IGF-I is also of considerable interest to cancer researchers,
because of mounting evidence that high levels of the protein contribute
to cancer risk. One of the study's co-authors, oncologist Wafik
El-Deiry, M.D., Ph.D., of the University of Pennsylvania, is internationally
prominent for his studies of the p53 protein. "This work provides
a novel and important insight into the regulation of growth by the
major tumor suppressor p53," Dr El-Deiry said. He added, "For years
we've known that p53 regulates another binding protein, IGBFP-3,
to inhibit IGF signaling, but now we know that was the tip of the
iceberg, as p53 appears to regulate the IGF axis at multiple nodes.
It took collaboration between an endocrinologist and a medical oncologist
to break this new ground, which has impact on both fields."
"We have no evidence now that either growth hormone or IGF-I actually
causes cancer, but IGF-I may contribute to cancer progression and
aggressiveness," said Dr. Grimberg. "IGF-I doesn't ignite the fire;
it fuels it." At each stage that cancer progresses, she added, "IGF
signaling can stimulate cells to behave more dangerously."
The study may have implications for patients receiving growth hormone
or other growth-promoting therapies. Recombinant human growth hormone
has been prescribed for the past 21 years for children with deficiency
of normal growth hormone, to avoid abnormally short stature. However,
in a controversial usage, that growth hormone is also prescribed
for some short but healthy children with normal IGF-I levels to
increase their height. "Excess levels of growth hormone and IGF-I
may have long-term health risks," said Dr. Grimberg. "This study
shows the interactions among pathways affecting growth and cancer
are more complex than we have previously appreciated."
Better understanding of those complexities may have eventual clinical
benefits as well, added Dr. Grimberg. "Understanding the fine-tuning
of the growth hormone/IGF system at the cellular level may also
lead to novel therapies for cancer. If we can develop drugs to safely
inhibit IGF signaling, these may improve the effectiveness of conventional
anti-cancer treatments such as chemotherapy and radiation."
###
The National Institute of Diabetes and Digestive and Kidney Diseases,
the Lawson Wilkins Pediatric Endocrine Society Genentech Clinical
Scholar Award and the McCabe Fund Pilot Project Award all contributed
grant support to this study. Dr. Grimberg's and Dr. El-Deiry's co-authors
were Carrie M. Coleman, Zonggao Shi, Timothy F. Burns, Timothy K.
MacLachlan and Wenge Wang, all from the University of Pennsylvania
School of Medicine.
About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare professionals
and pioneering major research initiatives, Children's Hospital has
fostered many discoveries that have benefited children worldwide.
Its pediatric research program is among the largest in the country,
ranking third in National Institutes of Health funding. In addition,
its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for
children and adolescents. For more information, visit http://www.chop.edu/.
Contact: John Ascenzi
Children's Hospital of Philadelphia
Artificial Light At Night Stimulates Breast Cancer Growth In Laboratory
Mice
Main Category: Breast Cancer News
Article Date: 20 Dec 2005 - 0:00 PST
Results from a new study in laboratory mice show that nighttime
exposure to artificial light stimulated the growth of human breast
tumors by suppressing the levels of a key hormone called melatonin.
The study also showed that extended periods of nighttime darkness
greatly slowed the growth of these tumors.
The study results might explain why female night shift workers
have a higher rate of breast cancer. It also offers a promising
new explanation for the epidemic rise in breast cancer incidence
in industrialized countries like the United States.
The National Cancer Institute and the National Institute of Environmental
Health Sciences, agencies of the federal National Institutes of
Health, provided funding to researchers at the Bassett Research
Institute of the Mary Imogene Bassett Hospital in Cooperstown, New
York and The Thomas Jefferson University in Philadelphia, Pa. The
results are published in the December 1, 2005 issue of the scientific
journal Cancer Research.
"This is the first experimental evidence that artificial light
plays an integral role in the growth of human breast cancer,"
said NIEHS Director David A. Schwartz, M.D. "This finding will
enable scientists to develop new strategies for evaluating the effects
of light and other environmental factors on cancer growth."
"The risk of developing breast cancer is about five times
higher in industrialized nations than it is in underdeveloped countries,"
said Les Reinlib, Ph.D., a program administrator with the NIEHS'
grants division. "These results suggest that the increasing
nighttime use of electric lighting, both at home and in the workplace,
may be a significant factor."
Previous research showed that artificial light suppresses the brain's
production of melatonin, a hormone that helps to regulate a person's
sleeping and waking cycles. The new study shows that melatonin also
plays a key role in the development of cancerous tumors.
"We know that many tumors are largely dependent on a nutrient
called linoleic acid, an essential fatty acid, in order to grow,"
said David Blask, M.D., Ph.D., a neuroendocrinologist with the Bassett
Research Institute and lead author on the study. "Melatonin
interferes with the tumor's ability to use linoleic acid as a growth
signal, which causes tumor metabolism and growth activity to shut
down."
To test this hypothesis, the researchers injected human breast
cancer cells into laboratory mice. Once these cells developed into
cancerous tumors, the tumors were implanted into female rats where
they could continue to grow and develop.
The researchers then took blood samples from 12 healthy, premenopausal
volunteers. The samples were collected under three different conditions
- during the daytime, during the nighttime following 2 hours of
complete darkness, and during the nighttime following 90 minutes
of exposure to bright fluorescent light. These blood samples were
then pumped directly through the developing tumors.
"The melatonin-rich blood collected from subjects while in
total darkness severely slowed the growth of the tumors. "These
results are due to a direct effect of the melatonin on the cancer
cells," said Blask. "The melatonin is clearly suppressing
tumor development and growth."
In contrast, tests with the melatonin-depleted blood from light-exposed
subjects stimulated tumor growth. "We observed rapid growth
comparable to that seen with administration of daytime blood samples,
when tumor activity is particularly high," Blask said.
According to the researchers, melatonin exerts a strong influence
on the body's circadian rhythm, an internal biological clock that
regulates sleep-wake cycle, body temperature, endocrine functions,
and a number of disease processes including heart attack, stroke
and asthma. "Evidence is emerging that disruption of one's
circadian clock is associated with cancer in humans, and that interference
with internal timekeeping can tip the balance in favor of tumor
development," said Blask.
"The effects we are seeing are of greatest concern to people
who routinely stay in a lighted environment during times when they
would prefer to be sleeping," said Mark Rollag, Ph.D., a visiting
research scientist at the University of Virginia and one of the
study co-authors. "This is because melatonin concentrations
are not elevated during a person's normal waking hours."
"If the link between light exposure and cancer risk can be
confirmed, it could have an immediate impact on the production and
use of artificial lighting in this country," said Blask. "This
might include lighting with a wavelength and intensity that does
not disrupt melatonin levels and internal timekeeping."
"Day workers who spend their time indoors would benefit from
lighting that better mimics sunlight," added Blask. "Companies
that employ shift workers could introduce lighting that allows the
workers to see without disrupting their circadian and melatonin
rhythms."
NIEHS, a component of the National Institutes of Health, supports
research to understand the effects of the environment on human health.
For more information on breast cancer and other environmental health
topics, visit our website at www.niehs.nih.gov .
John Peterson
peterso4@niehs.nih.gov
NIH/National Institute of Environmental Health Sciences
www.niehs.nih.gov
Anti cancer compound in vegetables blocks late stage breast cancer
cell growth
Main Category: Cancer / Oncology News
Article Date: 01 Sep 2004 - 0:00 PST
|
A well-known anti-cancer agent in certain vegetables has just
had its reputation enhanced. The compound, in broccoli and other
cruciferous vegetables, has been found to be effective in disrupting
late stages of cell growth in breast cancer.
Keith Singletary and doctoral student Steven Jackson of the University
of Illinois at Urbana-Champaign report their finding involving sulforaphane
(SUL), which they say could ultimately be used to enhance the prevention
and treatment of breast cancer, in the September issue of the Journal
of Nutrition.
"This is the first report to show how the naturally occurring
plant chemical sulforaphane can block late stages of the cancer
process by disrupting components of the cell called microtubules,"
said Singletary, a professor in the department of food science and
human nutrition. "We were surprised and pleased to find that
SUL could block the growth of breast cells that were already cancerous."
SUL is abundant in such vegetables as broccoli, brussels sprouts
and kale. Chewing causes the cell walls of these vegetables to break,
and SUL is released into the body.
Singletary, a researcher in phytochemicals and cancer chemoprevention,
and Jackson exposed cultures of malignant human breast cancer cells
to SUL. Within hours, SUL blocked cell division and disrupted microtubules,
which are long, slender cylinders made up of tubulin (protein),
that are essential for the separation of duplicated chromosomes
during cell division.
"It is not yet clear whether the doses required to produce
inhibition of tubulin polymerization are higher than those achievable
via dietary intakes," wrote Jackson and Singletary. "However,
the results show that tubulin disruption may be an important explanation
for SUL's antiproliferative action."
"These findings are significant since SUL's actions appear
similar to a group of anticancer drugs currently in use, such as
Taxol," Singletary said.
SUL is studied extensively for its effects against cancer. Previous
reports have shown that SUL induces defensive mechanisms that are
effective in protecting normal cells from the initiation of cancer.
"More than 10 years ago, researchers at Johns Hopkins University
reported that SUL is a potent inducer of enzyme systems that can
defend against carcinogens," Singletary said. Such defense
mechanisms are effective during the early stage of cancer.
The Illinois research extends the 1992 discovery at Johns Hopkins
and pinpoints how SUL works during later stages of cancer, such
that SUL can suppress the orderly division process in human breast
cancer cells.
"The findings may be helpful in the development of new breast
cancer prevention and treatment strategies," Singletary said.
"For example, it may be possible that ingesting SUL in combination
with certain natural compounds or drugs could enhance their anticancer
effectiveness and reduce side effects."
According to the American Cancer Society, breast cancer this year
will account for 15 percent of all cancer deaths in women, and approximately
275,000 new breast cancer cases of various forms will be diagnosed.
Improvements in treatments such as chemotherapy have led to an
88 percent survival rate in Caucasian women and a 74 percent survival
rate in African-American women, according to the most recent ACS
survey in 2003.
However, some current chemotherapy drugs have side effects that
have the ACS and other organizations seeking new strategies that
combine chemotherapy drugs with other treatments to potentially
lessen the toxic effects.
The new Illinois study confirms a previous study in mice. In the
February 2004 issue of the journal Carcinogenesis, Singletary and
Jackson reported that SUL treatments in mice with implanted cancer
cells resulted in decreased tumor size.
More research is needed to assess SUL's potential in countering
breast cancer development, Singletary said. "What we do not
know is how specific SUL and other similar phytochemicals are toward
cancer cells compared to normal cells," he said. "We also
do not know against which cancers SUL's microtubule-targeting actions
are most effective."
Future studies in Singletary's lab will address those issues.
The University of Illinois Agricultural Experiment Station and
the U.S. Department of Agriculture funded the research.
Contact: Molly McElroy or Jim Barlow
mmcelroy@uiuc.edu
217-333-5802
University of Illinois at Urbana-Champaign
Cellular molecule spurs growth of prostate cancer - May provide
target for treatment, study shows
Main Category: Prostate News
Article Date: 01 Dec 2005 - 7:00 PST
|
University of North Carolina at Chapel Hill scientists have identified
a molecule that stimulates the aggressive growth of prostate cancer.
The molecule, Ack1, a member of the growth-promoting tyrosine kinase
gene family, stimulates tumor formation in part by signaling prostate
cells to rid themselves of a tumor-suppressor protein. Normally,
this suppressor protein would inhibit rapid cell growth by signaling
the cell to destroy itself.
A report on the study, which appeared Nov. 15 in the journal Cancer
Research, also points to Ack1 as a potential target for developing
novel drugs against prostate cancer.
The study's senior author, Dr. Shelton Earp, directs the UNC Lineberger
Comprehensive Cancer Center and is Lineberger professor of cancer
research and a professor of pharmacology and medicine.
Tests of Ack1 demonstrate a profound effect on tumor growth in
experimental systems, Earp said. "It's a remarkable effect.
Tumors grew more rapidly and invaded as if they were converted to
advanced prostate cancer."
Another major finding of the study involved an experimental drug
developed by the National Cancer Institute, called geldanamycin.
In laboratory tests, the UNC Lineberger group found Ack1 activity
could be inhibited through interference with its molecular interactions,
thus offering a target for treatment. First, the group discovered
that Ack1 bound to a protein called Hsp90 (heat shock protein 90),
which associated with many oncogenic, or cancer-causing, signaling
proteins.
"If you add geldanamycin to the prostate cancer cell, the
drug knocks Hsp90 off oncogenic signaling molecules. This dramatically
decreases Ack1 activity and slows tumor formation," Earp said.
In addition, the team compared Ack1 activation in advanced prostate
cancer tissue from patients with that found in benign prostatic
hypertrophy, or non-cancerous prostate enlargement. The team showed
the levels of the activated Ack1 to be much higher in the advanced
tumors.
In earlier work, Earp's UNC laboratory was the first to clone a
cell surface tyrosine kinase, Mer.
"We saw that Mer was expressed at reasonably high levels in
prostate cancer cells. And so Dr. Nupam Mahajan, the study's first
author, decided to look at whether Mer had an effect on prostate
cancer growth signaling," Earp said.
In experiments, which used the university's Michael Hooker Proteomics
Core Facility, the team discovered that Mer activated Ack1. This
finding led to the current study.
"Because we found Ack1 is more active in advanced prostate
tumors, and its inhibition blocks experimental tumor growth, we
believe Ack1 should be a target for novel drug development."
Along with Earp, UNC collaborators include UNC Lineberger members
Dr. Nupam P. Mahajan, assistant professor of pharmacology; and Dr.
Young E. Whang, assistant professor of medicine. Dr. James L. Mohler,
chairman of the department of urologic oncology at Roswell Park
Cancer Institute in Buffalo, N.Y., and a UNC Lineberger member,
also collaborated on the study.
The research was funded by the National Cancer Institute.
By LESLIE H. LANG
UNC School of Medicine
L. H. Lang
llang@med.unc.edu
University of North Carolina School of Medicine
http://www.med.unc.edu
|
