Angiogenesis is a normal process in the body, and involves the formation of new blood vessels from existing ones. Angiogenesis is needed whenever there is growth of new tissues, such as during fetal development, wound healing, and the menstrual cycle. An extensive network of fine blood vessels (called capillaries) is needed to provide the cells with necessary nutrients and oxygen. Vessel growth is normally controlled by a finely tuned balance between angiogenic inhibitors and stimulators (activators). When new capillary growth is needed, the angiogenic stimulators send out signals to the endothelial cells that line blood vessels. The activated endothelial cells then make enzymes that break down the surrounding tissue (extracellular matrix). This allows the endothelial cells to advance beyhond the confines of the blood vessel. The endothelial cells continue to divide and differentiate, forming new capillary branches.2
Angiogenesis in the cancer process
If it weren't for the process of angiogenesis, cancer tumors would remain at microscopic size. In order to continue to grow, the tumor effects a shift in the equilibrium between stimulators and inhibitors. In particular,researchers have found out that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)are overexpressed in many tumors and seem to be the most important activators in sustaining cancer growth. In some cases, angiogenic inhibitors can become downregulated and even nonfunctional.
this has been shown to occur with mutation of the tumor suppressor gene, p53.With new capillary growth, the cancer cells now have nourishment to continue to grow, and with access to the circulatory system, can spread to other parts of the body. Tumor cells produce inhibitory as well as stimulatory factors. In many cases, the amount of inhibitory factors produced is sufficient to keep secondary tumors in check. This may account for those cases where the cancer spreads rapidly after the surgeon removes the primary tumor.
Dr. Folkman's breakthrough
After toiling for endless years in the lab, a breakthrough finally came in 1994. Dr. Folkman and his colleagues isolated the first natural angiogenesis inhibitor in mice, naming it angiostatin.The following year, another inhibitor even more potent was discovered,which was named endostatin. With guarded optimism, the first human clinical trials using endostatin began in 1999. This trial is a Phase 1 trial that is designed more to study safety of the drug rather than its effectiveness.This type of trial typically uses small numbers of patients;in this case the patients were in advanced stages of cancer. To learn more, please click on the following PBS link to access the PBS web page that is a companion piece to the excellent PBS program on television, "Cancer Warrior" broadcast on February 28. The program describes in dramatic detail how Dr. Folkman and his colleagues discovered angiogenesis inhibitors. While on the web page, click on "Designing Clinical Trials". The article explains why the public should not expect to see definitive cancer cures from these preliminary trials. Even so, endostatin has shown to be remarkably non-toxic compared to chemotherapy, and many patients have shown an arrest in tumor growth. The actual determination of effectiveness will take place during follow-up trials.
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