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The zebrafish model as a tool to explore tumor immunology

Animal models in cancer research are an indispensable instrument in drug and therapeutic targets discovery. Mice have been used widely to study tumor progression and metastasis, however, since early stages of cancer cell dissemination occur when tumors are very small it is very difficult to visualize it in this model. It is known that metastasis is the principal cause of death among cancer patients, thus, understanding how this process is initiated is an utmost priority.

 

Almost two decades ago the zebrafish emerged as a promising cancer model. Zebrafish advantages such as easy genetic manipulation, embryo transparency, obtaining results in just a couple of days and low maintenance cost among others make the zebrafish a feasible model for cancer research.

 

Cancer cells are in constant interaction and communication with their surroundings. They shape the way in which cancer-associated cells will behave in order to secure their survival and disseminate to other tissues. In the tumor microenvironment, immune cells are one of several types of cancer-associated cells that are important players in the metastatic initiation. For instance, it has been shown that lymphocytes promote brain metastasis by increasing the ability of breast cancer cells to cross the blood-brain barrier (1), neutrophils promote lung metastasis by creating a favorable microenvironment for cancer cells (2) and macrophages promote early cancer cell dissemination by disrupting cell-cell junctions (3).

Zebrafish transparency allows the imaging of cancer cell interaction with immune cells in real time. By performing time-lapse imaging in the living embryo, it is possible to observe not only how cancer cells interact with immune cells in the primary tumor, but also how the immune cells guide cancer cells out of the primary tumor, co-migrate in the blood stream, and create a new metastatic niche at distant sites in the zebrafish embryo (4, 5). Multiple methods and treatments have been used in order to unravel the biological processes that propitiate this cancer cell dissemination mediated by immune cells. Some of these treatments include the use of antibodies (4) or cytokines (5) that will affect the way in which cancer cells and immune cells interact. By using this technique, scientists can analyze the mechanisms that drive this immune-dependent metastasis and uncover novel mechanisms and therapeutic targets that could reduce or prevent the metastatic process in the future. In the last couple of years, the zebrafish model has also inspired the foundation of companies (6, 7, 8) that offer the identification of effective anti-cancer treatments that are customized for each patient. Cancer cells derived from the patient’s tumor are injected into the zebrafish embryos, which are treated with various anti-cancer drugs and results can be obtained after just 3-5 days. This helps the physician to decide which treatment is best for the patient. Although, the mouse tumor model is of great importance in the study of tumor biology and will continue to be, the zebrafish model has become an excellent complement and/or alternative to the mouse model in the fight against cancer and little by little, the zebrafish has helped to fill in the gaps of our knowledge about the carcinogenic process.

 

(1) T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression.
PMID:29350274 DOI: 10.1007/s00401-018-1806-2

 

(2) Neutrophils support lung colonization of metastasis-initiating breast cancer cells.
PMCID: PMC4700594 DOI: 10.1038/nature16140

 

(3) Macrophages orchestrate breast cancer early dissemination and metastasis.
DOI:10.1038/s41467-017-02481-5

 

(4) Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils.
DOI: https://doi.org/10.1158/2326-6066.CIR-16-0150PubMed: 28159748

 

(5) Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development.
PMID: 25492861 DOI:10.1158/0008-5472.CAN-14-2819

 

(6) Osteofunction

 

(7) Zeclinics

 

(8) IKanBiotech

 

Picture 1. Zebrafish adults in an aquarium.

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Picture 2. 5-days old zebrafish embryo with human breast cancer cells expressing green fluorescent protein.

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Picture 3. Disseminated breast cancer cells (red) with neutrophils (blue) in the zebrafish embryo (green blood vessels).

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Last modified: May 30, 2018

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