Hooking the big one: the potential of zebrafish xenotransplantation to reform cancer drug screening in the genomic era

Abstract

The current preclinical pipeline for drug discovery can be cumbersome and costly, which limits the number of compounds that can effectively be transitioned to use as therapies. Chemical screens in zebrafish have uncovered new uses for existing drugs and identified promising new compounds from large libraries. Xenotransplantation of human cancer cells into zebrafish embryos builds on this work and enables direct evaluation of patient-derived tumor specimens in vivo in a rapid and cost-effective manner. The short time frame needed for xenotransplantation studies means that the zebrafish can serve as an early preclinical drug screening tool and can also help personalize cancer therapy by providing real-time data on the response of the human cells to treatment. In this Review, we summarize the use of zebrafish embryos in drug screening and highlight the potential for xenotransplantation approaches to be adopted as a preclinical tool to identify and prioritize therapies for further clinical evaluation. We also discuss some of the limitations of using zebrafish xenografts and the benefits of using them in concert with murine xenografts in drug optimization.

Keywords: Cancer; Drug screening; Microenvironment; Xenotransplantation; Zebrafish.

Fig. 1.

The most common injection sites used in xenotransplantation of 48 hpf zebrafish. The yolk sac is the most frequently used site of injection. Several human cancer cell lines (indicated in parentheses) and primary cancer samples (indicated in bold text, as well as their accompanying references) have been transplanted into various anatomic sites.

Fig. 2.

Transgenic zebrafish can be used concurrently with xenotransplantation models to study the interactions between injected human cancer cells and fundamental elements of the host microenvironment. Panel A shows a brightfield image of a 4 dpf casper embryo (White et al., 2008), and panel B, a fluorescence image, shows the same embryo with injected Cm-Dil-labeled TC32 Ewing’s sarcoma cells (in red). Panel C, a brightfield image, shows an uninjected 5 dpf fli1a:eGFP (Lawson and Weinstein, 2002) casper embryo, and panel D, a fluorescence image, shows the same embryo with GFP-labeled vasculature. Panel E is a brightfield image showing an uninjected 4 dpf mpeg1:eGFP (Ellett et al., 2011) casper embryo, and panel F, a fluorescence image, shows the same embryo with GFP-labeled monocytic cell lineages, including macrophages. dpf, days post-fertilization; GFP, green fluorescent protein.