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
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
We and others have shown that xenotransplantation of human cancer into zebrafish embryos can be optimally carried out from 48-hour post-fertilisation when gastrulation is complete and the main body plan of the animal is established
Summary
Metastasis is a clinical term describing the spread of tumour cells from a primary location to distant sites. An orderly cascade of cellular behaviours was presumed to underlie the progression from a well circumscribed and localised tumour growth to distant spread, based on initial local invasion, entry into the vascular or lymphatic system, survival in those fluid channels followed by extravasation and colonisation in a distal site (Massagué et al, 2017). This orderly progression is not borne out by current research and the mechanisms of metastatic spread remain controversial. In prostatic cancer the primary site is rarely a clinical problem in comparison to the pain and pathological fractures from osteolytic vertebral deposits (Akakura et al, 1996)
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