques such as fluorescence microscopy in transgenic embryos facilitate macroscopic and microscopic observation of the entire angiogenesis process (52)(53)(54)56).…”

“…Regarding the study of tumour metastasis in Zebrafish, several tumours were studied, such as liver carcinoma, glioblastoma, breast cancer, rhabdomyosarcoma, melanoma, neuroblastoma, among others (14,52,58). All the stages of the metastatic process were able to be studied including the beginning, approaching, clustering, invading, migrating, transmigrating and metastatic colonization (52,54,58,61). Several techniques are used to observe invasion and metastatic dissemination, such as the fluorescent zebrafish model and the development of transparent Casper adult zebrafish.…”