Abnormal and dysfunctional blood vessels are a hallmark of solid tumors, one that contributes directly to malignant properties of a cancer as well as preventing treatments from reaching and attacking tumor cells.
Normalizing tumor vessels allows cancer therapies to penetrate the mass and to function more effectively.
Unexpectedly, drugs originally designed to destroy tumor blood vessels act to repair them for a time, opening a new avenue for cancer treatment as well as restoration of abnormal vasculature in other diseases.
Editor's Note: This story, originally printed in the January 2008 issue of Scientific American, is being posted in light of two new studies showing that angiogenesis inhibitors, discussed in this article, may actually make tumors bigger, not smaller.
While still a graduate student in 1974, I had a chance to see malignant tumors from a most unusual perspective. I was working at the National Cancer Institute in the laboratory of the late Pietro M. Gullino, who had developed an innovative experimental setup for studying cancer biology—a tumor mass that was connected to the circulatory system of a rat by just a single artery and a single vein. As a chemical engineer, I decided to use this opportunity to measure how much of a drug injected into the animal would flow to the tumor and back out again. Amazingly, most of the substance injected into the rat never entered the tumor. To make matters worse, the small amount that did reach the mass was distributed unevenly, with some areas accumulating hardly any drug at all.
My immediate concern was that even if a small fraction of the cancer cells in a human tumor did not receive an adequate dose of whatever anticancer drug was being applied, those cells could survive—causing the tumor to grow back sooner or later. Perhaps the engineer in me was also drawn to trying to understand and solve the apparent infrastructure problem inside tumors that posed a major obstacle to the delivery of cancer therapies.
Over the subsequent decades my colleagues and I have investigated what makes the vasculature within tumors abnormal and how these disordered blood vessels not only stymie traditional cancer treatments but also contribute directly to some of the malignant properties of solid cancers. Building on these insights, we developed approaches to normalizing tumor blood vessels and tested them successfully in mice. In the process, we also discovered a seeming paradox—a class of drugs designed to destroy the blood vessels of tumors actually acts to repair them, creating a window of opportunity to attack the cancer most effectively.
In recent years we have finally been able to start testing this idea in cancer patients, and the excitement in our lab was overwhelming when we saw the first clinical evidence of tumors shrinking in response to vascular normalization, just as we had anticipated. Much more work remains before we can perfect this therapeutic approach and gauge its usefulness in patients with different types of malignancy. But what we have already learned about restoring blood vessels is also opening doors to treating other vascular disorders, such as macular degeneration, the leading cause of blindness in the U.S.