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Serendipity in lab turns blood into stem cells Cutting blood supply to tumors could stop them Argonne Update
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Cutting blood supply to
tumors could stop them
by Amy Kile
Proteins that could lead to drugs that stop tumor growth and cancer have been identified by Argonne biologists studying capillary formation, or angiogenesis.
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CAPILLARY GROWTH — Endothelial cells are coaxed into growing in petri dishes with protein gel. Eventually the cells treat the protein gel as body tissue and release enzymes to chew through the gel. Biologists monitor the eight-hour-long process. At five hours, most cells have formed networks. By eight hours, the cells have formed capillaries.  Endothelial cells after one hour.  Endothelial cells after two hours.  Endothelial cells after four hours.  Endothelial cells after eight hours. |
Argonne's scientists are the first to study the earliest steps in capillary formation in tumors. They learned what proteins were secreted by endothelial cells — cells that form blood vessels — and how these proteins work. By learning the quantity, location and types of proteins produced, Argonne's biologists hope to better understand capillary formation and use this understanding as the basis for developing treatments that arrest tumor growth by halting angiogenesis.
This research could also spawn new treatments for eczema, macular degeneration and rheumatoid arthritis-diseases related to capillary formation.
A tumor's life
Diane Rodi, a biologist in the Biosciences Division, compares tumor development to embryo maturation, only in reverse. Developmental processes, such as cell division and differentiation, stop once an embryo has matured, but a tumor causes this differentiation process to reverse.
As in embryos, tumor cells divide and grow quickly. They also de-differentiate, forgetting to make the proteins specific to their usual function. For example a T-cell — a type of white blood cell that attacks infected cells — that is becoming a lymphoma will stop producing the proteins that make it act like a T-cell.
Tumor cells also metastasize, or move to other locations in the body, similar to the cells in developing embryos.
Metastasis makes cancer fatal. If a tumor never moves, it is usually benign and can be surgically removed. Re-growth may require additional surgery, but the tumor is not fatal. Metastatic tumors are responsible for more than 90 percent of cancer deaths.
"Tumors kill by invading the body's normal tissues and crowding them out, preventing them from doing their job," says Rodi. "A patient dies because those tissues cannot function properly."
Leukemia patients, for example, often require oxygen and blood transfusions because the leukemia seeps into the bone marrow, crowding the normal cells and preventing red blood cell production. Because red blood cells carry oxygen to body tissues, the leukemia suffocates the patient.
Stopping tumors in their tracks
Tumors need to be near capillaries to metastasize. Capillaries are the tumor's lifeline, delivering oxygen to and removing waste from it. And tumors are so resilient, that if one pathway is cut off, they will find another.
Finding proteins that cells need to create capillaries could lead to drugs that block capillary formation, inhibiting tumor growth and metastasis. The tumor may not be gone, but as long as it cannot grow or metastasize, the patient can live with it, explains Rodi.
Researchers predict that the treatments will be a mixture, or cocktail, of medicines that attack capillary growth by inhibiting as many molecular pathways as possible. Optimally, this anti-angiogenic treatment would not cause the side effects typical of existing chemotherapy.
Chemotherapy patients usually receive a cocktail of drugs that target fast-growing cells such as tumor cells. Unfortunately, this therapy attacks not only the tumor but also the other fast-dividing cells in the body, such as hair follicles and cells that line the gastro-intestinal tract. When these normal, healthy cells are attacked, chemotherapy patients may become nauseated or lose their hair.
Anti-angiogenic therapy will work by blocking capillary formation, which is a much rarer occurrence in adults. Rapidly growing cells will not be targeted, and tumors will be starved without the side effects associated with traditional chemotherapy. Adults normally grow capillaries only while healing from an injury or during a women's menstrual cycle, when blood vessels form in the uterine lining. Most other capillary formation in adults is associated with pathologies such as tumors.
"There is not a lot of capillary growth in normal adults, so if we can come up with a cocktail of drugs to knock out all capillary formation in the body, it might be a method of treating cancer patients that does not make them sick," says Rodi.
Angiogenesis at Argonne
Other tumor-angiogenesis studies have led to drugs that are currently being tested in clinical trials. These anti-angiogenic drugs have stopped tumors in mice, but have not yet been successful in human clinical trials. That is because these studies have targeted only individual molecular pathways, Rodi explains.
Tumors in people are much different than those found in mice.
"People get messy tumors. If you take a tumor out of a person and look at the chromosomes in the different cells, they're heterogeneous — they're all different — whereas mice model tumors all have the same genetic make-up," says Rodi.
By determining angiogenesis' interim steps, Argonne researchers are learning what proteins are secreted by endothelial cells — the cells involved in blood vessel formation — and how these proteins work.
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