Zebrafish xenograft models of cancer and metastasis for drug discovery

ABSTRACT

Introduction: Patients with metastatic cancer suffer the highest rate of cancer-related death, but existing animal models of metastasis have disadvantages that limit our ability to understand this process. The zebrafish is increasingly used for cancer modelling, particularly xenografting of human cancer cell lines, and drug discovery, and may provide novel scientific and therapeutic insights. However, this model system remains underexploited.

Areas covered: The authors discuss the advantages and disadvantages of the zebrafish xenograft model for the study of cancer, metastasis and drug discovery. They summarise previous work investigating the metastatic cascade, such as tumour-induced angiogenesis, intravasation, extravasation, dissemination and homing, invasion at secondary sites, assessing metastatic potential and evaluation of cancer stem cells in zebrafish.

Expert opinion: The practical advantages of zebrafish for basic biological study and drug discovery are indisputable. However, their ability to sufficiently reproduce and predict the behaviour of human cancer and metastasis remains unproven. For this to be resolved, novel mechanisms must to be discovered in zebrafish that are subsequently validated in humans, and for therapeutic interventions that modulate cancer favourably in zebrafish to successfully translate to human clinical studies. In the meantime, more work is required to establish the most informative methods in zebrafish.

KEYWORDS:

• Cancer
• metastasis
• xenotransplantation
• zebrafish

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Article highlights

• Zebrafish allow unrivalled in vivo imaging of cellular behaviour thanks to optical clarity and a range of tissue specific transgenic lines.

• An increasing number of zebrafish cancer studies have now been reported, most using xenotransplantation of human cancer cell lines.

• Mechanisms known to drive metastasis in human and rodent models appear conserved in the zebrafish, and novel mechanisms of cancer metastasis discovered in zebrafish appear to be reproduced in rodents.

• The ability to treat zebrafish by immersion in the drug greatly facilitates testing of drug effects, and such studies suggest drugs discovered in zebrafish are likely to be effective in mammalian models.

• Although it is too early to be certain, it seems likely that the zebrafish will contribute novel insights that ultimately lead to patient benefit.

This box summarizes key points contained in the article.

Additional information

Funding

The authors are supported by the Bone Cancer Research Trust under research project No. 144681, the British Heart Foundation, Cancer Research UK and the Sir Jules Thorn Charitable Trust.