Home > Newsroom > Publications
> Progress Fall, 2002 Index
Research Roundup
U-M scientists find new genetic marker for prostate cancer
Using the power of
advanced DNA microarray technology, scientists at the U-M Medical Shcool
have identified a gene that triggers production of a specific protein
in cancer prostate cells. Because the protein is present in large amounts
only in malignant cells and is easily visible when stained, it could improve
the accuracy and sensitivity of screening tests for prostate cancer --
the second leading cause of cancer-related deaths in men.
The protein is an
enzyme involved in fat metabolism called a-methylacyl-CoA racemase, or
AMACR for short. AMACR has never before been associated with any type
of cancer, according to Mark A. Rubin, M.D., and Arul M. Chinnaiyan, M.D.,
Ph.D., the scientists who directed the U-M research study. Results were
published in the April 3 issue of the Journal of the American Medical
Association.
"We detected high levels of AMACR protein in over 95 percent of more
than 300 prostate tissue samples that contained localized cancer,"
says Dr. Chinnaiyan, an assistant professor of pathology in the U-M Medical
School. "Equally important, we found very little or no AMACR protein
in benign prostate tissue or in tissue with non-malignant cell changes.
We then evaluated the clinical utility of AMACR immunostaining on 94 prostate
needle biopsies; the sensitivity and selectivity ratings were 97 percent
and 100 percent."
"AMACR is one of approximately 20 genes which we found to be over-expressed
consistently in prostate cancer," Dr. Chinnaiyan adds. "This
doesn't mean that these genes cause prostate cancer, but they can be a
marker or indicator of prostate cancer for diagnostic or prognostic purposes."
Improvement over PSA tests
AMACR's accuracy and specificity is a major improvement over the Prostate
Specific Antigen (PSA) test-the only diagnostic screening test currently
available to physicians. "The beauty of AMACR is that it is cancer-specific
and concentrated only in malignant cells," says Dr. Rubin, an associate
professor of pathology and surgery in the U-M Medical School. "PSA
can't differentiate between cell changes caused by cancer and those caused
by benign changes in the prostate. As a result, PSA tests have a high
rate of false positives, which can mean repeat needle biopsies and unnecessary
surgery."
U-M researchers say AMACR could act as a diagnostic marker for other types
of cancer too. When Drs. Rubin and Chinnaiyan surveyed cells from different
types of cancer looking for AMACR over-expression, they found it in colorectal,
prostate, ovarian, breast, bladder, lung, renal cell, lymphoma and melanoma-with
the highest amounts present in colorectal and prostate cancer.
Research on the genetic and molecular profile of prostate cancer using
DNA microarray analysis is part of a major initiative under way at the
U-M Comprehensive Cancer Center. Its goal is to link molecular genetics
with clinical outcome for all types of cancer.
"By looking at gene expression, we can learn so much more about a
tumor," says Cancer Center Director Max Wicha, M.D., U-M distinguished
professor of oncology, and a professor of internal medicine. "It
explains why one patient's tumor remains localized, while another tumor
spreads. It will allow us to tailor specific therapies to the gene expression
profile of each patient."
"Previous prostate cancer studies focused on one gene at a time,"
Dr. Chinnaiyan says."With DNA microarray technology, we can look
at thousands of genes in prostate cells simultaneously. This is important,
because it is most likely that many genes are involved in the development
and progression of prostate cancer-each controlling a different step in
the process."
The complete news release is on-line.
return to top
U-M
study finds new target in war against graft-versus-host disease (GVHD)
University
of Michigan scientists have recently discovered how graft-versus-host-disease,
a common and deadly complication of life-saving bone marrow transplants,
attacks and often kills its victims.
At
least 500 Americans die from GVHD every year. this discovery could help
prevent these deaths and reduce the risk of hospitalization and debilitating
side effects for more than 5,000 Americans who receive donor bone marrow
transplants annually, primarily to treat leukemia and other cancers.
Results
from the U-M study, published in the June 2002 issue of Nature Medicine,
show how skin, liver and gastrointestinal cells in mice with GVHD are
destroyed from a distance by a fire-storm of immune system proteins called
inflammatory cytokines. Human clinical trials, based on findings from
the Nature Medicine study, are now underway at the U-M Comprehensive
Cancer Center.
Understanding
the role of cytokines in GVHD
"Cytokines turn healthy immune cells in
donated bone marrow -- something given to cure patients -- into lethal
weapons capable of killing them," says James L. M. Ferrara, M.D.,
Director of the U-M Blood and Marrow Transplant Program and a profesor
of internal medicine and pediatrics in the U-M Medical School.
Dr. Ferrara says the
study calls into question a widely accepted assumption that T cells-immune
cells that attach to and kill just one target cell at a time-are the major
cell-killing agents of graft-versus-host disease. "It's the difference
between a direct attack by ground troops and a general air strike,"
Dr. Ferrara explains.
The study's findings will help scientists focus GVHD prevention strategies
on its primary killing agents-especially two powerful cytokines called
tumor necrosis factor-alpha and interleukin-1. "Now that we know
cytokines are the major cause of GVHD-induced cell damage, we can look
for ways to neutralize them or block their production," Dr. Ferrara
says.
The risk of GVHD is highest following a bone marrow transplant from an
allogeneic donor-someone other than the patient or the patient's identical
twin. Symptoms of acute GVHD usually begin three to six weeks after the
transplant, often after the patient has been discharged and appears to
be recovering well.
Instead of the patient's body rejecting a donated organ, as occurs in
an organ transplant, the donated bone marrow, called the graft, rejects
cells in the host or patient. GVHD's primary targets are skin, liver and
epithelial cells lining the stomach and intestines of the host. Damaged
by heavy doses of radiation and chemotherapy used to destroy the patient's
cancerous bone marrow before the transplant, these cells secrete substances
that activate antigen-presenting cells that are in the patient's immune
system.
"Until now, researchers assumed that pre-transplant radiation killed
all the host's antigen-presenting cells (APC's), so scientists discounted
the importance of these cells in GVHD," says Takanori Teshima, M.D.,
Ph.D., a former U-M research scientist now at Japan's Okayama University.
"But we found that a few APCs remain deep inside tissue. If even
one percent survive, it is enough to trigger the graft-versus-host reaction."
When immune cells from the donor's bone marrow meet APCs carrying substances
from host cells, some of the donor cells are sensitized to see the patient's
cells as the "enemy." These cells respond by firing salvos of
inflammatory cytokines, especially tumor necrosis factor-alpha and interleukin-1.
The cytokine barrage transforms "good" immune cells in the patient's
new bone marrow into an army of destructive effector cells all primed
to attack and kill the host.
"Cytokines can travel through the bloodstream and, therefore, inflict
their damage from a distance," Dr. Ferrara adds. "So there's
no need for direct contact between donor effector cells and host target
cells, and antigen expression on the host's epithelial cells is not required
for development of graft-versus-host disease."
In his study, Dr. Teshima used strains of genetically altered laboratory
mice, which expressed specific classes of antigens on APCs derived from
donor bone marrow, but not on host target cells. "The availability
of these chimeric mice allowed us to test most donor-recipient combinations
involving major antigens called MHC molecules," he says. "Neutralizing
TNF-alpha and interleukin-1 suppressed dramatically the mortality and
morbidity of GVHD in mice."
Developing methods to block cytokines
Drs. Teshima and Ferrara believe blocking cytokines could preserve the
ability of donor T cells to bind to and kill the patient's leukemia cells
without risking the toxic effects of GVHD. "Since 90 percent of bone
marrow transplants are given to patients with leukemia, it is important
not to interfere with the direct-contact killing mechanism," Dr.
Ferrara says.
In clinical trials under way at the U-M Cancer Center, Dr. Ferrara and
colleagues are investigating new drugs that bind to and neutralize tumor
necrosis factor. U-M physicians are testing these drugs to determine if
they can prevent cell damage in patients with GVHD and lung disease after
a bone marrow transplant. In a future study, Dr. Ferrara hopes to determine
whether other drugs can block the original interaction between host APCs
and donor immune cells, preventing the initial activation phase of acute
GVHD.
For information on
bone marrow transplant clinical trials, call the Cancer AnswerLine™ at
(800) 865-1125.
The complete news release is on-line.
Return to top
