Clues to Blockade of Neovascularization through Targeting of SDF-1

New research shows that a novel secreted protein called stromal-derived factor 1 (SDF-1) helps build new blood vessels by encouraging the migration of cells from the marrow to tissues in need of new vasculature. Investigators say SDF-1 does soindependently of VEGF-A, a well-studied growth factor already known to be involved in this process.That finding, reported in Nature Medicine by a team of researchers at Weill Medical College of Cornell University, New York City, may allow scientists to move closer to treatments for vascular diseases afflicting patients with diabetes or atherosclerosis, and other patients threatened by dangerously poor circulation.The finding may have significant implications for cancer research, as well."Up till now, we've been looking for a 'missing link' in the process whereby blood-forming cells in the marrow head to the site of injury to rebuild and sustain the vasculature. SDF-1 looks like it could be that missing link," explains the study's senior researcher, Dr. Shahin Rafii, an investigator at the Howard Hughes Medical Institute, and Arthur Belfer Professor of Genetic Medicine and director of the Ansary Center for Stem Cell Therapeutics at Weill Cornell Medical College.Each year, more than 100,000 Americans lose a foot or leg because of peripheral vascular disease, a gradual loss of circulation in the lower extremities that's usually linked to chronic diabetes and atherosclerosis."One method of preventing these tragic disabilities would be to manipulate the body's own vessel-building or 'angiogenic' capacity, a process called neovascularization," Dr. Rafii explains. Experts have long recognized one key player in this process: vascular endothelial growth factor-A (VEGF-A), a substance secreted by cells that stimulates new blood vessel formation."Previous studies have shown that VEGF-A-focused therapies do work in rebuilding vessels -- but only over the short-term. The effect isn't sustained. In this study, we tried to find out why that might be," says lead researcher Dr. David K. Jin, chief fellow ofHematology-Medical Oncology at Weill Cornell. Specifically, the Weill Cornell team sought to determine the mechanism by which bone marrow-derived hematopoietic("blood-building") cells get mobilized to leave the marrow and help assemble vessels elsewhere in the body.In studies involving mice, the researchers turned their sights on SDF-1, a potent motility and growth factor that is released fromblood platelets under the direction of specific cytokine signaling chemicals. Those cytokines included soluble Kit-ligand (sKitL),thrombopoietin (TPO), erythropoietin (EPO) and granulocyte/macrophage-colony stimulating factor (GM-CSF).It may seem complicated, but the researchers tested the importance of SDF-1 in a simple way. First, they induced vascular damage in the mice's hind limbs, mimicking the impaired lower-limb blood flow that's often seen in human diabetics.As expected, levels of sKitL, TPO, EPO, and GM-CSF rose as a result of this injury, confirming the cytokines' role in blood vessel repair.Next, the researchers took advantage of genetically engineered mice that were incapable of expressing either TPO or sKitL."The result was a profound suppression of neo-angiogenesis -- these mice simply didn't start or complete the process of new blood vessel growth in the way you'd expect," Dr. Jin said.A similar, but less marked, effect was seen in mice genetically engineered to lack the other two cytokines, EPO and GM-CSF.The common thread linking all of these chemicals with neo-angiogenesis is their shared connection to SDF-1."Our experiments show that without the participation of SDF-1, neovascularization is greatly impaired," Dr. Rafii says.SDF-1's involvement occurs downstream of VEGF-A's involvement in the process, he notes."It looks like VEGF-A gets activated, and that starts a chain of events that eventually activates SDF-1. But if you block SDF-1, youinhibit 50 percent to 70 percent of VEGF-A's effects," Dr. Rafii explains. "The release of high amounts of SDF-1 from plateletsappears to mobilize pro-angiogenic, blood-building cells -- cells we have christened 'hemangiocytes.' These cells then go to work building new vasculature."The findings might have implications for cancer, as well."We have shown that mobilized blood cells with similar properties to hemangiocytes could also direct the spreading of certain tumors to pre-metastatic niches. Whether SDF-1 may also regulate this process is not known and is the subject of ongoing studies," states Dr. David Lyden, associate professor of pediatrics at Weill Cornell and a collaborator in this study.The finding could explain why VEGF-A-focused therapies have only been partially effective in restoring proper blood flow to limbs affected by peripheral vascular disease. "Without SDF-1, you've only got a part of the mechanism," Dr. Jin says.The Weill Cornell discovery may also open the door to whole new targets for research focused on jump-starting the body'sneovascularization cascade."We believe that this factor, SDF-1, provides a new mechanism for neo-angiogenesis in addition to VEGF-A," explains Dr. Jin. "That could mean that someday we'll find effective treatments to prevent disabling amputations and other problems in patients threatened by peripheral vascular disease, by introducing SDF-1 or delivering hemangiocytes directly into ischemic diabetic or atherosclerotic foot ulcers."The findings also raise important questions about the safety of growth factors such as TPO, EPO and others included in the study.Doctors often use these factors to help ease marrow suppression as patients undergo high-dose chemotherapy, Dr. Rafii points out."But our findings suggest that these growth factors might actually promote cancer as they spur tumor angiogenesis through the induction of SDF-1," he says. "This means that physicians might need to use them with caution in patients with residual disease."This work was supported by funds from the Howard Hughes Medical Institute, American Cancer Society, the Lymphoma and Leukemia Society, the National Institutes of Health, the National Cancer Institute, the Hermione Foundation, the Doris Duke Charitable Foundation and the Children's Blood Foundation.Other researchers include Dr. Koji Shido, Hans-Georg Kopp, Dr. Isabelle Petit, Dr. Sergey Shmelkov, Lauren Young, Hideki Amano,Scott Avecilla, Dr. Beate Heissig, Dr. Koichi Hattori, Dr. Fan Zhang, Dr. Neil Hackett, Dr. Ronald Crystal and Dr. David Lyden -- all of Weill Medical College of Cornell University; Dr. Daniel Hicklin, Dr. Yan Wu and Dr. Zhenping Zhu -- of ImClone Systems, Inc., New York City; Dr. Zena Werb of the University of California, San Francisco; Dr. Hassan Salari, of Chemokine Therapeutics Corp., of Vancouver, Canada; and Dr. Ashley Dunn, of the Ludwig Institute for Cancer Research in Melbourne, Australia.For more information,contact Jonathan Weil (212) 821-0560 jweil@med.cornell.edu

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