Angiogenesis: The slow growth of a science


Sometimes a scientific idea takes a long time to make its way forward. Angiogenesis is a case in point. As surgeon-in-chief at Boston Children’s Hospital, Judah Folkman, MD, noted that malignant tumors often had a bloody appearance. In The New England Journal of Medicine in 1971, he hypothesized that tumors cannot grow beyond a certain size without a dedicated blood supply, and that “successful” tumors secrete an unknown substance that encourages blood vessel growth, or angiogenesis.

If angiogenesis could be blocked, he argued, tumors might not grow or spread. Rather than waging a toxic chemical and radiation battle with a tumor, one could starve it into submission by shutting down its blood supply.

The idea was roundly criticized. In fact, when Folkman’s team applied for their first grant based on their hypothesis, reviewers at the National Cancer Institute summarily turned them down:

“It is common knowledge that the hypervascularity associated with tumors is due to dilation of host vessels and not new vessels and that this dilation is probably caused by the side effects of dying tumor cells. Therefore, tumor growth cannot be dependent upon blood vessel growth any more than infection is dependent upon pus.”

Nevertheless, he persisted

Folkman hung in, gathering data. He left his position as surgeon-in-chief to pursue research full time, convinced that unlocking the secrets of angiogenesis would help revolutionize cancer treatment.

His lab grew and became Boston Children’s Vascular Biology Program. Then, he and his team proved, in mice, that by shutting down the blood vessels feeding cancerous tumors, a cancer itself could be shut down. They started identifying factors secreted by tumors that stimulate angiogenesis, such as vascular endothelial growth factor (VEGF), as well as natural angiogenesis inhibitors.

Folkman in the early 1970s. Chicken eggs were commonly used an an assay to test anti-angiogenic compounds because it was easy to observe blood vessel growth.
Reviving an abandoned drug
angiogenesis thalidomideThe discovery of one angiogenesis inhibitor, now a top-selling drug for multiple myeloma, has an interesting backstory. Revlimid and its next-generation analog, Pomalyst, are both derivatives of the infamous sedative thalidomide. Thalidomide’s disfiguring birth defects turn out to result from a potent anti-angiogenic effect. Robert D’Amato, MD, PhD, in the Vascular Biology Program discovered this through a kind of reverse-engineering approach. He systematically inventoried drug side effects throughout the body, looking for effects that might involve angiogenesis. When he also considered pregnancy, one drug had side effects that stood out: thalidomide.

The lab also began investigating other diseases influenced by angiogenesis, such as diabetic retinopathy and vascular anomalies. In short, Folkman founded a new scientific field. If you search the term “angiogenesis” on PubMed today, you’ll pull up more than 90,000 journal articles — compared with just three papers in the entire literature in the early 1970s.

To date, more than a dozen angiogenesis inhibitors have been approved by the U.S. Food and Drug Administration for various cancers, starting with Avastin (bevacizumab), in 2004. Combination therapy with other types of cancer therapies also shows promise. Last week, a study in Science Translational Medicine suggested that anti-angiogenesis can enhance the effects of cancer immunotherapy, and vice versa.

With the approval of Macugen and Lucentis, anti-angiogenic therapy is also a mainstay of treatment of vascular eye diseases such as macular degeneration and diabetic retinopathy.

Therapeutic angiogenesis

On the flip side of anti-angiogenesis is the idea of stimulating blood vessel growth for therapeutic application.

In 2008, the lab of Joyce Bischoff, PhD, in the Vascular Biology Program was the first to grow functional human blood vessels in mice, using cells from human donors. There are now many approaches to stimulating angiogenesis, and research is active in wound healing, tissue engineering (many engineered tissues require a blood supply) and cardiovascular disease.