| Study
links proteins to patient prognosis
originally posted on August 22, 2001
ANN ARBOR, Mich. – Like most killers, prostate
cancer leaves fingerprints. Every malignant cell has a unique
pattern of active genes and proteins that spells the difference
between benign, localized or metastatic tumors. Hidden in
this molecular profile are answers to questions doctors hear
every day: Is surgery really necessary? Can I afford to wait?
Will the cancer come back?
 |
| Normal prostate tissue (left)
has an organized structure with prostate epithelial
cells (stained blue) which surround and line prostate
glands (white areas).
Photo credit: Mark Rubin, University of Michigan
Medical School |
Until now, physicians have been unable to decode these fingerprints,
which hold the key to understanding the relationship between
gene expression and future prognosis for men with prostate
cancer. But a new study from the University of Michigan Medical
School, published in the Aug. 23 issue of Nature,
offers scientists their first look at the genetic and molecular
profile of prostate cancer.
"Our study has important applications in the diagnosis, prognosis
and treatment of prostate cancer," says Mark Rubin, M.D.,
a co-author of the Nature paper and an associate professor
of pathology and urology in the U-M Medical School. "The ultimate
goal is to help physicians determine which patients need immediate,
aggressive treatment and which can be watched and treated
conservatively."
Researchers at the U-M's Comprehensive Cancer Center analyzed
prostate tissue samples from 50 men and found nearly 200 genes
or gene fragments in which expression profiles varied consistently,
depending on whether the tissue was normal or malignant.
U-M researchers used more than 80 complementary DNA microarrays
to assess gene expression profiles in four types of tissue.
These included normal prostate tissue from men with and without
prostate cancer, tissue with benign changes, localized prostate
cancer and aggressive, metastatic cancer.
 |
Cancerous tissue (right) s completely
disorganized. The uncontrolled growth of malignant cells
has destroyed the normal glandular structure.
Photo credit: Mark Rubin, University of Michigan
Medical School |
Tissue samples were obtained from the U-M Prostate Specialized
Program of Research Excellence (SPORE) tumor bank, funded
by the National
Cancer Institute and directed by study co-author Kenneth
Pienta, M.D., a professor of internal medicine and surgery
in the U-M Medical School.
"Previous prostate cancer studies focused on
one gene at a time," says Arul Chinnaiyan, M.D., Ph.D., an
assistant professor of pathology in the U-M Medical School,
who directed the study. "Using microarray technology, we were
able to 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."
While some of the genes identified in the U-M
study are well known to cancer researchers, many others have
never before been associated with prostate cancer. Two of
these new genes are hepsin and pim-1, which could turn out
to be important new clinical biomarkers for prostate cancer,
according to Rubin.
When U-M scientists tested more than 700 prostate
specimens for the presence of hepsin protein, the highest
levels were found in pre-cancerous tissue - the type seen
just before prostate cancer develops, according to Chinnaiyan.
Lowest levels were found in benign prostate tissue. While
hepsin's exact function is still unknown, U-M researchers
suspect it plays a key role in establishment of tumors. Pim-1,
a known cancer-causing gene, also was highly expressed in
prostate cancer. Importantly, levels of hepsin and pim-1 protein
both were correlated with patient prognosis.
To ensure accuracy, the genetic profile of normal
human prostate tissue was used as an experimental control
at each stage of the study. "Our reference point was always
normal tissue, not generalized cell lines," says Chinnaiyan.
"When we say a gene is up-regulated or more frequently expressed
in prostate cancer, it means as compared to normal prostate
tissue -- often normal tissue from the same patient, which
was adjacent to the tumor."
"Without the U-M's prostate tissue bank this
work would not have been possible," says Rubin. "We were also
fortunate that U-M is one of only three medical schools in
the United States with a rapid autopsy program where tissue
samples are obtained within hours of death," adds Chinnaiyan.
"Since RNA is prone to rapid degradation, it's impossible
to track gene expression in cells from autopsied tissue, unless
RNA is isolated soon after the patient dies."
According to Chinnaiyan, the next step is determining
the functional role for each gene identified in the study
as having an association with prostate cancer. "This paper
will generate a great deal of work for researchers in many
laboratories," he predicts.
"It has been 15 years since the Prostate Specific
Antigen (PSA) test became available in 1987," says Rubin.
"This approach could give us many new diagnostic tests within
three to five years. Eventually, it could lead to a diagnostic
kit physicians could use to determine the best treatment and
prognosis for their patients with prostate cancer."
The research was supported by the National Cancer
Institute's Specialized Program of Research Excellence in
Prostate Cancer (#P50 CA 69568). The U-M has applied for a
patent on prostate cancer gene expression profiles for future
diagnostic and therapeutic use.
Other U-M scientists involved in the study include:
Saravana M. Dhanasekaran, Ph.D., research fellow; Terrence
R. Barrette, research associate; Debashis Ghosh, Ph.D., assistant
professor of biostatistics in the U-M School of Public Health;
Rajal Shah, M.D., assistant professor of pathology; Sooryanarayana
Varambally, Ph.D., research fellow; and Kotoku Kurachi, Ph.D.,
professor of human genetics.
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