THERAPIES OF THE FUTURE
FIGHTING
CANCER BY ATTACKING ITS BLOOD SUPPLY
by
Judah
Folkman
By interfering with the expanding network of blood
vessels in tumors, researchers hope to cut off the underlying support system.
The tiny blood vessels known as capillaries extend into virtually all the
tissues of the body, replenishing nutrients and carrying off waste products.
Under most conditions, capillaries do not increase in size or number, because
the endothelial cells that line these narrow tubes do not divide. But
occasionally-for example, during menstruation or when tissue is damaged-these
vessels begin to grow rapidly. This proliferation of new capillaries, called
angiogenesis or neovascularization, is typically short-lived, "turning off"
after one or two weeks.
But neovascularization can also occur under abnormal conditions: tumor cells can
"turn on" angiogenesis. As new blood vessels bring in fresh nutrients and
proteins known as growth factors, the tumor mass can expand. In fact,
neovascularization appears to be one of the crucial steps in a tumor's
transition from a small, harmless cluster of mutated cells to a large, malignant
growth, capable of spreading to other organs throughout the body. Tumor cells
are usually unable to stimulate angiogenesis when they first arise in healthy
tissue; unless the deranged cells become vascularized, the mass will not become
larger than about the size of a pea. Thus, if researchers can determine how
mutated cells trigger angiogenesis and, more important for patients, how to
interrupt the process, they will have a powerful new anticancer therapy at their
disposal. Furthermore, because antiangiogenic drugs stop new growth but do not
attack healthy vessels, they should in theory do no harm to blood vessels
serving normal tissues. (Angiogenesis inhibitors can stop menstruation or delay
wound healing, however.)
Research into the importance of angiogenesis to the progression of cancer has
been a vital area of laboratory investigation for several decades-I wrote an
early article on the subject in the mid-1970s [see "The Vascularization of
Tumors," by Judah Folkman; Scientific American, May 1976]. But only in the past
seven years has research moved out of the laboratory and into the clinic. In
1989 the first clinical trial of an anti-angiogenic agent-interferon alpha-began
for the treatment of life-threatening hemangioma (a noncancerous blood vessel
tumor found primarily in infants).
By 1992 the first antiangiogenic drug for cancer patients, TNP-470 (a synthetic
analogue of the substance fumagillin), entered clinical trials. The first
studies were restricted to a few kinds of tumors, but the Food and Drug
Administration now allows physicians to administer TNP-470 in clinical trials
for a wide variety of cancers in humans. In the past four years, at least seven
other angiogenesis inhibitors have entered clinical trials for the treatment of
advanced cancer, and one of these compounds is also being tested in patients
with abnormal blood vessel growth in the eyes.
The effort to explore the practical applications of antiangiogenic compounds
reflects years of work by many researchers-unfortunately too numerous to list in
this short space. For example, during the past several years, scientists have
identified at least 14 different proteins found in the body that can trigger
blood vessel growth and several others that can halt it. Most recently,
researchers have discovered that one of these natural angiogenesis inhibitors is
normally under the control of the tumor suppressor gene p53, which has been
implicated in various cancers. With such clues, cancer researchers continue to
refine their understanding of angiogenesis in tumor growth and of ways to block
it.
Angiogenesis Is Required for Spread
As with most aspects of cancer progression, angiogenesis distorts a normal
biological process-in this case, regulation of blood vessel growth. Capillary
blood vessels, each thinner than a hair, are arranged so that almost every
healthy cell in the body can live directly on the surface of a capillary. If a
healthy cell becomes cancerous and begins dividing rapidly, the resulting
daughter cells accumulate in a microscopic mass. As the cells pile up, they find
themselves farther and farther from the nearest capillary. When a few million
such cells have accumulated, the small tumor-often called an in situ
carcinoma-stops expanding and reaches a steady state, in which the number of
dying cells counterbalances the number of proliferating cells. This restriction
in size is caused in part by the lack of readily available nutrients, protein
growth factors and oxygen. These minuscule carcinomas can be detected if they
are on the skin or cervix, but in the breast, lung or colon, they may go
unrecognized for several years. Regrettably, we do not yet have the technology
to detect most small in situ tumors in internal organs until after the tissue
has been removed and examined under a microscope.
After many months or even years in this steady state, an in situ tumor may
abruptly induce new capillary growth and start to invade surrounding tissue. The
tumor calls into service naturally occurring proteins that promote
neovascularization. The mutated tumor cells might themselves produce high levels
of such proteins; alternatively, they can mobilize angiogenic proteins found in
nearby tissue, or they may prompt other types of cells, such as macrophages, to
release angiogenic proteins.
Yet even after employing these mechanisms, malignant cells may still fail to
trigger angiogenesis. Recent discoveries by Noel Bouck's group at
Northwestern University and in Douglas Hanahan's laboratory at the University of
California at San Francisco suggest that certain tumor cells
make two types of protein: one kind stimulates angiogenesis, and the other
inhibits it. The balance between them determines whether the tumor can switch on
angiogenesis. And experiments indicate that the ability to turn on angiogenesis
most likely depends on a decrease in the production of those proteins that
inhibit the process. So, in effect, angiogenic cancer cells release the natural
brakes on the spread of new capillaries-once a tumor becomes angiogenic, it
tends to stay that way.
Once neovascularization occurs, hundreds of new capillaries converge on the tiny
tumor; each vessel soon has a thick coat of rapidly dividing tumor cells. Some
of these cells are not angiogenic but are nonetheless sustained by capillaries
recruited by neighboring cells. Now the tumor can expand rapidly-in a matter of
months, the mass may reach one cubic centimeter in size and contain around one
billion tumor cells.
Further promoting the progress of the disease, the newly dividing endothelial
cells release at least six different proteins that can stimulate the
proliferation or motility of tumor cells. For example, in breast cancer, the
capillary endothelial cells recruited to the tumor produce the protein
interleukin-6, which can increase the probability that breast cancer cells will
leave the tumor, migrate into the bloodstream and spread to other organs-in
other words, metastasize. Some of the metastases contain cells that are already
angiogenic and thus will grow rapidly. Other metastases, however, contain mainly
nonangiogenic cells and may lie dormant for years, becoming angiogenic long
after the original tumor has been treated or removed.
When a tumor has advanced to this stage, it often causes readily identifiable
symptoms. Blood appearing between menstrual periods or in the urine, stool or
sputum indicates that angiogenesis has taken place in the cervix, bladder, colon
or lung, respectively. By the time a breast cancer can be seen on a mammogram,
the tumor has already undergone vascularization. The bloody abdominal fluid seen
with ovarian cancer, the bone pain of prostate cancer, the swelling around brain
tumors and the obstruction of the intestinal tract common in colon cancer all
result from angiogenic tumors. Biologically active molecules released by the
expanding tumor can cause additional symptoms, such as weight loss and formation
of blood clots.
Shrinking Tumors
At present, patients diagnosed with any form of cancer typically rely on surgery
or radiation to remove or eradicate the original tumor and on follow-up
radiation or chemotherapy, or both, to try to eliminate any remaining cancerous
cells in the body. Antiangiogenic therapy, in contrast to many other therapeutic
approaches, does not aim to destroy tumors. Instead, by limiting their blood
supply, it attempts to shrink tumors and prevent them from growing.
Antiangiogenic drugs stop new vessels from forming around a tumor and break up
the existing network of abnormal capillaries that feeds the cancerous mass.
Currently, in addition to the angiogenesis inhibitors that are in clinical
trials, many potential inhibitors are under study in university laboratories and
in some 30 pharmaceutical and biotechnology companies around the world.
In particular, two of the compounds being looked at are very potent angiogenesis
inhibitors, suggesting that they eventually will be quite useful for treating
cancer patients. David A. Cheresh and his colleagues at the Scripps Institute
discovered the first of these substances: a protein that interferes with another
molecule known as an integrin, which is found in large quantities on the surface
of growing endothelial cells. If the integrin (named alphavbeta3) is blocked,
the proliferating endothelial cells die.
The second of these promising compounds, the protein angiostatin, was discovered
in mouse urine by Michael S. O'Reilly in my laboratory at Children's
Hospital
Medical Center in Boston. Angiostatin is among the most potent of the known
angiogenesis inhibitors. In animals, it can stop nearly all blood vessel growth
in a large tumor or in its metastases. Human prostate, colon and breast cancers
that have been implanted in mice and allowed to grow to 1 percent of the
animals' body weight can be reduced to a microscopic size and held in a dormant
state for as long as angiostatin is administered. Furthermore, angiostatin is
very specific, halting only the multiplication of endothelial cells and not of
other cells or of normally quiescent endothelial cells. This specificity has
powerful benefits: researchers have not detected in animals any toxic side
effects of the drug. In addition, resistance to angiostatin does not appear to
develop in animals.
Angiostatin is actually a fragment of the larger protein plasminogen, which is
not antiangiogenic itself. Indeed, several angiogenesis inhibitor proteins exist
as internal fragments of larger proteins (for instance, another inhibitor is a
fragment of the protein prolactin), suggesting that normal angiogenesis
inhibitors may be, in a sense, stored within larger proteins. Thus, when the
body needs to stop normal angiogenesis-after wound healing or ovulation-these
natural inhibitors may be available for immediate use by simply breaking down
the larger proteins.
Offering Treatment
Laboratory studies as well as ongoing clinical trials of angiogenesis inhibitors
provide important guidelines for how these drugs may eventually be used in
cancer patients, if they receive approval from the FDA. For example, when
angiogenesis inhibitors are first introduced into clinical practice, they will
most likely be used in combination with current conventional therapy. Beverly A.
Teicher of the Dana-Farber Cancer Institute in Boston has shown in animals that
combinations of angiogenesis inhibitors and chemotherapeutic agents are more
effective than either therapy alone. In one instance, 42 percent of the animals
were cured by a combination of treatments but not by either drug alone.
A possible explanation for the apparent synergism between these two therapies is
that the two types of cells in a tumor-the endothelial cells and the tumor
cells-respond differently to therapy. For example, endothelial cells have a low
or virtually undetectable mutation rate as compared with that of tumor cells and
thus do not usually become drug-resistant. In addition, every 10 to 100 new
tumor cells require at least one new endothelial cell. (One gram of tumor
contains approximately 20 million endothelial cells and 100 million to one
billion tumor cells.) Therefore, when an angiogenesis inhibitor halts the growth
of one endothelial cell, the effect on tumor cells may be amplified.
Angiogenesis inhibitors have also been studied in conjunction with radiation
therapy. Oncologists and radiologists initially debated whether radiation
therapy would be enhanced by coupling it with antiangiogenic drugs. But Teicher
recently found that treatment of mouse tumors with angiogenesis inhibitors did
increase the effectiveness of radiation therapy. Several antiangiogenic drugs,
including TNP-470 and minocycline (a relative of the antibiotic tetracycline),
are being examined in conjunction with radiation therapy in animals.
After the completion of conventional chemotherapy or radiation therapy,
angiogenesis inhibitors might be used as a long-term treatment against cancer.
If the cancer has metastasized, antiangiogenic therapy may be needed
indefinitely. In other situations, antiangiogenic drugs may be given for a brief
period, perhaps before surgical removal of a large tumor. Antiangiogenic
treatment could possibly be administered intermittently, even for a few months
or years, to maintain a tumor's dormancy. Fortunately, the general lack of drug
resistance developed against these compounds as well as their low toxicity makes
them amenable to extended use.
Future Directions
Although scientists have been investigating angiogenesis for more than two
decades, many questions remain about the process, how it is regulated and how it
can be controlled therapeutically. For instance, no one understands why some
tumors, particularly in the cervix, undergo neovascularization much earlier than
others. And antiangiogenic drugs now in development face the traditional
uncertainties of all clinical trials: unforeseen side effects could surface, or
a drug might be ineffective in humans despite its efficacy in mice.
In addition, as with any new drug, there are potential economic hurdles to
overcome. Many of the angiogenesis inhibitors are newly discovered proteins or
other types of molecules. Chemists must now figure out how to make these
compounds on a large scale. This process can be expensive, but experience
suggests that prices should fall with time.
Despite the obstacles, antiangiogenic substances offer the promise of an
additional anticancer therapy for our current armamentarium. Angiogenesis
inhibitors may turn out to have significant benefits because they are not as
likely to induce resistance and because they generally have fewer side effects.
These agents may also be used to treat other diseases characterized by abnormal
angiogenesis. Among these other conditions are diabetic retinopathy, macular
degeneration and neovascular glaucoma-all diseases of the eye in which abnormal
vessels proliferate and destroy vision. In addition, psoriasis, arthritis,
hemangioma and other benign tumors may be susceptible to treatment with
angiogenesis inhibitors. Clearly, then, antiangiogenic drugs have exciting
potential as therapies for a number of serious conditions-in addition to cancer.
Further Reading
Barriers to Drug Delivery in Solid Tumors. Rakesh K. Jain in Scientific
American, Vol. 271, No. 1, pages 58-65; July 1994.
Antiangiogenic Agents Can Increase Tumor Oxygenation and Response to Radiation
Therapy. B. A. Teicher, N. Dupis, T. Kusomoto, M. F. Robinson, F. Liu, K. Menon
and C. N. Coleman in Radiation Oncology Investigations, Vol. 2, No. 6, pages
269-276; 1995.
Tumor Angiogenesis. Judah Folkman in The Molecular Basis of Cancer. Edited by J.
Mendelsohn, P. M. Howley, M. A. Israel and L. A. Liotta. W. B. Saunders, 1995.
Angiostatin Induces and Sustains Dormancy of Human Primary Tumors in Mice. M. S.
O'Reilly, L. Holmgren, C. Chen and J. Folkman in Nature Medicine, Vol. 2, No. 6,
pages 689-692; June 1996.
The Author
JUDAH FOLKMAN is director of the surgical research laboratory at Children's
Hospital Medical Center of Harvard Medical School. His laboratory reported the
first purified angiogenic molecule and the first angiogenesis inhibitor.
Folkman's group then proposed the concept of angiogenic disease. Folkman is a
fellow of the
American
Academy of Arts and Sciences and a member of the National Academy of Sciences.
The author gratefully acknowledges the nearly uninterrupted support of
angiogenesis research for more than 25 years by the National Cancer Institute.
