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The eye has played an important role in angiogenesis research over the past several decades, and it will continue to do so, according to Judah Folkman, MD, considered the founder of the field.
In addition to ophthalmologic applications such as diabetic retinopathy, age-related macular degeneration (AMD), and retinopathy of prematurity, angiogenesis inhibitors and stimulators have seen success or are showing promise as therapies for cancer, obesity, cardiovascular disease, hemangiomas, infertility, and other diseases and conditions. Dr. Folkman, considered to be "the father of angiogenesis," treated attendees to a presentation detailing the history of angiogenesis research, beginning with his speculation about the process in the 1960s and the formal introduction of the term angiogenesis in a 1971 New England Journal of Medicine article in which he hypothesized that tumors depend on neovascularization for growth. The article "also suggested that there might someday be angiogenesis inhibitors and even an antibody," he said.
"When this paper was published, I was very happy, and I thought maybe now the field would really take off. But nothing happened for 10 years," said Dr. Folkman, who was the director of the vascular biology program at Children's Hospital Boston and the Julia Dyckman Andrus Professor of Pediatric Surgery and professor of cell biology at Harvard Medical School at the time of his death.
"In 1971, for the whole year, there were three papers on angiogenesis: two from my lab, and one criticizing the first one," he said, adding that he thought that all of the angiogenesis-related research published over the next 10 years was performed in his laboratory. "No one believed that tumors needed new blood supply. The belief was [that] they grow on old blood supply, and the vessels that surgeons complained about were thought to be inflammation from dying tumor cells."
Bioassay for the cornea
During that 10-year period, Dr. Folkman said, his lab developed bioassays for angiogenesis, including one for the cornea that was "one of the key assays, because you could plant a pellet in the cornea that contained a fragment or a fraction of an angiogenic factor."
Rabbit corneas proved to be ideal for detecting new blood vessels.
"First we put tumors in the cornea at a distance, and you could see that the vessels were recruited across the cornea in a rabbit model. But when we then extracted the tumor, looking for an angiogenic protein-this was in the 1970s-it just diffused away, and we couldn't keep it at a focal spot, could not establish the grading," he said.
When the protein was put inside soft contact lens polymer and then inserted into the cornea, however, "You could see in 10 days beautiful vessels would come, and that turned out to be the first angiogenic protein purified from a tumor," Dr. Folkman said. He credited Robert S. Langer, PhD, a postdoctoral fellow in the lab at the time, with the effort.
"The neatest thing was, you could then incise the cornea . . . and take out the pellet. And that's what would happen, and everybody thought the vessels would be established, but they went away," Dr. Folkman said. "They regressed over a period of 10 weeks, and this gave us some confidence against all the ridicule that was going on, that if you had a drug that could stop the vessels, they would go away."
More recently, he said, the mouse cornea has been used to study lymphangiogenesis for the discovery of lymphangiostatins. "The most potent one right now is semaphorin 3A," Dr. Folkman said.