Oxygen Generated by NOX1 Enzyme Triggers Angiogenesis
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
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
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
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
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
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