Ohio – In an unexpected finding, scientists have linked the activation of a stress
gene in immune-system cells to the spread of breast cancer to other parts of
say the study suggests this gene, called ATF3, may be the crucial link
between stress and cancer, including the major cause of cancer death – its
spread, or metastasis. Previous public health studies have shown that stress is
a risk factor for cancer.
already know that ATF3 is activated, or expressed, in response to stressful
conditions in all types of cells. Under typical circumstances, turning on ATF3 can
actually cause normal and benign cells to commit suicide if the cells decide that
the stressors, such as irradiation and a lack of oxygen, have irrevocably damaged
research suggests, however, that cancer cells somehow coax immune-system cells
that have been recruited to the site of a tumor to express ATF3. Though it’s
still unclear how, ATF3 promotes the immune cells to act erratically and give cancer
an escape route from a tumor to other areas of the body.
like what Pogo said: ‘We have met the enemy, and he is us,’” said Tsonwin Hai,
professor of molecular and cellular biochemistry at The Ohio State University
and senior author of the study. “If your body does not help cancer cells, they
cannot spread as far. So really, the rest of the cells in the body help cancer
cells to move, to set up shop at distant sites. And one of the unifying themes
here is stress.”
stress gene could one day function as a drug target to combat cancer metastasis
if additional studies bear out these results, Hai said. In the meantime, she
said the results provide important insights into how cells in a tumor use their
signaling power to coopt the rest of the body into aiding cancer’s survival and
movement to distant organs.
research is published in a recent issue of the Journal of Clinical Investigation.
a member in the Ohio State
University Comprehensive Cancer Center, has studied ATF3 in cancer cells
for years. When she had a chance to examine human samples from about 300 breast-cancer
patients, she was stunned to find that the expression of ATF3 gene in certain immune-system
cells was associated with worse cancer outcomes in this group of patients. ATF3
in cancer cells showed no such association.
test that clinical data, she and colleagues conducted two rounds of studies in
mice. The researchers first injected breast cancer cells into two groups:
normal mice and mice that cannot express ATF3 in any cells. The cancer in
normal mice metastasized to the lungs far more rapidly and extensively than did
cancer in the mice lacking ATF3. In the second round of experiments, they used
genetically altered mice that could not express ATF3 in a group of immune
system cells called myeloid cells, and the results were similar.
cancer cells were always the same, but we had different hosts. The primary
tumors were similar in size, but only in the host that can express ATF3 – the
stress gene – did the cancer cells metastasize efficiently,” Hai said. “This suggests
that the host stress response can help cancer to metastasize.
the body is in perfect balance, there isn’t much of a problem. When the body
gets stressed, that changes the immune system. And the immune system is a
double-edged sword,” she said.
general, when cancer cells first appear, the immune system recognizes them as
foreign and various immune cells travel to the site to attack them. Early on in
cancer’s development, this process typically works.
as cancer cells grow and thrive in a tumor, they send out certain molecular
messengers to promote a chronic wound-healing response. Cancer cells, by acting
like a wound that never heals, hijack this process to help themselves survive
induction in immune cells is one way this probably happens. We’re not saying
it’s the only way,” Hai said.
is a master switch type of gene: Its gene product, the ATF3 protein, turns on
and off other genes. Knowing this, the researchers analyzed the genes that are
controlled by ATF3 using a genome-wide global approach. Combining this set of
data with another set of data from human samples, Hai and colleagues were able
to identify an ATF3 gene signature that can predict whether cancer patients had
a low or high risk of dying.
our global gene analysis was carried out using samples from mouse models, our
ability to identify a gene signature to partition patients into high risk or
low risk suggests that our mouse model has relevance to human breast cancer,”
the work suggests a drug to dampen ATF3’s effect could lower the risk for
metastasis, Hai noted that scientists don’t fully understand what the overall
effects of that dampening would be.
have this gene for a reason. It’s a gene that helps us adapt to changes. So
it’s a question of how and when to target ATF3,” she said.
are lots of ways to turn on ATF3 in cells, and stress signals sent out by
cancer cells represent just one method to express this gene in immune-system
cells and produce a chronic would-healing response. Other ways include
radiation, chemotherapeutic agents, a high-fat diet, UV damage and even chronic
plans to test whether these other kinds of stressors also affect the immune cells
through ATF3 induction, changing them from attacking cancer cells to helping
research is supported by NIH/National Cancer Institute grants CA118306, CA090223; NIH/National Institute of Environmental Health Sciences grant ES021018; National Institutes
of Health grant NS045758; a Pelotonia
Idea Grant and research programs in Australia.
include Chris Wolford of Ohio State’s Integrated Biomedical
Graduate Program; Stephen McConoughey and Stephanie Roller of molecular and
cellular biochemistry; Swati Jalgaonkar, Yiseok Chang and Erik Zmuda of Ohio
State’s Molecular, Cellular
and Developmental Biology Program; Marino Leon of pathology;
Anand Merchant, Charles Shapiro and Michael Ostrowski (chair of molecular and
cellular biochemistry) of the OSUCCC; Johnna Dominick and Xin Yin of the Ohio State Biochemistry Program; and Sandra
O’Toole, Ewan Millar and the late Robert Sutherland of the Garvan Institute of Medical Research in
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Tsonwin Hai, (614) 292-2910; Hai.2@o
by Emily Caldwell, (614) 292-8310; Caldwell.151@os