Previous studies have shown that the blood circulation of cancer patients has an abnormally high number of endothelial cells, which help construct blood vessels including those that feed the cancerous tumor.
"For a cancer to survive, grow and spread, a tumor needs to make more endothelial cells and construct new blood vessels to provide oxygen and other nutrients," said NCI scientist Haiqing Li, Ph.D., first author of the study.
"In addition to growing them directly from nearby blood vessels, tumors can also signal the body's bone marrow to boost the supply of endothelial cells in the blood circulation," Li added.
Results were presented at the first international meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.
Anti-angiogenic drugs inhibit blood vessel development at the tumor by killing the endothelial cells lining tumor blood vessels and/or cutting off the supply of endothelial cells from bone marrow. These drugs are typically paired with chemotherapy agents. Unlike anti-angiogenic drugs, chemotherapy agents directly assault tumor cells, and a reliable therapeutic biomarker for evaluating these agents is whether there are fewer cells in the tumor, or more, or just the same amount as before the treatment. Some chemotherapy drugs, Li noted, also have the benefit of being toxic to endothelial cells, providing a possible second biomarker for those agents.
But biomarkers have yet to be defined for anti-angiogenic drugs. "Many anti-angiogenic drugs may encounter problems during clinical studies, because they can't reduce tumor size rapidly like chemotherapies can," noted Li. "Thus, a biomarker is needed for the effectiveness of anti-angiogenic drugs in an early stage."
The NCI study, conducted with the European Institute of Oncology (EIO), suggests that the anti-angiogenic drugs enhance chemotherapy's ability to kill endothelial cells, as indicated by increases in dead endothelial cells circulating in the patient's blood stream.
The NCI and EIO scientists also discovered that anti-angiogenic drugs might combat cancer by preventing immature cells in the bone marrow from developing into endothelial cells.
This research was conducted with four groups of immunodeficient mice in which human prostate cancer cells had been implanted. Each group received a different treatment: a control agent (no drug); a chemotherapy agent (docetaxel) only; an anti-angiogenic drug (thalidomide) alone; and both chemotherapy and the anti-angiogenic drugs.
Circulating endothelial cell (CEC) levels were measured before all four groups were treated and at specific times during the study. In the group receiving only chemotherapy, blood levels of dead CECs soon increased, up to 2.6 fold. In the animals treated with the two drugs, CEC death was higher - up to 4.3 fold -- suggesting that the anti-angiogenic agent may have enhanced chemotherapy's ability to kill the tumor vascular endothelial cells.
Tests conducted later in the study revealed that treatment with the anti-angiogenic drug alone reduced the level of viable CECs by 18 percent, while treatment with only chemotherapy decreased it by 61 percent. The combination of both drugs further diminished the blood levels of viable CECs by 75 percent, indicating that the anti-angiogenic drug may have inhibited the immature endothelial cells in the bone marrow from reproducing and differentiating into adult cells.
Li is continuing her research on CECs in cancer. "We are in the process of testing whether this biomarker is exclusive for anti-angiogenic therapy," she added. "Hopefully, the knowledge we learn pre-clinically will be translated into a useful biomarker for patients."