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?
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Contact: Peta Gillyatt
pgillyat@warren.med.harvard.edu
617-432-0443
Harvard Medical School
20-Mar-1998