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April 26, 2001
Building a Better Mouse Model of Lung Cancer
Researchers have genetically engineered cancer-prone mice that carry
cells that switch on a cancer-causing gene spontaneously, generating
lung and other cancers much like humans do. The scientists believe that
the technique for generating the mice will be widely applicable and may
be used to model many kinds of human cancers in mice.
In an article published in the April 26, 2001, issue of the journal
Nature, Howard Hughes Medical Institute (HHMI) investigator Tyler
Jacks of the Massachusetts Institute of Technology (MIT) and his
colleagues reported that they used a "hit-and-run" approach to
producing gene alterations in mice whose cells harbor an inactivated
form of the K-ras cancer gene, or oncogene. Co-authors of the
paper include Leisa Johnson, who is now at Onyx Pharmaceuticals, and
colleagues at MIT, as well as collaborators at Tufts University Schools
of Medicine and Veterinary Medicine and the Dana-Farber Cancer
Institute.
“We believe that this new mouse model more accurately mimics tumor development in humans, which may lead to new insights into the genetic changes that occur in human disease.”
Tyler Jacks
Mutations in K-ras are highly prevalent in human cancers,
occurring in 90 percent of pancreatic tumors, 50 percent of colon
tumors and 30 percent of non-small cell lung cancers. Previous mouse
models of these forms of cancer have been informative, said Jacks, but
they have not accurately recapitulated the kind of spontaneous
mutations that characterize cancers involving K-ras. Some of the
obstacles have been technical in nature. For example, said Jacks,
creating a mouse embryo with cells that contain mutated K-ras,
which is a dominant mutation, would either be severely damaging or
lethal to the embryo.
"Researchers have tried to overcome the problem of dominance by
making transgenic mouse strains that only express the dominant oncogene
in cells of a given tissue," said Jacks. "The problem is that neither
embryonic insertion nor such tissue-specific transgenic mice
recapitulate what one finds in normal human cancer, where individual
cells acquire an oncogenic mutation, but they are otherwise surrounded
by normal cells.
"Our strategy was to create a kind of genetic Trojan horse," said
Jacks. They did this by introducing latent K-ras genes into
mice. The genes were inactivated because they had duplicated segments
of DNA that prevented the genes from activating themselves.
"Then as the mice grew, individual cells underwent rare spontaneous,
sporadic recombination events that deleted one copy of the duplicated
sequence, such that the K-ras gene was activated and began to
initiate tumor development." The technique was based on the hit-and-run
gene-targeting technology developed by HHMI investigator Allan Bradley
at Baylor College of Medicine. The two-part technique consists of
"hitting" cells with an inserted mutated gene and then allowing the
recombination event to "run," activating the inserted gene.
The mice carrying the mutated K-ras gene system that Jacks
and his colleagues inserted did, indeed, develop several types of
tumors, including skin cancers and lymphomas. The animals also showed
high incidence of early onset lung tumors.
"We believe that this new model more accurately mimics tumor
development in humans, which may lead to new insights into the genetic
changes that occur in human disease," said Jacks. "We can isolate
tumors at various stages of progression, and thus, discover genes and
processes that accompany tumorigenesis."
Furthermore, said Jacks, "the idea of creating a silent, or latent,
version of an oncogene could be applied to any dominant mutation that
you want to activate only sporadically in a small percentage of
cells."
In an additional experiment, the scientists also produced
K-ras mice with a mutant form of p53, a tumor suppressor
gene whose malfunction is known to spur the progression of
K-ras-based human lung cancers. These double-mutant mice showed
reduced lifespan when compared to mice with either p53 or
K-ras mutation alone. This further demonstrates the relevance of
their mouse model to human lung cancers, said Jacks.
The only significant limitation to the technique, said Jacks, is
that the lung tumors arise so rapidly that the mice are overcome by
tumors before there is a chance to observe the process of metastasis,
the spread of lung cancer to other tissues. However, Jacks and his
colleagues are developing a second-generation mouse model that will
allow them to control and monitor the "run" part of the hit-and-run
system in order to study metastasis more effectively.
Although Jacks’s laboratory will focus mainly on lung cancer,
their studies of the mice have already offered new insights into other
K-ras-related cancers. "These mice don’t develop colon
tumors, although we might expect them to because K-ras is
mutated in human colon cancer at high frequency," said Jacks. "This
tells us that the order of mutation matters in colon cancer, which is
caused by multiple mutations." The idea that the order of mutation is
important is an argument that has been advanced by HHMI investigator
Bert Vogelstein at Johns Hopkins University, based on his studies of
human colon cancers, said Jacks.
Particularly promising, said Jacks, is the immediate potential for
using the new mouse model to test both chemotherapies and
chemopreventives for lung cancer. "These animals develop early-onset
lung cancer and even earlier onset lung lesions," he said. "This rapid
development, and the fact that these lesions develop spontaneously mean
that animals can be tested for their response to drugs very quickly,
and without having to be treated first with carcinogens, as in past
testing regimes. And, since mutations in K-ras occur with high
frequency in this type of lung cancer, these mice should respond to
therapeutics aimed at K-ras." Also, added Jacks, strategies to
prevent such lung cancers, which formerly required expensive, long-term
clinical trials in humans, could be tested quite readily using the new
mouse strain.
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