Zebrafish xenograft models of cancer and metastasis for drug discovery

Abstract

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.

New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells

“…Previous articles highlight that cancer cell lines maintain their morphological features and metastatic potential in zebrafish xenografts and further validate the chemosensitive profile of HCT-116 cells in zebrafish and mouse xenografts. The results in mouse xenografts closely matched with zebrafish xenografts 20,30 . It is worth noting that in our study, imipramine did not seem to be toxic to zebrafish at anti-invasive doses.…”

Systems Biology of Cancer Metastasis

“…Even when longitudinal data is available, the integration of multiple data types, such as bulk and single-cell whole-genome sequencing and transcriptomic profiling may be required to predict an outcome with accuracy (Brady et al, 2017). Finally, single-cell sequencing of metastatic lesions coupled with computational methods and lineage tracing of metastases in animal models amenable to imaging, such as C. elegans, or zebrafish, holds the potential to address outstanding questions about the origins and clonality of metastasis, as well as the emergence of new phenotypes such as drug resistance (Brown et al, 2017;Heilmann et al, 2015;Kyriakakis et al, 2015).…”

Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signalling

“…CMT‐U27 RED cells were injected in the yolk sac or in the duct of Cuvier . Cells injected into the yolk sac have to migrate to the blood circulation before they may form distant metastases, whereas direct injection into the bloodstream using the duct of Cuvier does not require intravasation and can form distant metastases more easily …”

“…50 Cells injected into the yolk sac have to migrate to the blood circulation before they may form distant metastases, whereas direct injection into the bloodstream using the duct of Cuvier does not require intravasation and can form distant metastases more easily. 51,52 The embryos were directly inspected for proper injection and were fixed on day 3 or 5 (dpi) and imaged under a confocal microscope. The experiments were performed in triplicate with 30 to40 well-injected embryos for dasatinib and 10 embryos for the everolimus experiments.…”