From Defense to Offense

Hypoxia typically triggers a defensive, “batten down the hatches” response, in which cells enter a less active, less vulnerable, non-oxygen-burning state. But in some cells, reduced oxygen levels also trigger more proactive changes designed to improve the long-term oxygen supply.

When tissues are wounded and cut off from oxygen-supplying blood vessels, their surviving, oxygen-starved cells usually start producing vascular endothelial growth factor, which causes the local vascular network to sprout new vessels into the wounded tissue. Liver cells also respond to drops in ambient oxygen by producing more erythropoietin, a growth factor that stimulates the production of oxygen-carrying red blood cells.

In a series of high-profile papers in the late 1990s, Simon and her colleagues showed that the same blood vessel- and blood cell-proliferation responses occur in embryos, whose fast growth routinely depletes local oxygen levels. “Hypoxia in these cases serves as a normal developmental signal,” says Simon.

Over the past decade, Simon’s lab has been one of several to show that hypoxia plays a similar growth-promoting role in tumors. Even with adequate oxygen, tumors sometimes find ways to activate hypoxia-signaling pathways to spur extra blood vessel growth.

Hypoxia seems to regulate the growth of tumor and other cell types more directly as well, and this is now one of the main themes of Simon’s lab. “We’ve shown that in the developing bone marrow and heart, for example, oxygen levels affect the production of key transcription factors in local stem cells, effectively regulating their state of activity,” she says. “Our most recent work extends this concept of hypoxia as a stem cell regulator to the adult brain.”

-- Jim Schnabel
HHMI Bulletin, May 2011

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