Rare disease offers major insights into what makes tumors tick

What can a disease so rare most people have never heard of it teach researchers about a process that affects virtually every type of large tumor?

If you’re William Kaelin, M.D., potentially enough to devise a way of halting one of the most dangerous phases of tumor growth.

Kaelin and his colleagues in the Division of Medical Oncology are among the leading investigators of von Hippel-Lindau syndrome (VHL), a condition in which blood vessels grow excessively in certain parts of the body. Some patients develop small "knots" of blood vessels that can leak or interfere with surrounding tissue. The tangles of blood vessels, called angiomas, usually occur in the eye, brain, or spinal cord. The condition also can involve the development of tumors of the kidney, pancreas, liver or adrenal glands.

VHL is a genetically transmitted condition, caused by a flaw in a single gene. It can be inherited from a parent or arise when the gene begins to function improperly. It is one of the most common familial cancers, although it is a rare disease, striking one person in 40,000 or a total of just over 6,000 in the United States.

"It was always considered a fascinating clinical oddity," says Kaelin, who first learned about the condition during medical school. "It was one of those rare diseases that the attending physician would ask you about when you were making rounds."

What makes the condition so interesting is that it "fools" cells into behaving as though they are being starved of oxygen when, in fact, they are not. Cells normally respond to a shortage of oxygen by issuing a chemical call for additional red blood cells (which carry oxygen) and new blood vessels, which carry red blood cells to the desired location. VHL triggers the growth of blood vessels even though blood-oxygen levels are normal.

Study of the disease mushroomed in 1993 when the gene for VHL was found by researchers at the National Cancer Institute. The gene turned out to be a tumor-suppressor gene. That is, when functioning properly, it acts as a brake on cell growth. When the gene is mutated or otherwise malfunctioning, it is as if the brakes are left off, permitting runaway cell growth and the development of tumors.

Kaelin and his colleagues sought to discover how the gene works, first by plugging its chemical formula into a computer to determine if it was structurally similar to any other genes. It wasn’t, prompting researchers to take another tack.

An experiment of nature

Studies of kidney cancer cells had shown that, three times out of four, the cells lack the protein product of the VHL gene, either because the gene is mutated or because it is handcuffed by certain groups of molecules. "It’s as though nature did an experiment and told us what happens when you knock out VHL genes," Kaelin said. "The growth of the cells goes unchecked."

Studies of other tumor-suppressor proteins had shown that if malfunctioning tumor-suppressor proteins had shown that if malfunctioning tumor-suppressor genes can be replaced with properly functioning ones (in a laboratory dish), then cells can be prevented from turning cancerous. Kaelin and his colleagues attempted something similar with VHL. They reintroduced VHL protein into kidney cancer cells which had lost a copy of the VHL gene. In the laboratory dish, the cells remained cancerous. When they were injected into mice, however, the cancer cells had lost the ability to form tumors.

The next question researchers sought to answer was, how does VHL issue this powerful restraining order?

In 1995, Kaelin and his colleagues identified two proteins -- Elongin B and C -- that bind to VHL protein. The lab team knew that when Elongin B and C are bound to another protein -- Elongin A -- it serves as a signal to certain genes to switch on. "We theorized that if Elongin A-B-C turned the genes on, then VHL protein with Elongin B and C turns them off," says Kaelin.

What turns genes "on"?

But which genes? "We went back to one of the original curiosities about von Hippel-Lindau syndrome -- the fact that it causes blood vessels to grow even though cells are not being deprived of oxygen," Kaelin says. They found that in cells with Elongin A-B-C, the genes that stimulate the growth of blood vessels were on, leading to the creation of angiomas. In cells with VHL protein, by contrast, the genes for blood vessel growth were off. It’s as if VHL protein and Elongin A are in competition: whichever one predominates in the cell determines whether blood vessel-growing genes are on or off.

The case is not as cut-and-dried as it may seem. For one, VHL binds to three other proteins beside Elongin B and C. No one is sure which of these, or which combination of them, turns VHL protein into an anti-tumor switch. Researchers need to demonstrate that it is the inhibition of Elongin A-B-C that is responsible for shutting down tumor growth. Just because the binding of VHL protein to Elongin B and C coincides with a stoppage of tumor growth doesn’t mean it causes that stoppage.

If VHL protein proves to be as potent a tumor-stopper as it seems to be, it may inspire a new form of cancer therapy. One of the most dangerous activities in the life of a tumor is known as angiogenesis -- when a tumor taps into the body’s blood supply by growing a network of blood vessels. Angiogenesis not only enables tumors to grow to a larger, more dangerous size, but provides a route for individual cells to break off the main tumor and travel to other parts of the body.

"If we can prove that VHL protein is able to halt the process of blood vessel growth, then we may be able to develop similar substances that can be used as drugs to prevent angiogenesis and bring tumor growth under control," Kaelin says.