 Like
an expanding city lobbying for more freeways, growing tumors need
to stimulate the development of new blood vessels. As a tumor
grows, cells in its center find their oxygen supply reduced, and
respond by sending out chemical signals that make blood vessels
proliferate. Drugs that prevent a tumor from recruiting blood vessels
starve it of oxygen and nutrients, and prevent it from growing.
However, cancer cells mutate frequently, and can develop
drug resistance. Now UCSD biologists and colleagues may have found
the Achilles’ heel of a developing tumor.
In a study published in the journal
Cancer Cell, the researchers show that the blood vessels themselves
actively respond to oxygen
levels and not just to the signals sent by the tumor. According
to the researchers,
developing drugs that interfere with the blood vessels’ response
to low oxygen may be a potent anti-tumor strategy.
The researchers identified a gene, HIF-1alpha, which gets switched
on when endothelial cells—the cells lining the blood vessels—are
deprived of oxygen, as occurs in the vicinity of
a tumor. When HIF-1alpha is activated, endothelial cells proliferate
and migrate. In mutant mice that lack the gene, blood vessels do
not form a supply route to the tumors and the tumors are shrunken,
relative to those normal mice that have the gene.
“We showed that the blood vessels’ response to lack of oxygen
is just as important
as the response of cancer cells to lack of oxygen,” says
Randall Johnson, a professor of
biology at UCSD who headed the research team. “Drugs that
interfere with HIF-1alpha, or another gene involved in the blood
vessels’ response,
should block tumor growth.”
Researchers believe there are advantages
to developing drugs that target the blood
vessels directly, rather than the tumor cells.
“Endothelial cells are normal cells and would be much less likely
to develop drug resistance,” says Nan Tang, a graduate
student who is first author on the paper and works with Johnson. “The
endothelial cells are also in direct contact with the blood,
simplifying the
delivery of drugs.”
— Sherry Seethaler
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