|
|
 |
 | ||
|
|
| ||
|
|
|
|
|
Wednesday, February 25, 2004 12:00 p.m. EST
|
|
|
For Further Information:
Bess Andrews
617-355-6420
|
|
|
|
|
|
Natural Angiogenesis Inhibitors May Lead to Next Wave of Protective Drugs
|
|
|
|
Many people have tiny tumors, but the vast majority of these are pinhead in size, dormant, undetected, and never develop into true, life-threatening cancers, write cancer researchers Judah Folkman, MD, of Children's Hospital Boston, and Raghu Kalluri, PhD, of Beth Israel Deaconess Medical Center. In an essay in the February 26th issue of Nature, Folkman and Kalluri suggest that most tumors don't develop a blood supply that would allow them to grow and progress to cancer, because people produce natural inhibitors of blood vessel growth, or angiogenesis. They write that a better understanding of these inhibitors may yield a new generation of nontoxic anticancer drugs that could be given preventively to people at high risk for developing the disease.
The essay, titled ''Cancer without Disease,'' cites autopsy studies which have revealed that more than a third of women aged 40 to 50 have small in situ breast carcinomas, whereas only 1 percent are diagnosed with clinical breast cancer. Analagous findings hold for prostate cancer in men. Similarly, autopsies show that virtually all people aged 50 to 70 have small in situ thyroid tumors, yet well below 1 percent are diagnosed with clinical thyroid cancer.
''We may have to define cancer as having two critical phases,'' Folkman and Kalluri write. In the first phase, which isn't inherently lethal, genetic mutations develop that transform normal cells in the body into cancerous cells. The second phase involves what Folkman and colleague Douglas Hanahan termed the ''angiogenic switch'' in Cell in 1996, in which growth factors secreted by a tumor to attract a blood supply overcome the defense provided by natural angiogenesis inhibitors.
|
|
|
|
But many small cancers never reach this second phase. For example, people with Down syndrome rarely develop solid tumors. It's thought that their extra copy of chromosome 21 endows them with elevated levels of endostatin, a natural angiogenesis inhibitor.
Inspired by such examples, a major current focus of Folkman's Vascular Biology Program at Children's Hospital Boston is on predicting the ''angiogenic switch'' and delaying or preventing it with natural angiogenesis inhibitors. Preventive therapy could be offered to people with a genetically increased risk for cancer (such as women carrying the BRCA1 gene), people with a family history of cancer, and people whose cancer has been treated but are at risk for recurrence. Eventually, Folkman says, it may be possible to treat patients with angiogenesis inhibitors before a tumor can even be visualized by radiologistsand then monitor the results with additional urine or blood tests.
|
|
|
Ongoing investigations in Children's Vascular Biology Program include:
- Pinpointing the angiogenic switch. Using mice as a model, Folkman's lab has found that the switch often occurs at a predictable time for a given tumor type.
- Novel blood or urine tests to measure angiogenic activity. Such tests could be used to screen patients at risk for cancer, or monitor them for a cancer recurrence. John Heymach, M.D., Ph.D., a fellow in Folkman's lab who also practices at Dana-Farber Cancer Institute, has discovered that levels of certain types of cells circulating in the blood can be used as a measure of angiogenic activity. A non-invasive diagnostic and prognostic urine test for cancer is now being developed for clinical application by Marsha Moses, Ph.D. The test looks for matrix metalloproteinases, a family of enzymes required for angiogenesis, tumor growth, and metastasis.
- Genetic predictors of angiogenesis: Nava Almog, Ph.D., has identified genes whose activity is increased or decreased during the angiogenic switch. Along with Moses, she is developing molecular and biochemical interventions to prevent the switch from occurring.
- Variations in angiogenic activity. A 2001 study in the Journal of the National Cancer Institute showed that even within a single tumor, cells have different levels of angiogenic activity. Transplanted into mice, a human liposarcoma gave rise to three tumor types: highly angiogenic, fast-growing tumors; weakly angiogenic, slow-growing tumors; and nonangiogenic dormant tumors. This observation may help explain dormant metastases, late tumor recurrence, and changes in the rate of tumor progression, and offers a model for testing whether the angiogenic switch can be prevented.
|
|
|
- Population differences in angiogenesis. African-Americans are known to have lower rates of certain diseases, such as the wet form of macular degeneration, that result from excess angiogenesis. Robert D'Amato, M.D., Ph.D., is studying genetic differences in angiogenesis in black and white mice, and has found a difference tied to the pathway for making the skin pigment melanin. Deleting a key gene in this pathway created albino mice whose blood vessels grew faster. Differences in genetic susceptibility to angiogenesis could provide leads for new treatment approaches.
|
|
|
|
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults for more than 130 years. More than 500 scientists, including seven members of the National Academy of Sciences, nine members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Children's research community. Children's is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital visit: www.childrenshospital.org.
Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical School, and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a founding member of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox.
###
|
|
|
|
|
|
