Better model of cancer development sheds light on potential angiogenesis target
Johns Hopkins Kimmel Cancer Center researchers have learned that a common, cancer-linked gene thought to control blood vessel growth may not turn out to be useful as an effective target for cancer drug development. Their research, published in the October issue of Cancer Cell found that results of previous studies that pinned hope on the Id1 gene may not hold up in a mouse model thought to more accurately represent how humans get cancer.
The scientists began their study attempting to confirm previous work, including their own, suggesting that Id1 activation was an important step in tumor angiogenesis, a process that builds blood vessels needed for tumor growth.
In the earlier research on Id1, scientists used a mouse model in which tumor cells were injected directly into the animals to stimulate cancer growth: in effect, a tumor transplant. The tumors grew in the animals with Id1 activation while the injected tumors failed to grow in mice whose Id1 genes were inactivated.
“But this is not how people get cancer,” says Rhoda Alani, M.D., director of the study and assistant professor of oncology, dermatology, molecular biology and genetics at the Johns Hopkins Kimmel Cancer Center. “We get cancer through a series of genetic events that occur over time, triggered by both internal and external factors.”
In the Hopkins investigators new model, mice were exposed to carcinogens placed on their skin and allowed to gradually develop cancer. Results showed a completely opposite outcome with respect to Id1: all mice with the Id1 gene turned off developed more tumors that also were larger than in previous studies.
“Clues to promising cancer drug development are only as good as the model in which you study a process,” says Alani. “If knocking out the Id1 gene in two different models produces two different results, then we need to reevaluate the role that Id1 plays in angiogenesis.”
In the model using skin carcinogen exposure, the teams preliminary findings suggest that cancers may develop faster in mice without Id1 because inactivation of the Id1 gene triggers alterations in a receptor on skin immune cells called gamma delta T cells. With a faulty receptor, these cells fail to migrate to the skin to fight off cancer cells.
“We realize that studies based on tumor transplant models are quicker and easier to perform in the laboratory, but its important to study both the transplant and genetic models to get a clear picture of how genes interact,” she says. The researchers believe that the tumor transplant model is most similar to the process of cancer metastasis, in which Id1-associated angiogenesis is likely to play an important role.
The research was funded by the National Institutes of Health, the Flight Attendant Medical Research Institute, the American Skin Association, and the V Foundation.
Study participants include Hashmat Sikder, David L. Huso, Binghe Wang, Byungwoo Ryo, and Jonathan D. Powell from Johns Hopkins; Hong Zhang and Sam T. Hwang from the National Cancer Institute.
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