Children's Hospital And Harvard Medical School Researchers Show That Cancer-Linked Angiogenesis And Brain Development Share Protein
A protein that helps wire the developing brain by preventing nerve cells from entering off-limits areas does double duty during the formation of blood vessels, Children's Hospital and Harvard Medical School researchers have found. Michael Klagsbrun, HMS professor of surgery at Children's Hospital and his colleagues describe this molecular convergence of two ostensibly separate organ systems in the March 20 Cell.
The paper joins by the hip two fast-paced fields of research. One is angiogenesis, the process of new blood vessel growth that occurs mostly during development, but also in the menstrual cycle, wound healing, and cancer. Buoyed by hope that angiogenesis inhibitors and promoters may one day yield treatments for tumors and heart disease, the field is attracting increased attention from basic researchers trying to understand this fundamental process. The second field, axonal guidance, has taken on the herculean task of sorting out how a trillion neurons navigate the developing brain, each one of them connecting with about a thousand target cells as they assemble the adult nervous system.
By showing that these two processes share at least one important molecule, the study raises intriguing questions about how much crosstalk exists between the growth of blood vessels and nerve cells, says Klagsbrun. It also broadens the scope of the preeminent growth factor involved in triggering angiogenesis, called vascular endothelial growth factor (VEGF), and has implications for cancer research, he adds.
Known to attract nourishing blood vessels to tumors, VEGF is the target of efforts in academia and industry to block vessel growth. In unrelated clinical trials, VEGF is used to coax blood vessels into sprouting collaterals that reestablish blood flow at sites of blockage in the heart and legs.
Klagsbrun's lab has studied VEGF for the past five years. A postdoc in the lab, Shay Soker, HMS instructor in surgery at Children's Hospital, discovered that VEGF uses a third receptor in addition to the two receptors already known.
This third receptor is neuropilin-1, a brain protein shown last summer to be a receptor for protein ligands variously called collapsins or semaphorins. The collapsin/semaphorin family is the latest in a slew of proteins implicated over the past 20 years in axonal guidance. They function by inducing the collapse of outgrowing axon tips that venture into inappropriate brain areas, causing the affected axon to veer in another direction.
This finding turns VEGF from a growth factor thought until now to act only on endothelial cells into one that may have a broader range of action, says Klagsbrun. For one, his group found that breast and prostate cancer cells make large amounts of neuropilin.
This seemed confusing at first. Researchers believe that tumor cells release VEGF, which diffuses and then binds to the two traditional VEGF receptors expressed on the endothelial cells of a nearby capillary, triggering new blood vessels to form and penetrate the tumor. What would a third VEGF receptor do on the cancer cell itself? Klagsbrun notes that previous research has suggested VEGF can block a cell's genetic suicide program. Maybe VEGF, in addition to its established effect on endothelial cells, also acts back on the tumor cells themselves to help them hold cell death at bay, he speculates.
But the most intriguing questions revolve around what this molecular link between nerves and blood vessels means for embryology. Could it mean, for example, that blood vessels are subject to some of the brain's principles of carefully shepherding the path of cell growth?
"For blood vessels, people really have not thought of it that way. We tend to think that you throw in a growth factor and sprouting vessels go in all directions. Now we are wondering whether there may be a guidance system for blood vessels as well," says Klagsbrun.
It seems only logical that there would be a mechanism for guiding blood vessel growth, he adds. Though at first glance, blood vessels appear less intricate than neuronal circuits--mere plumbing to carry blood, one might think--they do form an exquisite structure that is largely identical in all people. What is behind this order?
In the current study, Klagsbrun's team reports initial experiments asking in a simple way whether neuropilin somehow affects the way blood vessels move. They engineered endothelial cells to contain either neuropilin, a long-known VEGF receptor called KDR, or both and then measured how avidly the cells were migrating up a gradient of VEGF. They found that, indeed, neuropilin more than doubled this chemotactic response of the cells, but only if they also expressed KDR.
This suggests that neuropilin might impart a sense of direction to the growth of capillaries, but does so by acting in conjunction with another receptor. This finding jibes with a growing notion among molecular biologists that receptors often work in pairs and that it is the particular combination of individual receptor molecules mediating a given signal that defines a cell's specific response.
Many other questions remain, such as how far the two systems overlap. In collaboration with Johnathan Raper of the University of Pennsylvania, who codiscovered the collapsin/semaphorins, Klagsbrun is now testing whether VEGF acts on neurons or whether semaphorin acts on endothelial cells, which carry neuropilin. If semaphorin turned out to inhibit endothelial cell movement, much like it repels neurons, he says, it might become a candidate angiogenesis inhibitor for cancer therapy.
Klagsbrun seems to have a knack for growth factors that play dual roles in the brain and blood vessels. The only other example known is fibroblast growth factor (FGF), which his lab first purified in 1983 as an angiogenic protein. FGF soon turned out to be a neurotrophic factor, as well, and now is in clinical trials on both fronts, one using FGF to induce blood vessel growth around blockages, the other using it to promote nerve cell survival after a stroke.
Children's Hospital is an independent 300-bed specialty care hospital, a leader in the field of pediatric research and education, and the primary pediatric teaching affiliate of Harvard Medical School.
Editors, please note: a black-and-white diagram of neuropilin-1 and VEGF is available.
Journal
Cell