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," said Rhoda
Alani, 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," Alani
said. "If knocking out the Id1 gene in two different models
produces two different results, then we need to re-evaluate
the role that Id1 plays in angiogenesis."
In the model using skin carcinogen exposure, the
team's 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 it's important to study both the transplant and genetic
models to get a clear picture of how genes interact," she
said. 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; and Hong Zhang and Sam T. Hwang from the
National Cancer Institute.
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