MetroHealth researcher learns a key secret about a two-faced protein that can promote or suppress cancer

by John Mangels/Plain Dealer Science Writer

Monday July 06, 2009, 12:00 PM

CLEVELAND ?Oh, the lure of the psychodrama! From Teresa dumping the dinner table on her girlfriends in "Real Housewives of New Jersey" to South Carolina Gov. Mark Sanford's AWOL love romp in Argentina, we can't get enough of seemingly respectable people misbehaving.

Scientists aren't immune to this good-goes-bad fascination. But they can get their fix from a test tube as well as reality TV. Take Bingcheng Wang, a cancer researcher at MetroHealth Medical Center and Case Western Reserve University. Wang is intrigued by the conversion of normal cells into cancerous ones. Specifically, he has spent years trying to decipher a Jekyll-and-Hyde molecule called EphA2 which seems to be both an "on" and "off" switch for malignancy.

In normal cells, EphA2 is a good cop. Among other duties, it keeps the cell on the straight and narrow, holding in check the biological machinery that otherwise would allow the cell to roam to places in the body it perhaps shouldn't.

Cancerous cells produce a boatload of EphA2, way more than normal cells do. While that would seem to restrict the cancer cells' movement, paradoxically, the opposite is true. EphA2 morphs into a bad cop that helps cancerous cells spread and form additional tumors. This two-faced conduct has been a major mystery to cancer researchers, who have wondered how the molecule can function as both a tumor promoter and suppressor.

As Wang and his collaborators at MetroHealth and CWRU's Comprehensive Cancer Center report today in the journal Cancer Cell, they believe they've figured out EphA2's split personality -- how one molecule can manifest contradictory behaviors, and how it morphs from benevolent to malevolent. Whether EphA2 is good or bad depends on the company it keeps.

While their research was done in cell cultures in the lab, not in people, Wang is hopeful the findings will lead to new strategies to block cancer's growth.

"I would say we're three to five years from human trials," he said. "We have a long way to go."

Elena Pasquale, a cancer researcher at LaJolla, Calif.'s Burnham Institute for Medical Research who has extensively studied EphA2, said the work of Wang and his team represents a "breakthrough," providing "the first convincing explanation" for the molecule's dual roles.

"EphA2 has been considered a highly promising target for cancer therapy, but its paradoxical activities have made it difficult to decide how best to interfere with its function," Pasquale said via e-mail. Wang's research should clarify how to target the molecule, she said.

At its most basic, cancer is a disease of miscommunication. Cells get their cues on how to act from their own DNA from other cells, and from the environment around them. If these internal or external signals are faulty, a cell may start churning out copies of itself rather than self-destructing as it's supposed to when things go wrong.

Flawed, mishandled or missing messages also may trigger a cell to travel to sites where it doesn't belong, then invade and put down roots -- a lethal process called metastasis. Treatment can wipe out the primary tumor, but these widely disseminated cells, which multiply and form tumors far from the original cancer site, are often what kills patients.

Much of the communication between a cell and its surroundings is made possible by molecules called receptors. Cells make many different kinds, for different jobs. They jut from the cell's surface and function roughly like the various jacks, ports and slots on a computer.

Receptors are a docking point for signaling molecules circulating outside the cell. The signaling molecules carry instructions for the cell: come over here; stay away; start reproducing; shut down, and so on.

Signaling molecules physically fit into specific receptors, the way an iPod plugs into your computer's USB port but not its memory card slot. If the receptor linkage works, the signaling molecule launches a chemical chain reaction inside the cell that carries out its instructions.

EphA2, the protein that Wang is interested in, is one such receptor. It sits on the exterior of epithelial cells, which line most of the body's organs (and which are the origin point for most human cancers). Scientists don't know all of EphA2's functions, but a vital one is helping epithelial cells sense the environment around them, so they know what areas are favorable to move into and grow.

This navigating function is especially significant before birth, when a fetus' organs are forming and its developing brain is snaking out nerve fibers to wire up the body. EphA2 also helps guide the formation of blood vessels. The molecule "is there for a good reason," Wang said. "It's designed by nature to do very important things."

Previous research has shown that EphA2 has an "off" switch. When a signaling molecule called ephrin-A1 hooks up with the EphA2 receptor, the partnership shuts down the cell's growth and migration machinery. That's an important safety feature to keep epithelial cells from cropping up in tissues where they don't belong and might cause damage if they congregate.

Cancer cells crank out huge amounts of EphA2; their surfaces are studded with as many as 10,000 times the receptors that normal cells have. It's as if the cells are waving a red flag, crying out for something to stop them.

But cells with lots of EphA2 can't bind as easily with the off-switch molecule, ephrin-A1, which is also in short supply. So without its partner to deactivate it, the switched-on, hyped-up EphA2 is vulnerable to being corrupted.

As Wang and his colleagues found, that's exactly what happens. A powerful gang of tumor-causing proteins within the cancer cell hijacks EphA2, chemically modifies it, and puts it to work steering the cell to a new home, where it can form additional tumors.

In a lab dish, Wang stimulated human brain cells to ramp up their production of EphA2, like cancer cells do. The switched-on cells had amplified abilities to migrate and invade surrounding tissue. When Wang switched off EphA2 by adding its calming partner, ephrin-A1, the cells' ability to malignantly grow and spread was blunted.

So a strategy to fight cancer metastases should be to find a drug that mimics ephrin-A1's knack for shutting down EphA2. Wang and his colleagues know the layout of EphA2's docking port, where ephrin-A1 plugs in. They're testing compounds that could fit it and turn off the cancer cells' navigational machinery.

Nothing in cancer research is easy, though. The brain, where cancers often spread, is protected by a natural barrier that blocks most toxins -- and unfortunately most drugs -- from reaching it. It would be hard to get at metastasizing brain cancer cells behind the barrier.

However, tumors need a blood supply, and the epithelial cells they send out to form blood vessels travel beyond the brain's barrier. Since those cells carry EphA2 receptors, switching them off and halting their migration in theory should starve a brain tumor, Wang said.