In the fight against cancer, zebrafish may seem like an unlikely weapon.
For TinChung Leung, PhD, with the North Carolina Central University Nutrition Research Program at the NC Research Campus (NCRC) in Kannapolis, zebrafish have the potential to deliver the answers to some of the most fundamental questions about cancer. Namely how tumors grow and metastasize, and how they hijack the human immune system in the process. By understanding how this happens, Leung identifies new therapeutic targets for cancer prevention and treatment. He uses zebrafish in his studies because they have specific biological features that make them the most advantageous research model.
The Best Fish for the Job
“The zebrafish model is transparent so you can see through the embryo under a microscope,” Leung said. “We use transgenic zebrafish lines that express green or red fluorescent proteins so we can identify the cell type and see how they develop. We can see how the cancer cells interact with the blood vessels as well as the immune cells.”
When zebrafish reproduce, the female lays hundreds to thousands of eggs at a time. Research can be conducted on zebrafish throughout their short life spans from embryo through adulthood, and they can be studied while they are alive. But that’s not all.
“The whole zebrafish genome has been sequenced that is why we can easily match the human gene to the zebrafish gene,” Leung explained. “The number of genes in humans are similar in zebrafish, but not just the number, the genetic pathways in humans have counterparts in the fish. So when we study a particular process, we identify the genes in the zebrafish that refer to the counterpart gene in humans. That helps us understand the function of a particular gene.”
The zebrafish’s circulatory system is also similar to the human system. Critical processes are comparable too, including angiogenesis (blood vessel formation), tumor angiogenesis and blood cell formation, which are the critical elements of cancer Leung studies.
Breast Cancer to Anemia
Sean Kimbro, PhD, with the Julius Chambers Biomedical/Biotechnology Research Institute (BBRI) on the main campus of NC Central University in Durham, NC, leads a research team that includes Leung, Xiaho Yang, MD, PhD, who is also with NCCU at NCRC, and other scientists at NCCU’s main campus. They are investigating the underlying cause of triple negative breast cancer.
Triple negative means that the cancer doesn’t have the receptor hormones for estrogen, progesterone or overexpression of the protein HER2. Triple negative is diagnosed in one out of 10 breast cancer cases and does not respond to common breast cancer therapies such as tamoxifen or trastuzumab. Kimbro and team are looking at specific genes related to inflammation and toll-like receptors, which are a class of proteins that are part of the human immune system.
“We are moving toward providing novel drug targets to treat the breast cancer disparities seen between African and European woman,” Kimbro said. “Such findings move us closer to precision medicine for breast cancer treatment.”
In previous studies, the researches verified that a small cohort of African American women have an increased risk of breast cancer because of a mutation in the pathway involving the protein kinase IRAK-4, which plays a role in telling the toll-like receptors to respond when the immune system is challenged. Their research, which was conducted in zebrafish and in cell culture models, confirmed that the “development of drugs that target IRAK4 and other regulators of the innate immune pathway” could control tumor growth and progression from BrCa, one of the main genes associated with breast cancer. These findings were presented at the 2014 American Association for Cancer Research annual meeting.
“People don’t know exactly what this genetic variation does,” Leung said, “but they know that it is predominantly in African Americans. So Dr. Kimbro’s research is important to find out how the genetic variation influences the outcome of breast cancer. The process is visible and more easily studied in the zebrafish model.”
In the past year, Leung also used zebrafish in a study that reported new therapeutic targets for the treatment of pancreatic cancer. He continues research with Shengmin Sang, PhD, who is with the NCAT Center for Excellence in Post-Harvest Technologies at the NCRC, on the ability of 10-gingerol, a metabolite from ginger, to promote the growth of blood vessels and red blood cells. Leung and Sang are moving closer to the initiation of a human trial as part of developing 10-gingerol into an approved treatment for anemia.
“We use a zebrafish with a defect in the aorta and in the production of blood cells,” Leung said. “They help us to understand better the developmental pathway of how blood cells are formed as well as the mechanism of 10-gingerol to help make hematopoietic stem cells, which are cells that come from the same precursor cells that form blood cells and blood vessels. We are looking at different signaling pathways and different inhibitors.”
In the fight against cancer and other human diseases, zebrafish are a research model that continues to prove its value because, Leung noted, “what takes a lifetime in a human to study only takes a few weeks in zebrafish.”