By David N. Leff

To hear biotechnologist George Yancopoulos tell it, his scenario could well join the "Star Wars" movie series under the title, "Blood Wars."

Yancopoulos, senior vice president, research and chief scientific officer at Regeneron Pharmaceuticals Inc., in Tarrytown, N.Y., is co-senior author of a paper in today's issue of Science, dated June 18, 1999. Its title: "Vessel cooption, regression and growth in tumors mediated by angiopoietins and VEGF [vascular endothelial growth factor]."

"I think the thing that's exciting about it," Yancopoulos told BioWorld Today, "is that there's really a battleground involving the tumor and the host tissue fighting over the blood vessels."

He cited "the old theory" - still current - "that when a tumor or its metastasis starts growing, they grow to a considerable size without a vasculature. And then, at some point, they have to acquire a blood supply to continue to grow.

"That was pretty much the simple view," Yancopoulos said. "People have assumed it to be a done deal in terms of understanding how tumors spread, and in particular how they interact with blood vessels. I believed it when we got into this field a couple of years ago. Now, with the cloning of things like the angiopoietins, which are key new players we discovered, and getting molecular probes for them and so forth, we can now re-look at the picture and see if everything still fits. It turns out that the old story just doesn't seem to apply to a lot, if not most, of the important tumor types. It's a much more complicated process."

How Regeneron Scientist Sees New Script

"The host blood-vessel tissue seems to have a host defense mechanism that's activated by tumor invasion. Now, tumor cells, contrary to previous notion, are not stupid," he said. "They immediately go for the blood, and start growing around the preexisting blood vessels. So, they start out being very well vascularized.

"That changes the local milieu around these blood vessels, and somehow the normally nice, quiescent vessels sense that they've been perturbed; that they've now been invaded by tumors. In such an aberrant situation, their defense mechanism activates a suicide process. Those blood vessels turn on the anti-angiogenic factor, angiopoietin factor 2, and that, by an apoptotic mechanism, causes it to regress. But that's just the beginning of the battle.

"That vessel regression takes a huge amount of the tumor with it," Yancopoulos said. "And this massive tumor loss can wipe out a huge percentage of the tumor. Maybe in a lot of normal situations, it can completely wipe out the aberrant process. On the other hand, the successful tumor defeats the host defense system here, and starts pumping out its own growth factors, most notably VEGF. This overcomes the suicide process in the vessels, and in fact when the host vessels are destabilized by angiopoietin-2, it seems that this facilitates VEGF. And now the tumor takes off."

"So, it's a much different picture," he said. "It's this ongoing battle of vessel regression and tumor regression that's being waged, and the bullets here are these growth factors, the angiopoietin and the VEGF - not the old theory's putative anti-angiogenic therapies, endostatin and angiostatin."

Neuroendocrinologist Stanley Wiegand, the Science paper's other senior author, doesn't anticipate a backlash of disagreement with Regeneron's new theory from the anti-angiogenesis community.

"I don't see why there should be disagreement," Wiegand told BioWorld Today. "First of all, what we're saying is not a negation of what has come before; it's a refinement." Wiegand is director of neuroendocrine and metabolic science at Regeneron.

"All we're saying," he said, "is that if the tumor originates as a metastasis, or if it grows in a solid tissue that has blood vessels, a large number of such tumor types can abduct the existing local blood vessels and grow without initiating angiogenesis. So, that's the real novelty in this paper."

Gliomas, Mammary, Lung Tumors Do It In Rat Brains

The co-authors have followed the blood-seeking behavior of glioma (brain tumor), mammary and lung tumor cells, by implanting them in the brains of rats.

"We first saw this cooption effect in the gliomas," Wiegand recounted, "and it was even more striking when we put mammary adenocarcinoma cells into the brain. We put only a very few cells in because we were trying to mimic a small tumor at its growth initiation. Within days of placing those solid tumor cells in the brain, we could actually see the solid tumor growing as a mass around the adjacent blood vessels. And we could also see little cuffs of tumor cells migrating along the blood vessels that emanate from the tumor core."

Wiegand continued: "I think we show pretty clearly that when tumors get to this stage of initiating angiogenesis - and they do, regardless of how they start out - VEGF is probably the prime switch for that. So, we think we have done something here to confirm that hypothesis, because we can show that in these early stages of tumor growth, which are characterized principally by vascular regression, or at least by any angiogenesis, VEGF levels are very low. When they start to come up, that's when we start to see angiogenesis in these tumors. So, we do agree that there's an angiogenesis switch, and VEGF is probably the key to it."

Regeneron is buying that script.

"I think our data totally validate the concept of anti-VEGF-based therapies," Yancopoulos said. "We and a number of other companies - from the Genentechs to the Sugens to the Zenecas - are certainly players, and we have an aggressive anti-VEGF program here as well. "Regeneron, is collaborating with the Proctor & Gamble Company [in Cincinnati] in the research, development and worldwide commercialization of the angiopoietins. Our data also suggest, that helping out the host defense system in terms of promoting the anti-angiogenic effects of angiopoietin-2 in particular might be a novel way of impacting on VEGF process. Not only do you try to block what the tumor is doing; you try to help out what the host is doing."