Cancer Drug, Tumor Growth Tied to Bone Formation

[an error occurred while processing this directive]

December 02, 1999

SEARCH THE GAZETTE

HARVARD GAZETTE ARCHIVES

By William J. Cromie
Gazette Staff

Bjorn Olsen checks a genetic map of mice bred without a gene that regulates production of a substance needed to control both blood vessel formation and tumor growth. Photo by Justin Ide

Cell biologist Bjorn Olsen studies the skeletons of genetically engineered mice to learn how the body makes blood vessels and bones. Photo by Justin Ide

Discoveries that link bone formation and tumor growth could lead to new drugs that strengthen weak bones and prevent growth of cancer cells.

The key to the link lies in a common need for blood vessels. Neither bones nor tumors can grow without them, and researchers are closing in on new ways to stimulate one kind of growth and block the other.

"Without blood vessels you cannot form bones," notes Bjorn Olsen, Hersey Professor of Cell Biology at Harvard Medical School, who recently identified a gene that is essential for bone growth. He also cloned a gene responsible for producing collagen 18, a protein found in the inner lining of blood vessels. One end of this collagen molecule contains a substance called endostatin, now being tested on humans as a potent cancer fighter.

Other researchers working at Harvard-affiliated Children’s Hospital in Boston found that endostatin blocks the growth of blood vessels to tumors, robbing the tumors of the oxygen and nutrients they need to survive.

"It is one of the most powerful anti-cancer drugs in existence," says Judah Folkman, Andrus Professor of Pediatric Surgery at Harvard Medical School, in whose laboratory the drug was first isolated. Folkman and his colleagues started testing the drug on human patients at Children’s Hospital in October.

Olsen, who is also Forsyth Professor of Oral Biology at Harvard School of Dental Medicine, now concentrates on finding how the body splits endostatin from collagen 18. He and his colleagues have just identified at least one protein that can do the job, an enzyme that neatly cleaves the smaller molecule from the larger.

"If we can understand how such cleavage is regulated in the body, we’ll be in a position to stimulate generation of endostatin and thus increase the amount of this natural cancer-fighter that the body makes," says Olsen. "Thus, it might act as a vaccine against the disease."

How Bones Are Built
&q uot;It’s likely that collagen 18 and endostatin help regulate bone formation by controlling growth of blood vessels," Olsen believes. Therefore, he is studying how collagen 18/endostatin might aid the development of drugs to treat osteoporosis, correct some inherited bone disorders, and even build replacement bones.

Two years ago, Olsen and collaborators in the United States, Europe, and Japan discovered a gene, called CBFA1, which is necessary for forming a complete skeleton. "This gene is essential for bone to form in the embryo," Olsen notes. "Without it, there is not a single bone-producing cell in the body."

In the womb, most bones begin as rubbery cartilage. By means not well understood, cartilage cells start to swell as an embryo develops. The cartilage then breaks down and blood vessels start to sprout at its surface. As these blood vessels grow inward, bone cells and bone marrow replace the cartilage.

If one of two CBFA1 genes that infants inherit from their mother and father is mutated, or not working properly, birth defects can occur. These include a soft spot in the top of the skull due to bone that never hardens, and improperly developed collar bones, which allow people to bend their shoulders across their chests.

"It was the study of such patients that led to the discovery of CBFA1 and its crucial role in bone formation," Olsen comments. "If we could increase the output of the unmutated gene by twofold, we could make up for the inactive gene. Doubling the activity of a single gene is something that’s possible in principle, so one day we may have a cure for these disorders."

Bones and Birthmarks
The bone-building process controlled by CBFA1 involves factors that stimulate growth of blood-vessel linings that contain collagen 18. The collagen, in turn, may release endostatin to put the brakes on this process, just as it inhibits constructing blood vessels to tumors.

Any substance th at increases the activity of CBFA1 should also increase bone formation. "Drug companies all over the world are searching for drugs that can do this in the hope of finding more effective treatments for osteoporosis, the weakening of bones with age," Olsen says. "It’s a very hot area."

Most osteoporosis treatments aim at preventing bone loss by interfering with the activity of cells that degrade bone. By contrast, Olsen directs his research at understanding how bone forms in the womb and applying that understanding to stimulating bone growth in old age.

Does he think it will someday be possible to grow replacements for bones severely broken or degraded by trauma or disease? "I think so," he says. "There’re a lot of factors involved; bone formation is an exceedingly complex process. But there’s no doubt that, as we understand more and more about it, we’ll learn to make bone in a controlled manner."

The knowledge needed to do this includes finding out how veins and other blood vessels are made, as well as how growth stimulators and growth inhibitors like endostatin work. This quest has taken Olsen down to road to birthmarks.

Birthmarks involve abnormal vein growths that include everything from harmless "stork bites" on the necks of newborns, and "port-wine strains" such as mark the forehead of Mikhail Gorbachev, to dangerous tumors known as hemangiomas. Studying why something is abnormal often provides clues to what is normal.

An old belief holds that birthmarks originate when passionate longings of a pregnant mother imprint themselves on her fetus. Olsen and his colleagues found a more scientific explanation: a genetic mutation that skews the control of blood vessel formation. Specifically, the mutation increases the activity of a molecule on the inner lining of blood vessels.

Olsen’s research team bred laboratory mice that carry this mutation and are studying the rodents t o find out whether they develop abnormal clusters of blood vessels similar to human birthmarks.

Folkman has successfully treated disfiguring hemangioma tumors with a drug similar to endostatin. The drug, called interferon, prevents tumors from secreting a growth factor that recruits new blood vessels from nearby tissues. In one case, the treatment shrunk a tumor the size of an orange growing in the jaw of a 6-year-old girl.

Olsen and colleagues also study mutated mice to learn more what endostatin does in the bodies of people without tumors.

"Endostatin is produced normally in humans and mice, not just in tumors," Olsen notes. "Fragments of collagen 18-like endostatin are floating in your body all the time. Why? What does endostatin do? When we find out, we’ll know much more about how blood vessels and bones form."