To date, most efforts to develop angiogenesis inhibitors--drugs to prevent growth of blood vessels-- have focused on inhibiting the signals sent out by the tumor in response to low oxygen. These latest findings suggest that targeting the endothelial cells' response to low oxygen is a viable alternative strategy to the development of angiogenesis inhibitors. Furthermore, the researchers point out that it may be easier to design effective treatments that target the endothelial cells rather than the tumor cells.
"Cancer cells mutate frequently," says Nan Tang, a graduate student working with Johnson and the first author on the paper. "This means that it is common for these cells to develop resistance to drugs. On the other hand, the endothelial cells are normal cells and would be much less likely to develop drug resistance."
"The endothelial cells are also in direct contact with the blood, simplifying the delivery of drugs," adds Tang.
Because HIF-1alpha is usually turned off in endothelial cells, and the mice lacking the gene in blood vessels were healthy and had normal lifespans, the researchers think that inhibiting the blood vessels' response to low oxygen should be relatively safe. One caveat is that interfering with blood vessels' response to low oxygen may also inhibit wound healing, as was observed in the mice lacking HIF-1alpha. According to the researchers, further work will be needed before their discovery can be applied to actually design new anti-tumor drugs.
"Since the response of the blood vessels to low oxygen likely involves multiple genes and chemical signals, we still need to tease apart the steps involved in the response," says Johnson. "It will also be important to understand how the signals sent out by the tumor, to stimulate t
Contact: Kim McDonald
University of California - San Diego