Ann Richmond's laboratory gains new insights into tumor growth and wound healing through studies of the "SOS gene"

Allison Byrum/Intern
Jan. 29, 2001

You 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 vessels.

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.

Scientists now 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 needed.

Problems can 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 .

Before Richmond 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.

The research 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.

Additional biographical details

Nevertheless, “these experiences lit a flame of work in us,” Richmond remembers. “We had to continue for each of these people.”

In addition 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.

Finally, however, 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.

Background on protein characterization

Midway through 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.

Influenced by 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.

Today, Richmond 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 well.

Background 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.
• Wound 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 special chemokines that block the growth of new blood vessels to the tumor, the team is testing ways to block tumors from growing.

Background on DNA extraction, digestion and PCR

Although much 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.