New Studies Show Stress Beneficial to Cancer:
Accelerating its Spread, Protecting from Therapy
Stress, even from physical exercise, helps cancer
survive chemo and radiation
Sept. 21, 2010 – Two new studies seem to have found
firm evidence that stress is a friend of cancer. Previous studies have
indicated stress fuels cancer growth, but this new research seems to
nail it down. One study found chronic stress acts as fertilizer to feed
breast cancer and the other says stress helps cancer survive treatment
therapy.
Stress accelerates breast cancer progression in
mice
Researchers at UCLA's Jonsson Comprehensive Cancer
Center report they have found chronic stress acts as a sort of
fertilizer that feeds breast cancer progression, significantly
accelerating the spread of disease in animal models,.
Researchers discovered that stress is biologically
reprogramming the immune cells that are trying to fight the cancer,
transforming them instead from soldiers protecting the body against
disease into aiders and abettors. The study found a 30-fold increase in
cancer spread throughout the bodies of stressed mice compared to those
that were not stressed.
It's long been thought that stress fuels cancer
growth in humans. This study provides a model that not only demonstrates
that stress can speed up cancer progression, but also details the
pathway used to change the biology of immune cells that inadvertently
promote the spread of cancer to distant organs, where it is much harder
to treat.
The study appears in the Sept. 15, 2010 issue of
the peer-reviewed journal Cancer Research.
"What we showed for the first time is that chronic
stress causes cancer cells to escape from the primary tumor and colonize
distant organs," said Erica Sloan, a Jonsson Cancer Center scientist,
first author of the study and a researcher with the Cousins Center for
Psychoneuroimmunology. "We not only showed that this happens, but we
showed how stress talks to the tumor and helps it to spread."
In addition to documenting the effects of stress on
cancer metastasis, the researchers were also able to block those effects
by treating stressed animals with drugs that block the nervous system's
reprogramming of the metastasis-promoting immune cells, called
macrophages.
Beta blockers, used in this study to shut down the
stress pathways in the mice, are currently being examined in several
large breast cancer databases for their role in potential prevention of
recurrence and cancer spread, said Dr. Patricia Ganz, director of cancer
prevention and control research at UCLA's Jonsson Comprehensive Cancer
Center.
If preliminary findings indicate benefit, early
phase clinical trials are being considered at the Jonsson Cancer Center
testing beta blockers as a means of preventing breast cancer recurrence.
Other healthy lifestyle behaviors may also influence the biological
pathways described in the study, such as exercise and stress reduction
techniques.
Focus on younger women - typically under more
stress
"We're going to be focusing on younger women,
because they may have a multitude of things weighing on them when
they're diagnosed with breast cancer. Younger women have more
significant life demands and typically are under more stress," Ganz
said.
Ganz said her proposed research will focus on "host
factors," or things affecting the patient, that may be aiding the cancer
progression and could help explain why a group of patients with the same
type and stage of disease have varying rates of recurrence and cancer
spread.
"This study provides evidence for a biological
relationship between stress and cancer progression and identifies
targets for intervention in the host environment," Ganz said.
"Because of this study, we may be able to say to a
patient in the future that if you follow this exercise regimen,
meditative practice or take this pill every day it will help prevent
recurrence of your cancer. We can now test these potential interventions
in the animal model and move those that are effective into the clinic."
In Sloan's study, mice with breast cancer were
divided into two groups. One group of mice was confined in a small area
for a short period of time every day for two weeks, while the other
group was not.
The breast cancer cells were genetically engineered
to include the luciferase gene, which is the molecule that makes a
firefly glow. The growth and spread of the cancer in the mice was
monitored using sensitive cameras that can pick up the luciferase signal
and allowed Sloan and her team to observe both the development of
primary tumors and the spread of metastases throughout the body, said
Steven Cole, an associate professor of hematology/oncology, a Jonsson
Cancer Center researcher and senior author of the study.
What was interesting, Cole said, was that the
primary tumors did not seem to be affected by stress and grew similarly
in both groups of mice. However, the stressed animals showed
significantly more metastases throughout the body than did the control
group. The cancer, in effect, acted differently in the stressed mice.
"This study is not saying that stress causes
cancer, but it does show that stress can help support cancer once it has
developed," Cole said. "Stress helps the cancer climb over the fence and
get out into the big, wide world of the rest of the body."
Cole said Sloan detailed the biology of the
stress-induced changes in the cancer cells along every step of the
pathway, providing a road map by which stress promotes cancer
metastasis. Additionally, she proved that using beta blockers in
stressed mice prevented the same cancer progression seen in the stressed
mice that did not receive medication.
When cancer occurs, the immune system sends out
macrophages to try to repair the tissue damage caused by uncontrolled
growth of cancer cells. The macrophages, in an attempt to help, turn on
inflammation genes that are part of the normal immune response to
injury. However, the cancer cells feed on the growth factors involved in
a normal immune response.
Blood vessels that are grown to aid healing instead
feed the cancer the oxygen and nutrients it needs to grow and spread,
and the extra cellular matrix, which provides structural support for
normal cells, is attacked during the immune response, In Sloan's study,
mice with breast cancer were divided into two groups. One group of mice
was confined in a small area for a short period of time every day for
two weeks, while the other group was not. helping the cancer cells
escape from the primary tumor and spread to distant parts of the body.
"Many of the genes that promote cancer metastasis
get turned on during the immune response by macrophages," Cole said.
"This study shows that stress signaling from the sympathetic nervous
system enhances the recruitment of macrophages into the primary tumor,
and increases their expression of immune response genes that
inadvertently facilitate the escape of cancer cells into other parts of
the body."
Sloan showed that the beta blockers prevented the
macrophages from hearing the signals sent by the sympathetic nervous
system, and stopped them from infiltrating the tumor and encouraging
cancer spread.
The study was funded by the National Institutes of
Health, the Department of Defense and the Jonsson Cancer Center. Visit
their website at
http://www.cancer.ucla.edu.
Stress before cancer therapy could help deadly
cells survive treatment, lead to disease recurrence
The second breaking research report finds that
patients who experience physical or psychological stress – including
rigorous exercise – one or two days before a cancer treatment might be
unknowingly sabotaging their therapy.
Stress in the body – even physical stress caused by
intense exercise – activates a stress-sensitive protein that can spark a
series of events that allow cancer cells to survive such treatments as
chemotherapy and radiation, according to the research.
Though the study involved a series of experiments
in breast cancer cell cultures, the researchers say the findings are a
clear indication that cancer cells have found a way to adapt and resist
treatment with the help of this stress-inducible protein.
This cancer cell survival can be traced to the
presence of heat shock factor-1, which previous research has linked to
stress. Ohio State University researchers first noticed that this common
protein can help heart tissue survive in a toxic environment, leading
the scientists to suspect that in cancer, this phenomenon could have
serious consequences.
A series of experiments using breast cancer cells
showed that a protein activated by the presence of heat shock factor-1
could block the process that kills cancer cells even after the cells'
DNA was damaged by radiation. The same was true when the cells were
subjected to a common chemotherapy drug.
The researchers hope to develop a drug that could
suppress heat shock factor-1 as a supplement to cancer therapy, but in
the meantime, they recommend that patients avoid both psychological and
physical stress in the days leading up to a cancer treatment.
"One of the known inducers of this factor is
exercise. I am not against exercise, but the timing is critical. It
looks like any intense or prolonged physical activity a couple of days
before the start of cancer therapy is highly risky, and has potential to
reduce the benefits of the treatment," said Govindasamy Ilangovan, lead
author of the study and associate professor of internal medicine at Ohio
State.
The study appears online in the journal
Molecular Cancer Research.
Ilangovan, an investigator in Ohio State's Davis
Heart and Lung Research Institute, specializes in cardiovascular
medicine. But when he observed in previous research that this
stress-inducible protein could salvage heart cells that otherwise were
doomed to die, he collaborated with radiology specialists to test the
protein's effects in cancer.
While he used breast cancer cells for this study,
he suspects that the widespread presence of heat shock factor-1 in the
body means the protein could have this same effect on any kind of
adenocarcinoma, a class of cancer cells that originate in a gland.
Heat shock factor-1 activates a specific protein,
known as Hsp27, that ends up helping the cancer cells survive, Ilangovan
said.
The researchers conducted numerous experiments to
observe how Hsp27 behaves in cancer cells after they undergo
ultraviolet-C radiation. The radiation is used as a model for treatments
designed to kill cancer cells by damaging their DNA. In this study, the
stress of the UV radiation itself also induced the heat shock factor
and, subsequently, Hsp27, which reduced the cell death.
In every experiment, a heightened presence of the
Hsp27 protein was associated with lower levels of other proteins that
participate in the process of cell death. When the researchers
introduced siRNA, a molecule that interferes with Hsp27's function, the
cell death mechanism was restored.
When the breast cancer cells were treated with
doxorubicin, a common chemotherapy drug, the experiment produced similar
results. When the Hsp27 protein was silenced, more of the cancer cells
died.
"We clearly showed that a reduction in the level of
the Hsp27 protein made the cancer cells more susceptible to both
treatments," Ilangovan said.
This finding suggested to the scientists that a
drug with the same effects as the interference molecule could stop Hsp27
from preventing cancer cell death. No such drug currently exists, and
the siRNA molecule isn't suitable for use in patients, Ilangovan said.
But the interfering molecule had a significant
effect, in one experiment leading to the death of at least 60 percent of
the cancer cells that had undergone UV radiation.
Among the key reactions the researchers observed
was Hsp27's relationship to a protein called p21, which allows cells to
pause, repair themselves and continue dividing, leading to their
survival. Damage to the DNA in cancer cells should disable this step in
cell division, but the research showed that the Hsp27 caused p21 to
change positions in a way that allowed for cell survival.
"It looks like a compensatory act. We are doing
something to kill the cell, but cells have their own compensatory action
to oppose that," Ilangovan said.
After irradiation, the levels of Hsp27 reached
their height within 48 hours, suggesting that the protein is highly
active in the two days following any stressful event that activates heat
shock factor-1.
"The process that sets these activities in motion
takes a couple of days," Ilangovan said. "It is not proven in a clinical
setting, but our hypothesis leads us to strongly caution cancer patients
about avoiding stress because that stress might trigger recurrence of
cancer cell growth."
Grants from the National Institutes of Health and
the American Heart Association supported this research.
Co-authors of the study are Ragu Kanagasabai,
Karthikeyan Krishnamurthy and Kaushik Vedam of the Department of
Internal Medicine, and Qien Wang and Qianzheng Zhu of the Department of
Radiology, all at Ohio State.
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Sept. 21, 2010 – Two new studies seem to have found
firm evidence that stress is a friend of cancer. Previous studies have
indicated stress fuels cancer growth, but this new research seems to
nail it down. One study found chronic stress acts as fertilizer to feed
breast cancer and the other says stress helps cancer survive treatment
therapy.
Stress before cancer therapy could help deadly
cells survive treatment, lead to disease recurrence