Cancer scientists use a wide variety of techniques to study the growth and development of tumor cells. Laboratory research often focuses on individual cells or tissue samples, but to learn how cancers grow and respond to therapies in living organisms, scientists rely on other experimental models. In recent years, zebrafish have become the model of choice for studying many cancer types. Dana-Farber’s A. Thomas Look, MD, who uses zebrafish in his own work, explains why.
To a cancer researcher like me, zebrafish offer several advantages for studying the disease. Their skin is translucent, which lets us observe the growth of tumors and see whether they shrink in response to experimental treatments.
Zebrafish reproduce prolifically. A mating pair can produce 200-300 embryos a week, which enables us to test anti-cancer drugs in hundreds or thousands of fish at a time. The more animals involved in the tests, the more compounds we can study to assess their activity against cancer cells and risks to normal cells.
Of particular relevance to my research into the basic mechanisms underlying leukemia and certain solid tumors is the fact that zebrafish share many genes with humans. They can develop most of the types of tumors that we can, often through the same gene pathways. Human cancer-causing genes can be easily introduced into zebrafish, which helps us generate fish that develop specific kinds of cancer, and study how the disease can be halted.
I initially became interested in using zebrafish for what are known as forward genetic screens. These tests help us determine which genes are responsible for certain traits in an organism – for example, which genes control blood cell development, and which control nerve cell growth.
In recent years, better techniques have arisen for obtaining this kind of information. But zebrafish have found another niche as models for cancer research. Today, we use them most often for making transgenic models – that is, introducing genes into the fish to see how genes work together to promote cancer. Transgenic models also help us understand the role gene mutations play in cancer and how gene pathways can be altered to stop cancer growth. New technology makes it possible to inactivate specific tumor supressor genes, which restrain cell growth and division. This enables us to test the combined roles of cancer-causing oncogenes and tumor suppressor genes in the development of cancer.
A decade ago, my colleagues Leonard Zon, MD and David Langenau, PhD, now of Massachusetts General Hospital, and I inserted a mouse cancer gene into zebrafish chromosomes to produce the first “transgenic” cancer model in fish, which in this case developed T cell leukemia. To confirm that the gene had made its way into the zebrafish DNA, we attached a fluorescent protein to the gene. When we saw green-glowing cells multiplying in the bodies of the fish, we knew we had succeeded.
A. Thomas Look, MD, leads a laboratory at Dana-Farber Cancer Institute that focuses on abnormal gene pathways involved in the development of leukemia and solid tumors. Research from his lab has expanded the basic understanding of several forms of cancer and pointed the way to new therapies.