As the proteins that stimulate the growth of these endothelial cells were discovered, inhibitors that could be used as drugs also were identified.
About 10 years ago, the first inhibitor was discovered. Clinical trials began in 1992 to establish the use of the inhibitor--TNP-470--as a cancer drug, largely as an adjunct after chemotherapy.
"Tumor growth could be slowed significantly, but not reversed [using TNP-470]," Folkman said. "Nevertheless, for the first time, there was no drug resistance."
About two years ago, it was discovered that tumor growth could be slowed almost completely by using normal proteins to signal the vascular endothelial cells which line blood vessels.
"For the first time, it became possible to shut off angiogenesis and cause [tumor] regression," Folkman said. "This was caused by a specific signal which only talks to endothelial cells."
The proteins are part of the larger regulatory system that maintains the layer of endothelial cells in blood vessels. The cells rarely divide, and are normally replaced by a completely new set every three years. However, when they are stimulated by the proteins sent out by the cancerous tumors, the cells' turnover rate skyrockets to every four days, fueling the growth of the vessels to feed the tumors.
"When anything in the body grows, there are factors that promote and factors that inhibit the growth," said Strominger. "The balance between the two determines the rate of growth."
Folkman said that existing tumors actually provide inhibitors for growth of blood vessels elsewhere in the body--this spread is known as metastases.
"It is well known that some tumors suppress the growth of metastases," Folkman said. "Our question was [that] if tumor size is ultimately controlled by endothelial proliferation, could a primary tumor suppress growth of a distant metastasis by delivering an endothelial inhibitor to it through the circulation?"
Folkman's group showed that mice which had tumors with naturally occurring inhibitors had lower metastases than those with surgically removed tumors.
In the past, the spread of cancer even after tumors had been removed was blamed on stress induced by the surgery, not the removal of natural inhibitors.
Folkman's group began to consider using angiostatin as a treatment to maintain dormancy of the tumors two years ago.
Since then, Folkman's group has demonstrated that these natural inhibitors can be injected into tumors, causing them to shrink. This creates the possibility of using the inhibitors as a first-line therapy against cancer. These results are unpublished.
According to Folkman, over 60 pharmaceutical companies are focusing on angiogenesis for cancer therapeutics, and large-scale clinical trials of some of the first inhibitors are likely to occur in the near future.
The drugs may have side effects, however, such as reducing the rate at which wounds heal and preventing fetus development. However, Folkman said the side effects are minimal when contrasted to those caused by chemotherapy: hair and weight loss, nausea and diarrhea.