Richmond's laboratory gains new insights into tumor growth and wound
healing through studies of the "SOS gene"
Jan. 29, 2001
might call MGSA the SOS gene. That’s because it is switched on in
the vicinity of a wound and produces a special protein, called MGSA,
that attracts the body’s repair crew-infection-fighting white blood
cells and cells involved in the formation of new skin and blood
In the 1980s,
however, when Ann Richmond began studying this lightweight protein,
it was in a much different context. She was searching for a factor
that helps melanoma tumors grow. Even before she and her collaborators
had proven that such a protein exists, they had dubbed the molecule
“melanoma growth stimulatory activity,” or MGSA.
As a result
of their persistent efforts, Richmond and her colleagues successfully
characterized MGSA and so proved the existence of factors that promote
tumor growth. Today, Richmond is a professor of cancer biology and
her laboratory in Vanderbilt’s Medical Center and the Nashville
Veteran’s Affairs Medical Center is still actively pursuing the
scientific trail that opened up when she identified MGSA more than
10 years ago.
Since its discovery,
researchers have found that MGSA plays a number of important roles
in the body. It is essential to wound healing and is actively involved
in inflammatory diseases such as rheumatoid arthritis and psoriasis.
Since its initial characterization, MGSA has also been linked to
several other types of cancer including lung, breast and other skin
cancers. The statistics on melanoma deaths alone are frightening
When combined with the death toll of the other cancers in which
MGSA is implicated ,
the resulting figures dramatize just how great the potential payoff
from a better understanding of MGSA’s activities can be.
If that weren’t
enough, further investigation has shown that MGSA is a member of
a larger group of proteins, called chemokines, that play a number
of critical roles. Close to 100 chemokines
have now been found. Some, like MGSA, recruit white blood cells
to wounds and act as growth factors for many cancers. But others
aid in the formation of the immune system during the embryonic development
and some have been found that even counteract tumor growth.
know that MGSA is found in all animals and is one of the keys to
wound healing. Any injury, for example a cut on an arm or blistering
sunburn, causes cells near the wound to send out SOS messages to
the surrounding tissues. This message is sent in the form of MGSA,
which travels into the cells around the wound and attracts white
blood cells, new skin cells, and cells required to form new blood
vessels to the damaged site. Once this repair team is assembled,
the SOS message is cut off. Help has arrived and no more MGSA is
arise, however, when the SOS message does not turn off normally.
When MGSA is continuously produced, the body continues to respond
long after the appropriate help has arrived. In certain circumstances,
this can give rise to tumors. In addition, established tumors produce
MGSA in order to establish connections to nearby blood vessels.
“In many ways, tumors are like never-healing wounds,” Richmond says
characterized MGSA, little was known about this class of proteins.
A postdoctoral fellow at Emory University at the time, she hypothesized
that melanoma tumor cells must be producing something that promotes
their growth. She and Dave Lawson ,
who was an oncologist at Emory, set out to purify the protein that
they guessed was helping tumors grow.
was not easy. In order to get samples of melanoma to experiment
with, Richmond and Lawson had to visit melanoma patients in the
hospital to get their informed consent. Richmond describes this
as one of the most trying experiences in her early research. Day
after day she would sit at the bedsides of patients at different
stages of the disease and listen to their stories, their hopes and
their dreams. She still remembers many of the patients vividly,
most of whom did not survive their illness.
“these experiences lit a flame of work in us,” Richmond remembers.
“We had to continue for each of these people.”
to the emotional strains specific to the work, Richmond’s team had
to cope with insufficient resources. The tiny lab they were given
for their experiments barely accommodated their equipment, much
less the researchers. That first summer “we only hired skinny people!”
Richmond recalls, laughing. Space problems were compounded by the
fact that the team did not have the funds they needed to buy new
equipment. So they were forced to work late nights using borrowed
equipment, which broke down all too frequently because of the unusual
demands they were putting on it.
grants came through and the research began moving. After seven years
of research, a few blind alleys and many sleepless nights, Richmond
and post-doctoral fellow Greg Thomas
managed to purify and characterize MGSA.
on protein characterization
their characterization effort, the team discovered that the protein
they were calling MGSA looked very similar to another already characterized
protein: platelet factor four. Platelet factor four is a common
factor found in the blood stream. Although the two proteins weren’t
exactly the same, they were similar enough that Richmond became
fearful that her protein was simply another version of the familiar
factor. That caused her to seriously consider abandoning the attempt
to complete her characterization of MGSA.
the counsel of a colleague ,
she decided to continue the effort. That was fortunate because not
only did MGSA turn out to perform a completely different function
than platelet factor four, but also the similarity that had alarmed
Richmond initially proved to be significant: It opened the door
to the discovery of the huge chemokine family, many of which have
structural similarities to platelet factor four.
continues to study MGSA and related chemokines. Her lab is currently
pursuing three different research projects:
- MGSA transcription.
Transcription is the first step in the process by which cells
make proteins. In this step the information coded in DNA is copied
onto a single strand of RNA. The information needed to form a
given protein is cut out and consolidated into a strand of messenger
RNA (mRNA), which serves as the template for the actual assembly
of the protein. Richmond is investigating what triggers the transcription
of MGSA mRNA and what shuts it off. If transcription can be regulated,
then the amount of MGSA that is produced can be controlled as
on Transcription and Translation
- MGSA receptors.
The researchers are characterizing receptors that recognize MGSA
and thus participate in the wound healing and tumor growth processes.
If these receptors can be understood in depth, then perhaps a
way can be devised to keep them from reacting to excess MGSA.
healing and tumor growth. By investigating how normal cells
heal, the researchers are attempting to determine the natural
mechanisms that start and stop the production of MGSA. By using
that block the growth of new blood vessels to the tumor, the team
is testing ways to block tumors from growing.
on DNA extraction, digestion and PCR
work remains before melanoma can be cured, Richmond’s outlook is
positive. So much advancement has been made in the field of chemokine
research since the characterization of MGSA, that new approaches
to the problem are being designed every day. Each new assay
yields new information and a renewed chance to discover what makes
tumors grow and how to stop them. Even if the exploration of MGSA’s
activities does not lead to a cure for melanoma, the family of chemokines
that it introduced could hold the answer to many of basic questions
about how the body works at a molecular level.