Reactive oxygen generated by Nox1 enzyme triggers angiogenesis

January 21, 2002

An enzyme called Nox1, which converts oxygen into "reactive oxygen," is a potent trigger of angiogenesis, according to research by scientists at Emory University School of Medicine and Harvard Medical School. Angiogenesis is the growth of microscopic blood vessels that nourishes cancerous tumors and leads to unregulated cell growth. Reactive oxygen, which is created during cellular metabolism and includes molecules such as hydrogen peroxide, nitric oxide and superoxide, has long been implicated in causing cellular damage. Emory dermatologist Jack L. Arbiser, M.D., Ph.D., and Emory scientist J. David Lambeth, M.D., Ph.D., and their Emory and Harvard colleagues published their findings in the January 22 issue of the Proceedings of the National Academy of Sciences.

A variety of cell lines from human cancers has been shown to have significantly high levels of reactive oxygen species (ROS), leading scientists to believe that reactive oxygen may play a role in the growth of tumors. In addition, antioxidants have been shown to enhance the activity of conventional chemotherapy agents in rodents.

Two years ago scientists at Emory, led by Dr. Lambeth, discovered the family of enzymes that includes Nox1 (previously called Mox1) and cloned the human Nox1 gene. When they introduced the Mox1 gene into mouse cells, they were surprised to observe that the cells took on the appearance of cancer cells and divided more rapidly than did normal cells. When they injected these transformed cells into mice, they found that the cells were extremely powerful in producing tumors.

Although microscopic dormant tumors are believed to occur relatively frequently, few progress to form active tumors. The development of dormant tumors into actively proliferating tumors that grow beyond 1 to 2 mm. requires the recruitment and development of new blood vessels, a process called angiogenesis. The conversion to angiogenesis is known as the "angiogenic switch."

In their current research, when the Emory and Harvard scientists injected NIH3T3 cells that were expressing Nox1 into mice, the mice grew large tumors within two to three weeks. They observed similar results when they injected Nox1-expressing epithelial cells from a human prostate tumor into mice. These cells, which typically produce slow-growing tumors when injected into mice, grew markedly and were highly vascularized, which is an indication of angiogenesis. The researchers also measured an increase in the presence of Vascular Endothelial Growth Factor (VEGF) -- a common indicator of angiogenesis. In addition, they detected an increase in enzymes called matrix metalloproteinases (MMPs), which are a requirement for the invasive and malignant growth of tumors.

The research also indicates that Nox1 signals angiogenesis and tumor growth partly through the reactive oxygen molecule hydrogen peroxide. When the scientists introduced catalase, an enzyme that catalyzes the conversion of hydrogen peroxide to water and oxygen, the process of VEGF induction in the tumors was reversed.

"Our findings suggest that the growth of cancer cells that are expressing Nox1 may be decreased and that sensitivity to chemotherapy drugs may be increased by drugs that inhibit Nox1 activity or that lower levels of hydrogen peroxide," said Dr. Arbiser.

Dr. Lambeth stated, "These findings point for the first time to uncontrolled generation of reactive oxygen and to Nox enzymes as a possible cause in the progression of benign microscopic tumors into aggressive, life-threatening cancers. The work has the potential to lead to novel therapies for cancer treatment and prevention."
-end-
The research was supported by the American Skin Association, the National Institutes of Health and the American Cancer Society.

Copies of the article are now available to reporters from the PNAS news office, tel. (202) 334-2138, or email pnasnews@nas.edu.

Emory University Health Sciences Center

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