Fail-Safe Device Blocks Abnormal Growth of New Blood Vessels

Originally Published MDDI May 2002

R&D DIGEST

Cancer cells can secrete substances capable of promoting angiogenesis, the formation of new blood vessels that can supply oxygen and nutrients and remove wastes. Increasing the blood supply in this way enables the nest of cancer cells to grow larger. Similary, angiogenesis also speeds the development of diabetic retinopathy and macular degeneration. Although the use of inhibitors has been successful in controlling angiogenesis in some instances, the method has been limited. Researchers speculate that knowing more about the actual process involved with the use of inhibitors could lead to better treatment methods.

A study conducted by The Feinberg School of Medicine at Northwestern University (Chicago) and Washington University (St. Louis) suggests that some angiogenesis inhibitors prevent new blood vessel growth by triggering a so-called fail-safe device in vessel-forming endothelial cells that marks them for apoptosis, or programmed cell death.

Olga Volpert, assistant professor of urology at the Feinberg School and lead researcher in the study, believes it may be possible to design new antiangiogenic drugs or to improve already existing drugs to prevent abnormal blood vessel growth by identifying the molecular mechanisms that control this fail-safe device.

Growth of new blood vessels has been shown to rely on a critical balance of proteins. Depending on the proteins present, the growth of the endothelial cells that form the walls of new blood vessels can either be induced or inhibited. Research into this process has centered on identifying the components that influence this balance. Among the principal goals have been to better understand angiogenesis-dependent diseases and to develop therapies to prevent neovascularization.

Previous studies have examined the effects of administering certain natural inhibitors as drugs against angiogenesis-dependent diseases like cancer and diabetic retinopathy. It has been demonstrated that these inhibitors selectively destroy newly formed vessels and not preexisting ones. The process by which this is achieved, however, has remained unclear.

Results of the new study suggest that endothelial cells activated by an inducer express a cell-surface protein receptor called Fas. This makes the cells sensitive to the inhibitors in their environment. The inhibitors, thrombospondin-1 (TSP1) or pigment epithelial-derived factor (PEDF), activate the receptor's ligand, another cell-surface protein called FasL. The result is a molecular cascade in the cell that results in cell death.

Based on the study results, the researchers indicate that the angiogenesis-inhibiting activity of TSP1 and PEDF depends on the dual induction of Fas and FasL, and on the resulting apoptosis. They add that it has been known for some time that Fas/FasL interactions target immune cells for destruction in immune-privileged and diseased tissues when large populations of cells are to be eliminated. The results of the current study show that these interactions also affect the fate of vascular tissues where new vessels can be destroyed by inhibitors of angiogenesis.

According to the researchers, the study also suggests that TSP1 and PEDF reduce the expression of the inducer-stimulated molecule that blocks cell death. They believe that this unexpected cooperation between pro- and antiangiogenic factors may have major implications on the therapeutic use of these two inhibitors. Fas and its ligand may serve as new targets to design antiangiogenic drugs or to improve already existing drugs.

Says Volpert, "The data provide an unexpected explanation for the specificity of inhibitors for activated, remodeling endothelium, thus clarifying why they can be used so effectively without side effects." She adds, "The data also offer new means to enhance the efficacy of these inhibitors and predict synergies between various inhibitors and between inhibitors and conventional therapies."

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