Semenza's team used breast cancer cells grown in low oxygen to examine the activity of 88 genes known to play a role in metastasis. Looking for genes that are turned on in response to low oxygen they found one called angiopoietin-like 4 and one called L1 cell adhesion molecule, known as ANGPTL4 and L1CAM for short. Further examination of the DNA around these genes revealed regions where HIF-1 could bind, and removing HIF-1 from cells rendered them unable to turn on the two genes.

When breast cancer cells turn on ANGPTL4, it helps them travel through blood vessel walls, the team found by injecting these cells either with normal or "knocked-down" levels of ANGPTL4 into mice and examining their lungs. Cells lacking HIF-1 and containing extra ANGPTL4 were better able to invade the lungs than cells without extra ANGPTL4; the researchers concluded that ANGPTL4 promotes cell exit from blood vessels. And they found the same to be true for L1CAM.

Lastly, a few years ago Semenza's team found that digitalis/digoxin, commonly used to treat irregular heartbeats, can block HIF-1 production and can stop liver and prostate cancer cells from growing. To see if digitalis could do the same with metastatic breast cancer, the researchers transplanted human breast cancer cells into mice. After two weeks they gave the mice daily injections of digitalis or saline. They found both fewer and smaller lung metastases in mice treated with digitalis.

"This is really exciting," says Semenza. "The therapeutic range for digoxin is well established, and our findings warrant clinical trials to determine if these doses are enough to sufficiently block HIF-1 and slow breast cancer growth and metastasis."

Source Johns Hopkins