Down's Syndrome May Hold Important Clue

The study of the basic processes behind new blood vessel growth began in earnest during the late sixties and has since produced a sizable body of knowledge. Today, many pharmaceutical companies are producing drugs that can effect change in both primary cancer sites as well as the spread of metastatic disease. Angiogenesis is the creation of new blood vessels. Angiogenesis is a normal and necessary function of the body for wound healing, and during menstruation and pregnancy. In VHL and in cancer, that normal function can go out of control in certain cells, and knots of blood vessels are created where they are not needed, forming hemangiomas or feeding cancer tumors.

In presenting this year's John Duckett Memorial Lecture at the American Urological Association, Judah Folkman, M.D., said that the field of angiogenesis research has grown considerably since 1971 when there were only three papers in the literature with angiogenesis in the title, two from his lab and one criticizing a former paper of his.

"This has expanded to thousands of laboratories worldwide, and there are on average forty papers every six days published in the scientific literature that have angiogenesis in the title," said Dr. Folkman, Professor of Pediatric Surgery at the Children's Hospital and Harvard Medical School in Boston, Massachusetts.

The role of positive and negative regulators in angiogenesis is becoming clear and the study of oncogenes (cancer-promoting genes) has produced surprising results. The mechanism of these genes can be quite complicated. "In fact, many of the oncogenes up-regulate a stimulator and also down-regulate an inhibitor. It has been shown that at least twenty percent of the known oncogenes are essential for the angiogenic switch," said Dr. Folkman. The "angiogenic switch" is his term for the moment at which the tumor begins to recruit new blood vessels so that it can grow. A tumor needs a food supply in order to grow, much as an army travels on its stomach. Without a supply-chain of blood vessels to maintain the food supply, the tumor will stop growing at a very small size.

The original discovery of oncogenes and tumor suppressor genes was based mainly on their ability to promote or decrease tumor growth in laboratory dishes. A recently discovered new function of oncogenes and tumor suppressor genes is that they also regulate angiogenesis. VHL is a tumor-suppressor gene whose job is to be part of the "off" switch for angiogenesis. When the VHL protein is missing in the cell, the "off" switch doesn't work and the process of angiogenesis begins.

In experimental animals, microscopic tumors must grow, or they cannot spread. The offspring of this research is now producing treatments for cancer in the human body by either directly or indirectly interfering with various angiogenic switches. The Nova Series of WGBH Boston, an affiliate of U.S. National Public Television, has prepared a fascinating report on angiogenesis, called Cancer Warrior, describing Dr. Folkman's development of the theory of angiogenesis. The story is also recounted in the book Dr. Folkman's War.

One of the most studied inhibitors, endostatin, continues to offer surprises. With the relative ease that laboratories now have in producing endostatin (some 81 have), the rate of publication is increasing by three or four per week. Endostatin is much in the news, and sounds very exciting indeed. However the connection between endostatin and VHL has not yet been made. In 1994, Joyce Graff and Dr. Lloyd M. Aiello of our Medical Advisory Board met with Dr. Folkman and asked whether endostatin might be helpful for people with VHL. Dr. Folkman indicated that there were tracers in the urine which should tend to indicate whether endostatin might be beneficial.

VHLFA Members donated some 28 urine samples to do the assessment. Fellows in Dr. Folkman’s lab, examined these samples and determined that endostatin was not likely to be helpful for people with VHL. The urine test assessment is described in the Nova program, where researchers examined mouse urine to find endostatin. In subsequent research, however there is no proof that this urine test is definitive for humans. Angiogenesis is indeed the mechanism in which VHL participates, and with the complexity of this mechanism, endostatin cannot yet be completely ruled out.

An intriguing insight has been gained by studying the apparent low cancer rate in patients with Down’s syndrome. "A recent study of 17,000 age-matched American Down's patients showed that they have virtually no prostate cancer, virtually no breast cancer, virtually no pancreatic cancer, a mild leukemia, and the same incidence of testicular cancer." Dr. Folkman asked: "What does that mean in the big picture analysis?"

As it turns out, Down's patients have an extra copy of collagen 18 on chromosome 21 and endostatin is an integral component of collagen 18. The amount of circulating endostatin in these patients' blood is ten times greater than in the normal population. And the effect is felt on very different tissues and cancer types. Would the extra endostatin in the blood of a person with Down's syndrome effectively control VHL?

Is there a VHL family with a member with Down's Syndrome? This person might seem to be unaffected by VHL. DNA testing might be able to tell us, however, whether this person in fact has the VHL alteration, but that it is controlled by the extra endostatin created by Down’s Syndrome. Please write to Joyce Graff, editor@vhl.org, if you have a family member willing to get DNA testing for VHL and share their results with all of us. Similarly, if a person with Down’s does get VHL tumors, then it would tend to rule out the effectiveness of endostatin with VHL. Whatever the results, these answers would significantly shorten a clinical trial.

In the cells of someone with VHL, there is one altered copy of the VHL gene which is not making the correct VHL protein, and one copy that does make sufficient VHL protein to keep cell growth regulated correctly. If something happens to knock out this second healthy copy of the VHL gene, then a process of angiogenesis begins. In most cases, the body's own self-repair mechanisms take care of the problem. If not, however, where there is too little VHL protein, then there is too much Vascular Endothelial Growth Factor (VEGF). Much drug development work has focused not directly on VHL, but on VEGF. If we can control the amount of VEGF in the cell, we can also control cell growth. There are several new VEGF inhibitors now in clinical trials that may be helpful with VHL. Examples include PTK787 (Novartis), SU11248 (Sugen), and Avastin (Genentech).

"Angiogenesis research is providing a unifying principle for diseases which, although they have different names and are being treated by different specialists, are dominated by the same pathologic process -- uncontrolled angiogenesis." We have long wondered what connected the many tumor types involved in VHL. Dr. Folkman concluded with this analogy: "If you should happen to drain the Pacific Ocean, you should not be surprised to find that the islands are connected." Angiogenesis is the connection among VHL tumors and other cancers.

The Nova program is available on the internet as video or plain text at www.pbs.org/wgbh/nova/cancer/folkman.html

The program is also available on DVD from our bookstore, www.vhl.org/bookstore

See also the book Dr. Folkman's War, by Robert Cooke, Random House, 2001, www.vhl.org/bookstore