Snubbed by Scientists, Recognized 20 Years Later

Laird Harrison

November 08, 2019

SAN FRANCISCO — When a team led by pathologist Robert Folberg, MD, noticed that uveal melanoma tumors seemed to organize themselves in packets, and between the packs were unexplained structures, the trajectory of their careers changed.

The researchers found that some of the structures were solid and others were hollow, and the empty ones took the shape of channels containing red blood cells.

At first, they assumed that the tumors had remodeled pre-existing blood vessels, but they couldn't find any endothelial cells or fibroblasts to confirm this was the case.

There was another explanation.

They theorized that the tumors use these channels to nourish themselves, a process they dubbed vasculogenic mimicry. And the finding had clinical implications.

"When the patterns were present, the tumors seemed to assume a more aggressive form," explained Folberg, from the Michigan State University College of Human Medicine in East Lansing.

When the findings were published in the American Journal of Pathology in 1999, the reception was chilly.

Folberg vividly recalls being invited to present the research at a meeting in Boston and when he concluded his talk, no one asked him a single question.

Instead, his host escorted him out of the room, not to the lobby, but to the sidewalk.

Kicked to the Curb

The reason for this response, Folberg told Medscape Medical News, is that lot of momentum had built around the idea that tumors depend on blood vessels that they create or remodel to supply themselves with blood.

At the time, a team led by Judah Folkman, MD, from Children's Hospital in Boston, was working to create a class of drugs that would inhibit tumors from creating blood vessels. Their research was so promising that Nobel Laureate James Watson was quoted in a New York Times article, saying that "Judah is going to cure cancer in two years."

The implication of vasculogenic mimicry, however, was that tumors might be able to survive without blood vessels.

The news hurt the stock price of at least one company that was developing cancer treatments on the basis of tumor angiogenesis.

Criticism of the Folberg team's work soon appeared in the American Journal of Pathology. One objection was that the newly discovered channels didn't have the shape of blood vessels, which should be round or elliptical.

But this just proved the researchers' point: these channels were not blood vessels.

The criticism was so fierce that, at one point, a colleague warned Folberg that he would never get another grant from the National Institutes of Health.

Still, "we focused on the grouting rather than the bricks," Folberg told the audience as he delivered the Zimmerman Lecture here at the American Academy of Ophthalmology 2019 Annual Meeting.

And eventually, the theory of vasculogenic mimicry was confirmed by other scientists.

During his presentation, Folberg showed slides with the names of dozens of people who helped with this achievement. His voice broke when he added that his wife's name, Amy, was there written in "invisible ink."

"Monumental" Discovery

The genetic studies of vasculogenic mimicry have led to gene-expression profiles that provide very good tools for predicting which cancers will become most deadly, Dan Gombos, from the M.D. Anderson Cancer Center in Houston, told Medscape Medical News.

"It was monumental in its day," said Gombos, who is also president of the American Association of Ophthalmic Pathologists and was tasked with awarding Folberg a medal in recognition of his work at the AAO meeting.

Vasculogenic mimicry is currently being used to develop other treatments.

And that original report by Folberg's team that was met with a frosty reception at the outset has now been cited more than 1900 times.

Gombos placed a medal on Folberg to the sound of loud applause.

American Academy of Ophthalmology (AAO) 2019 Annual Meeting. Presented October 15, 2019.

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