NIH scientists find a potential new avenue for cancer therapies

Recent findings in mice suggest that blocking the production of small molecules produced in the body, known as epoxyeicosatrienoic acids (EETs), may represent a novel strategy for treating cancer by eliminating the blood vessels that feed cancer tumors. This research is the first to show that EETs work in concert with vascular endothelial growth factor (VEGF), a protein known to induce blood vessel growth. Together, EETs and VEGF promote metastasis, or the spread of cancer, by encouraging the growth of blood vessels that supply nutrients to cancer cells.

The research team comprised of scientists from the National Institute of Environmental Health Sciences (NIEHS), which is part of the National Institutes of Health, and several other institutions, published its data online in the Dec. 19 issue of The Journal of Clinical Investigation.

Preclinical research suggests that patients with a variety of vascular conditions, such as diabetes, hypertension, inflammation, stroke, and heart attack may benefit by increasing their EET levels, because the compounds cause blood vessels to dilate and reduce tissue inflammation and cell death. However, previous work has also demonstrated that EETs make tumor cells grow faster and cause them to migrate and become metastatic. Darryl Zeldin, M.D., NIEHS scientific director and author on the paper, said he believed that human metabolism has to achieve a certain harmony in regard to EETs.

"The body has to produce enough EETs to maintain a healthy cardiovascular system without promoting cancer. It has to balance the double-edged sword just right," Zeldin said.

To find out how EETs encourage the development of cancer, the team created two mice strains, one with high levels of EETs and one with low levels of EETs.

"The mice with higher EETs developed more metastatic tumors compared to the mice with lower EETs," Zeldin said. "Often, the tumor itself will produce more EETs, which can speed up tumor growth and its subsequent spread, but our analysis demonstrated that the EETs produced by the surrounding tissues encouraged tumor growth and migration."

Matthew Edin, Ph.D., a research fellow in Zeldin's group, is one of the authors on the paper and helped develop the mice strains. He said EETs directly lead to the creation of new blood vessels, also known as angiogenesis, which the cancer cells need in order to receive oxygen and nutrients to grow. He equated the process to what happens when a builder begins constructing a new housing development.

"One of the first things construction crews have to do is build the roads, so that materials and workers can be transported to the site," Edin said. "In cancer, EETs accelerate the road building, allowing the housing development to expand quickly."

According to Dipak Panigrahy, M.D., an author on the paper and a research associate at the Dana-Farber/Children's Hospital Cancer Center, Boston, EETs have a potent stimulatory effect promoting cancer growth and metastasis, a process that could be effectively inhibited using novel antagonists, such as EEZE, which are compounds that interfere with this pathway in mice. EEZE has not been approved for human use, and is only used for research.

"EEZE is structurally similar to EETs, but it blocks the effect of EETs and dramatically slows tumorigenesis," Panigrahy explained.

Mark Kieran, M.D., Ph.D., another author of this collaborative study and also from Dana-Farber, commented on the importance of the research.

"The identification of an old pathway studied for many years in cardiovascular disease has found a new role in regulating cancer growth and metastasis, the primary causes of cancer related deaths," he said. "With these findings, opportunities to better understand the underlying mechanisms that drive cancer, and thus the development of effective therapies for their treatment, moves one step closer to a reality."

Panigrahy D, Edin ML, Lee CR, Huang S, Bielenberg DR, Butterfield CE, Barnes CM, Mammoto A, Mammoto T, Luria A, Benny O, Chaponis DM, Dudley AC, Greene ER, Vergilio JA, Pietramaggiori G, Scherer-Pietramaggiori SS, Short SM, Seth M, Lih FB, Tomer KB, Yang J, Schwendener RA, Hammock BD, Falck JR, Manthati VL, Ingber DE, Kaipainen A, D'Amore PA, Kieran MW, Zeldin DC. 2011. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest; doi:10.1172/JCI58128 [Online 19 December 2011].

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