La Jolla, CA - February 6, 1998 -- For years scientists have studied angiogenesis, the process whereby new blood vessels are formed from pre-existing ones. Except in a few special circumstances, it does not occur in the normal adult. However, angiogenesis plays a key role in a number of diseases associated with new blood vessel growth such as cancer, diabetic retinopathy, macular degeneration and arthritis. Many scientists have worked to develop methods to promote the selective obliteration of new blood vessel cells that could ultimately lead to regression of the neovascularization associated with these diseases. Now, scientists at The Scripps Research Institute have not only uncovered a mechanism to help explain angiogenesis activity, but have developed a recombinant form of a protein fragment that blocks angiogenesis and tumor growth in an in vivo experimental model. This may provide a potentially novel therapeutic approach for diseases associated with neovascularization.
"Our findings show how an enzyme that promotes angiogenesis can be naturally cleaved to produce a fragment that inhibits this process. We determined that this enzyme fragment likely plays a role in normal blood vessel development. Thus, by taking advantage of this knowledge we have incorporated this into an anti-angiogenesis strategy to block tumor growth," according to one of the paper's authors, David A. Cheresh, Ph.D., Professor, Department of Immunology.
The work, "Disruption of Angiogenesis by PEX, a Noncatalytic Metalloproteinase Fragment with Integrin Binding Activity," by Peter C. Brooks, Steve Silleti, Tami L. von Schalscha, Martin Friedlander, and David A. Cheresh, is published in today's issue of Cell.
To grow and, ultimately, metastasize, malignant tumors must attract a rich blood supply to provide nourishment and remove wastes. In earlier studies, the Cheresh laboratory demonstrated that angiogenesis is dependent on the occurrence of specific biological events mediated by one of the integrin receptor molecules found on newly sprouting blood vessels. In experiments performed in 1994, they found that an antibody, LM609, specifically blocks the integrin v 3 and thereby blocks new blood vessel growth toward tumors.
The mechanism that controls the delicate balance of biological processes that tips the scales in favor of blood vessel formation--leading to tumor growth--was unclear. Now, the TSRI scientists report that a naturally occurring fragment of an enzyme known as matrix metalloproteinase 2 (MMP-2) can interact with the vascular cell integrin receptor v 3, thereby blocking MMP-2 from binding to the integrin. Without the functional cooperation of the integrin with the enzyme, it appears that cell invasion associated with angiogenesis and tumor formation may be shut down.
According to the scientists, the enzyme fragment, known as PEX, may serve as an on-off switch for blood vessel development, or a control mechanism that establishes appropriate blood vessel structure. Thus, the appearance of PEX at sites of neovascularization may not only control normal angiogenesis, but when administered in sufficient quantities, may provide a naturally-occurring therapeutic inhibitor of diseases associated with angiogenesis.
To test the theory, the scientists examined the potential antitumor activity of recombinant PEX on human tumors placed in chicken embryos. Within several hours the tumor fragments began to attract new blood vessels. After 24 hours the embryos were injected with PEX or a control enzyme fragment. PEX significantly inhibited the growth of these tumors; the control enzyme had little if any effect. To establish whether these effects were related to the ability of PEX to interfere with tumor-induced angiogenesis, blood vessel counts were determined in cross sections of tumors treated with or without PEX. The enzyme fragment produced a highly significant decrease in blood vessel density in these tumors relative to those treated with the control, providing further support for the idea that the effects of PEX on these tumors is, in fact, due to its anti-angiogenic activity.
According to Martin Friedlander, M.D., Ph.D., Associate Professor, Department of Cell Biology, "Our observation that a naturally occurring PEX fragment is present in angiogenic tumors as well as vascularizing eyes suggests that there is a common mechanism for regulating the development of new blood vessels."
Funding for the study was provided by the National Cancer Institute and National Eye Institute of National Institutes of Health (which accounted for approximately 50% of the funding) and Merck KGaA, Darmstadt, Germany.
Journal
Cell