Argonne researchers find 217 new targets for anti-cancer drugs
ARGONNE, Ill. (April 15, 2006) — By identifying novel genes critical to cancer
progression, biologists at the U.S. Department of Energy's Argonne National
Laboratory have expanded the number of drug targets researchers have available
for study to find ways to stop tumors in their tracks. The report is published
today in Cancer
Research.
The study centers on capillary formation, or angiogenesis, a process shown
to be essential to tumor progression as tumors attract capillaries to provide
oxygen essential for growth and frequently use those same vessels to send out
metastatic cells. By zeroing in on these capillary-forming proteins, drug researchers
may be able to treat a tumor by directly cutting off its blood supply.
Drug researchers, using tools available since the human genome was sequenced,
seek specific targets to develop more precise cancer drugs with fewer side
effects. "Once you have a unique target," explained biologist Diane
Rodi, "you don't have the side effects of the drugs – most cancer drugs
are anti-growth drugs that kill all the growing cells in the body. Most cancer
therapies are not very specific and that is why they are so toxic."
The Argonne biologists identified 217 proteins involved only in capillary
formation -- morphogenesis -- by finding all the gene products turned on during
capillary formation and subtracting out those related only to growth, or proliferation,
in a novel process called subtractive transcriptomics.
Argonne biologists grew human endothelial cells – the
cells involved in blood vessel formation – on a tumor tissue-mimicking plate.
As the capillaries grew over an 8-hour period, researchers isolated RNA samples
at intervals – at 30 minutes, 1 hour, 2 hours, 4 hours and 8 hours. To determine
which genes do not contribute specifically to blood vessel formation, endothelial
cells were grown on gelatin-coated plastic. RNA was isolated at the same intervals
as on the tumor tissue-mimicking plate.
Each RNA sample was tested using microarray analysis at the University of
Chicago. The microarrays hold 44,000 samples of known RNA coded by the human
genome. A reaction reveals the RNA that is being produced at each stage of
the biological process. RNA codes for proteins.
"We wanted to find the proteins that are only made when the endothelial
cells are making a capillary, not when they are just growing," Rodi said. "We
took all of the genes that were made on the tissue plate and subtracted out
those from the plastic plate. And we were left with 217."
The researchers sought the proteins in the capillaries using commercially
available antibodies. Of the 16 morphogenesis-specific proteins tested,
all were found in the capillaries after they were completely formed.
The capillary research revealed a bonus insight into a still mysterious nature
of cells – their polarity. Cells are not the same all over their surface – different
sections perform different tasks like acting as environmental sensors or making
little “feet” to mediate cell movement. But researchers do not yet know all
of the genes which are involved in polarity.
The majority of the 217 proteins identified by the Argonne group manage movement
within the cell, long distance migration, cytoskeletal reorganization and cellular
stickiness – all processes involved in cell polarity. The Argonne study revealed
that more angiogenic genes are involved in polarity than previously believed,
and identified a large number of novel proteins which may be rate-limiting
for the angiogenic process.
"This information will help with developing new drugs," Rodi said. "Once
you know a gene product helps out in a process, then it automatically becomes
a possible drug target."
The next step is to find antibodies to the rest of the 217 genes – only about
50 are commercially available – and determine if they all are present in the
capillaries. They are relying on a novel approach to express human proteins
high throughput in bacteria that other Argonne biologists are in the process
of developing. Long-term research could lead to new medications for cancer
as well as for eczema, macular degeneration and rheumatoid arthritis – other
diseases involving pathological capillary formation.
Argonne National Laboratory seeks solutions to pressing national problems in science and technology.
The nation's first national laboratory, Argonne conducts leading-edge basic
and applied scientific research in virtually every scientific discipline. Argonne
researchers work closely with researchers from hundreds of companies, universities,
and federal, state and municipal agencies to help them solve their specific
problems, advance America 's scientific leadership and prepare the nation for
a better future. With employees from more than 60 nations, Argonne is managed
by UChicago
Argonne, LLC for
the U.S.
Department of Energy's Office
of Science.
For more information, please contact Steve McGregor (630/252-5580 or
media@anl.gov) at Argonne.
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