Cancer would be little more than a nuisance if cancer cells would only stay put. Most localized tumors are easily removed, but once cancer cells spread, they make an elusive target. "Metastasis is what kills people," says H. Steven Wiley, a cell biologist at the University of Utah in Salt Lake City.

Wiley has spent the last 20 years studying cell signaling, hoping that by understanding how cells normally communicate with their environment, he can grasp what goes wrong when the system fails, as it does in cancer cells. Wiley's model system is the epidermal growth factor receptor (EGFR) pathway, which regulates proliferation and migration in epithelial cells. His group's study of how EGFR ligand release regulates EGFR signaling has uncovered new ways, recently highlighted in the May 25, 1999 issue of the Proceedings of the National Academy of Sciences, to block metastasis [1].

"Cells are free agents," says Wiley. Each cell's behavior is triggered individually by signals from its environment. As Wiley views it, cells "see" their environment using what Wiley calls "cell sonar." Enzymes called metalloproteases release EGFR-binding proteins called ligands from the cell surface into the surrounding environment. Once released, these ligands "interrogate" their milieu before quickly returning to bind with the EGFR. In the process, they pass along information about the environment to the cell.

Wiley's group gave batimastat (British Biotech), a metalloprotease inhibitor, to human epithelial cells known to require EGFR signaling for growth and proliferation. Batimastat halted proliferation of these cells, and it did so at the same rate at which it arrested EGFR ligand release. When the researchers coupled batimastat with C225 (ImClone Systems), a monoclonal antibody that prevents EGFR ligands from binding to their receptors, cell proliferation and migration dropped even further.

This study illustrates that ligand release is an essential step in the EGFR pathway, and it suggests that by blocking ligand release, researchers could effectively prevent metastasis in cancer cells that retain their sensitivity to EGFR, as they do in the majority of epithelial cancers. This approach could change the face of cancer therapy, Wiley says. Such drugs probably won't cure cancer, but if they can prevent metastasis they might downgrade it to a chronic disease, Wiley predicts. The same approach might also prove effective for treating other diseases, since related proteases also control the release of proteins involved in diseases such as Alzheimer's and some inflammatory diseases.

Batimastat was developed before researchers fully understood how it worked, but with Wiley's latest results in hand, industry scientists are busily working on a second generation of metalloprotease inhibitors. Wiley's next step is to test the drugs currently under development. "We want to verify that these things work in animals and eventually we hope these will be used as adjunct therapies for breast cancer and colon cancer," says Wiley. These drugs probably won't make it to the pharmacy for another ten years or more. But personal experience has motivated Wiley to carry on over the long haul. "We all have friends who die of diseases they shouldn't and we're scientists, we should be able to cure these, right?"

Wiley thinks "the big picture" is often neglected. "Modern molecular biology is in the parts hunting stage," says Wiley. "It's sort of similar to the situation that existed in systematics when Linnaeus had come up with his classification scheme. There was a mad rush to go out and find and name species, but no one was really thinking about how the species related to one another." Likewise, Wiley says, attempts to understand how receptor systems function are often left behind in the rush to name new receptors and ligands.

"It's essential to know the components of a system, but that's only the raw material. To understand how the system works you need a theoretical framework to hang these components on," says Wiley. To construct such a framework for cell signaling, Wiley turned to concepts developed by chemical engineers.

"You simply can't understand a receptor system until you know how its molecules behave in space and time," says Wiley. He approaches this problem like an engineer, using mathematical formulas, computer models, and engineered cells to solve it. "I was absolutely amazed when I first met Wiley," says cellular engineer Doug Lauffenburger (Massachusetts Institute of Technology, Cambridge, Massachusetts). "Here was a card-carrying biologist who understood engineering concepts. He was using a quantitative approach to cell biology." According to Lauffenburger, Wiley was among the first scientists to use an interdisciplinary approach to studying receptor systems.

Wiley has used this approach for the past twenty years, but it's only recently that others have begun to take notice. "Wiley was really a true pioneer in the field, and it's taken a while for people to appreciate that," says Lauffenburger. "It hasn't always been easy for him, but he's had the courage to persevere," says Alan Wells, a cell biologist at the University of Alabama in Birmingham.

Wiley began studying the EGF receptor system in 1979 as a postdoc in Dennis Cunningham's lab at the University of California at Irvine. At that time, researchers had amassed a wealth of data on the EGF receptor pathway, but the system's complexity made piecing the data together seem like an impossible mission.

So Wiley asked himself, "How did people in the good old days solve complex problems?" He found his answer in the field of enzyme kinetics, where scientists explained complex problems with simple equations. Wiley went to an old textbook and said, "OK, let's assume that a hormone receptor system is the same as an enzyme system. Can we model this system the same way?"

The answer was yes. Wiley taught himself to program computers, and he discovered that he could reproduce all the EGFR data in the literature with "an incredibly simple Apple II computer model." But then he faced another problem: where to publish the model. Few biologists were using mathematical models at that time, so "No one was publishing this kind of stuff back then," Wiley says. Cunningham encouraged Wiley to submit his model to Cell, and the journal quickly accepted the paper. His was the first computer model that Cell ever published. [2]

The model didn't garner Wiley much recognition at the time. "Bands on a gel are familiar, and people feel like they can evaluate them. But computer models weren't so familiar, and scientists are very wary of things they can't evaluate," recalls Wiley. Few people appreciated their model's utility, Wiley says. "A good computer model, as Doug Lauffenburger likes to say, is a precise, rigorous hypothesis that's brutal in its honesty," says Wiley. His model couldn't prove what was going on in the EGFR system, but "it could exclude 90 percent of the possibilities right off the bat," he says.

Wiley has persisted with the support of his closest collaborator, his wife Lee Opresko (University of Utah), an accomplished investigator in her own right. Opresko is focusing on HER2, a ligand-less receptor that activates when it associates with EGFR. HER2 gained widespread attention with the recent introduction of Herceptin (Genentech), a new breast cancer drug that blocks HER2 from binding EGFR. HER2 is overexpressed in some breast cancers, and "HER2 overexpression seems to indicate a very poor prognosis for cancer patients," Opresko says. Opresko aims to understand the interaction between HER2 and EGFR, a project instigated by former Wiley lab graduate student Becky Worthylake.

Wiley's current graduate students, Jianying Dong, Patrick Burke, and Kevin Schooler, each focus on a different aspect of the EGFR system. Technicians Margaret Woolf and Virginia Hill also contribute to the cause. The atmosphere in Wiley's lab is upbeat. "Steve is really excited about science, and it rubs off on everyone. He keeps people excited," says Opresko. Wiley encourages his lab members to be independent, but at the same time he's always available for discussion and guidance. "Steve's science is very discussive, it's a really open environment," says Burke.

Wiley has always been willing to give new technology a stab at solving old problems. "Steve is different from a lot of PIs in that he likes to think about where current technology can take us in our research. He has ideas that he has wanted to test for years and is just waiting for the technology to become available so we can do the experiments," says Schooler. "Steve isn't restrictive in his attitudes toward techniques. He's willing to work with whatever technology is necessary to answer the question," says Burke.

Christie Aschwanden is a freelance science writer and radio producer in Boulder, Colorado.

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Endlinks

Metastasis Research Society - provides information on all aspects of metastasis. Includes abstracts of the Seventh International Metastasis Research Society Conference in San Diego, October 1998.

OncoLink - a sprawling multimedia site. Maintained by the University of Pennsylvania Cancer Center.

National Cancer Institute - a prime jumping-off point for information. NCI also runs CancerNet, a site updated monthly that provides information geared to three categories of the curious: patients and the public; health professionals; and basic researchers.

Lawrence Berkeley National Laboratory - listings for scientific programs, research news, publications, computing sciences, educational programs, library, and technology transfer material. The ELSI Project covers ethical, legal, and social issues.

Related HMS Beagle articles:

• AACR: BioMednews reports - Meeting Brief on the 90th annual meeting of the American Association for Cancer Research, held in Philadelphia, April 10-14, 1999.
• Biology of the Mammary Gland - Site Review of a central resource for research information relating to the development and function of the mammary gland and to breast cancer tumorigenesis.