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A bit of history
For as long as doctors have been treating cancer, they've known that tumors nourish themselves by acquiring a network of tiny blood vessels linked to the rest of the body's circulatory system. To most scientists, though, such vessels were an inherent part of the tumor's makeup, with no bearing on its ability to grow.
Judah Folkman thought differently. In the early 1970s, he proposed that blocking or inhibiting the flow of blood to tumors might be a way to fight cancer. He and his associates at Children's began searching for substances emitted by tumors that stimulate blood vessel growth, a process known as angiogenesis. They and other researchers discovered that without such vessels, tumors can't grow larger than a centimeter or two in diameter, because cells in the tumors' interior begin dying from a lack of oxygen. Folkman reasoned that if blood flow could be halted, the tumors would remain too small to cause serious problems. And, since the adult body ordinarily doesn't generate new blood vessels, barring tumors from creating them wouldn't cause serious side effects.
The process of angiogenesis begins when tumors release substances, called growth factors, that attract blood vessels. Nourished by an increased supply of blood, tumors can grow beyond their initial, small size
(Illustration by Erinkate O'Donnell)
The idea that tumors could be tamed by blocking their access to the bloodstream — antiangiogenesis — held a further attraction. One of the main shortcomings of conventional cancer chemotherapy, along with its tendency to damage normal as well as cancerous tissue, is that cancer cells often become resistant to it. Tumor cells are so genetically unstable, so prone to breaks and rearrangements of their DNA, that they gain the ability to dodge drugs that initially worked against them. Because blood vessel cells are far steadier, drug resistance is less of a problem.
By the late 1980s, Folkman's team discovered that many tumors gain access to the bloodstream by secreting a protein called basic fibroblast growth factor. The protein, a combination come-hither signal and obstacle remover, entices blood-carrying capillaries to grow toward tumors while helping dissolve tissue standing in the way. That was followed by the discovery of a similar substance called vascular endothelial growth factor (VEGF).
In the late 1990s came the news that grabbed the nation's attention: Folkman's lab had isolated a natural substance, called angiostatin, that in animal studies impeded the growth of blood vessels to tumors. Shortly after came the discovery of its cousin inhibitor, endostatin. Omitted from many news reports was that Folkman's lab has identified nearly a dozen angiogenesis blockers over the past 25 years. The race to find agents that can starve human tumors of blood was already well under way.
- Next: Setting a trap
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