A component of snake venom has demonstrated its ability to inhibit cancer cell migration in two different cancer models. The protein, called contortrostatin, seems to block cell migration in a novel way.
Francis S. Markland, Ph.D., professor of biochemistry and molecular biology at the University of Southern California Keck School of Medicine, Los Angeles, was examining venom from the southern copperhead Agkistrodon contortrix contortrix for its clot-busting properties when he learned that a group in Taiwan had found disintegrinsintegrin antagonistsin the venom of another snake.
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The integrins are a family of transmembrane receptor proteins that bind to components of the extracellular matrix. One of their functions is to grip the extracellular matrix, providing traction and allowing cells to migrate from one place to another. Researchers in a number of laboratories are focusing on one integrin in particular, called v
3. This integrin is present on the surface of cancer cells and is thought to be critical in metastasis.
Contortrostatin appears to block cell migration both by binding to a cell-surface protein in the integrin family, preventing it from gripping the extracellular matrix, and by scrambling signals to the cytoskeleton.
"We knew on the basis of contortrostatins ability to inhibit platelet aggregation that it was interacting with integrins, and we also knew that there are integrins on the surface of cancer cells," noted Markland. "Therefore we reasoned that it might be fruitful to look at its anticancer activity."
The group found that contortrostatin had very effective inhibitory properties on adhesion to several extracellular matrix proteins such as fibronectin and vitronectin. They also found that it was effective in inhibiting tumor cell invasion. Using human breast cancer cells and human ovarian cancer cells in immunodeficient mice given daily intratumor injections of contortrostatin, they discovered that it inhibited tumor dissemination and angiogenesis.
Moreover, the side effects were relatively minimal, said Markland. "Theres some oozing at the side of the injections in the breast cancer model. And in the ovarian cancer model weve seen some petechiae [hemorrhagic spots], which is an anti-platelet effect. Aside from its effect on platelets, there have been minimal or no side effects, and certainly there has been no evidence of internal hemorrhaging."
Recently Matthew R. Ritter, a graduate student in Marklands lab, attempted to tease out contortrostatins exact mechanism of action. What he found was a surprise, said Markland. The researchers expected contortrostatin to work the same way other disintegrins did, namely by interfering with v
3s binding to extracellular matrix proteins. But contortrostatin apparently does more.
Integrins can bind to extracellular proteins only when they cluster in groups known as focal adhesions. Normally integrins are spread diffusely over the cell membrane, but when one molecule binds to its ligand it sends an intracellular signal that leads to the formation of a focal adhesion. In a poster session at the 40th Annual Meeting of the American Society for Cell Biology, Ritter and Markland (along with colleague Qing Zhou) reported that by crosslinking v
3 integrins, contortrostatin caused intracellular signals that are both spatially and temporally inappropriate. These faulty signals disrupt both the focal adhesions and the actin cytoskeleton.
David A. Cheresh, Ph.D., a professor in the departments of immunology and vascular biology at the Scripps Research Institute, La Jolla, Calif., who works on integrins in angiogenesis and neoplasia, is intrigued by Marklands work, but in an interview he expressed some skepticism. In particular Cheresh noted that Markland maintains that contortrostatin acts as both an antagonist, since it blocks v
3 binding to matrix proteins, and as an agonist, causing
v
3 to send a faulty signal.
"Its a very interesting molecule," said Cheresh. "Its a very exciting observation. Im not sure, however, what the mechanism is, and Im not sure how much of the biological activity they see in vitro is due to the agonistic effects or the antagonistic effects. Its a little hard to sort that out. Im not sure you couldnt get a similar effect with just a decent antagonist. [Are] the signaling properties really critical to its biological activity?"
Cheresh said that there are two monoclonal antibodies to v
3 integrin currently in phase II clinical trials. Vitaxin is being developed by MedImmune Inc., Gaithersburg, Md., and Cilengitide is being developed by Merck KgaA, Darmstadt, Germany. Markland said that although several pharmaceutical companies have expressed interest in contortrostatin, he has not yet developed a partnership with any of them to begin the clinical development.
And Cheresh cautioned that it may be a long road from the laboratory to the clinic. "Certainly in culture its an interesting molecule. The question is, can one develop this toward cancer? One has to be concerned with the pharmacodynamic properties, and of course those are major stumbling blocks going from an interesting cell-biological observation, as these folks have made, to a potential drug candidate."
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