Abstract
Cancer metastasis is the most important prognostic factor determining patient survival, but currently there are very few drugs or therapies that specifically inhibit the invasion and metastasis of cancer cells. Currently, human cancer metastasis is largely studied using transgenic and immunocompromised mouse xenograft models, which are useful for analysing end-point tumour growth but are unable to accurately and reliably monitor in vivo invasion, intravasation, extravasation or secondary tumour formation of human cancer cells. Furthermore, limits in our ability to accurately monitor early stages of tumour growth and detect micro-metastases likely results in pain and suffering to the mice used for cancer xenograft experiments. Zebrafish ( Danio rerio) embryos, however, offer many advantages as a model system for studying the complex, multi-step processes involved during cancer metastasis. This article describes a detailed method for the analysis of human cancer cell invasion and metastasis in zebrafish embryos before they reach protected status at 5 days post fertilisation. Results demonstrate that human cancer cells actively invade within a zebrafish microenvironment, and form metastatic tumours at secondary tissue sites, suggesting that the mechanisms involved during the different stages of metastasis are conserved between humans and zebrafish, supporting the use of zebrafish embryos as a viable model of human cancer metastasis. We suggest that the embryonic zebrafish xenograft model of human cancer is a tractable laboratory model that can be used to understand cancer biology, and as a direct replacement of mice for the analysis of drugs that target cancer invasion and metastasis.
Highlights
22 Oct 2018 report reportAny reports and responses or comments on the article can be found at the end of the article
Metastasis is a clinical term describing the spread of tumour cells from a primary location to distant sites
In this article we describe the techniques for performing embryonic zebrafish xenograft experiments and demonstrate the utility of using zebrafish embryos as a model system for studying human cancer metastasis, in particular metastatic melanoma and prostate cancer
Summary
Any reports and responses or comments on the article can be found at the end of the article. Keywords Zebrafish embryo, xenograft, cancer, melanoma, prostate cancer, metastasis, replacement. The new version of this article has been updated to, confirm details of when and how the experiment is terminated; reference FIJI imaging software as a method of analysis; emphasise the importance of establishing a baseline for the invasion of different cancer cell lines and the use of tracer beads to evaluate movement associated with organ development; reference other uses of this model such as analysis of angiogenesis or cancer cell proliferation; document product codes of important materials used; and confirm details of how 3D printed moulds were created. Current applications: S tudying tumour invasion and metastatic dissemination of different human cancer cell lines using time-lapse microscopy. S tudying the invasion of human cancer cells into zebrafish blood vessels and in the formation of secondary tumours
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