Targeting a master molecule that helps cancer cells survive when blood oxygen levels are low may offer a potentially powerful strategy for blocking tumor growth, say researchers at The University of Texas M. D. Anderson Cancer Center.
The molecule, "hypoxia-inducible factor 1," or HIF-1, controls production of a number of other proteins, such as vascular endothelial growth factor (VEGF), which work in concert to help nurture these stressed cancer cells. Researchers show that genetically jamming HIF-1 damages the vascular microenvironment and impairs tumor growth, according to the study, published in the June 16th issue of Journal of the National Cancer Institute.
The resarchers found, for example, that while new blood vessels will still grow in tumors when HIF-1 is blocked, the blood vessels were small, with thin walls, and no lumen -- the passage through which blood flows. The tumors were only about 1/10th the size of cancerous masses seen in a group of control mice.
Although the researchers caution that their study was conducted only in animals, they say the findings are of note because HIF-1, as a master molecule, could prove to be a target for anti-cancer drugs.
"We have shown, genetically, that inhibiting HIF-1 significantly impairs tumor growth, so it seems that targeting HIF-1 might offer a great deal of promise in regulating the growth of solid tumors," says the study's senior author, Lee Ellis, M.D., a professor in the Departments of Surgical Oncology and Cancer Biology at M. D. Anderson.
The value of inhibiting this "angiogenic" pathway has already been shown in federal approval of the drug Avastin, an antibody that binds VEGF and prevents its effect on angiogenesis. But there are no drugs currently available or in testing that specifically target HIF-1, Ellis says, so clinical validation of these findings in patients will probably be years away.
"The next step in the process is to seek or develop agents that specifically target HIF-1; until then, this work is limited to animal models," he says.
The study focused on HIF-1's role in gastric (stomach) cancer, but the master molecule is believed to play a role in growth and metastasis of colon, pancreatic and other cancers, and is directly associated with development of renal cell carcinoma, says Ellis.
Cells continually produce HIF-1 proteins, but they are quickly degraded if the cell is healthy, receiving a sufficient supply of oxygen. If the cell become hypoxic (lacking oxygen), HIF-1 is not destroyed. It binds with a partner protein and moves into the cell's nucleus, where it turns on a large number of genes that help support the cell in a relatively caustic environment "of low oxygen and nutrients, and increased acidity," says Ellis. "When cells grow faster than blood vessels, such as when cancer develops and there is not enough oxygen and glucose around, HIF-1 becomes active, pushing the growth of new blood vessels."
In the study, the researchers conducted a series of both cell culture and mouse experiments; previous studies conducted in one or the other system have been contradictory. They transferred a gene into human gastric cancer cells that would not allow HIF-1 to initiate gene activation in the cell nucleus, and then found that in hypoxic conditions, VEGF secretion was not increased, showing that HIF-1 controlled VEGF levels.
They then conducted animal studies, including one in which the altered cancer cells were injected into the stomach wall. Gastric tumors grew in both a control group and in the experimental group of animals. At 22 days, tumors growing in the experimental group, in cells that expressed low levels of HIF-1, were significantly smaller than those growing in the control group.
"We were able to markedly inhibit tumor growth, and we also found something interesting," says Ellis. "The number of blood vessels between the groups was unchanged, yet in experimental mice, the vessels were smaller, and without a lumen. They didn't appear to be able to remain open. They were not 'good' vessels."
The investigators evaluated the structure of these altered vessels and found they didn't contain many pericytes. Normal blood vessels have endothelial cells surrounded by pericytes, which provide structurally rigidity and also modulate endothelial cell survival. "We found that the endothelial cells had little pericyte coverage in tumors with decreased HIF-1 activity, suggesting that HIF-1 not only regulates molecules that mediate endothelial cell function, but also pericyte function," Ellis says.
These results suggest that HIF-1 not only regulates VEGF expression in cancer cells, he says, "but also contributes to the formation of a complex proangiogenic microenvironment in tumors, affecting both the structure and function of blood vessels."
The study was supported by grants from the National Institutes of Health. Co-authors include, from M. D. Anderson's Department of Cancer Biology: Oliver Stoeltzing, M.D., Fan Fan, BS, Weinbiao Liu, M.D., and Anna Belcheva, M.D.; from M. D. Anderson's Department of Surgical Oncology: Marya McCarty, Ph.D., and Jane Wey, M.D. Another co-author, Gregg Semenza, M.D., Ph.D., at the Johns Hopkins University School of Medicine, is a leading expert on HIF-1 research.