Low Oxygen, Key To Fetal Development, Also Offers Cancer Clues

September 11, 1997

Oxygen levels act as a switch controlling placental development, scientists show in a paper published in the September 12 issue of the journal Science. The study, led by Professor Susan Fisher of the University of California at San Francisco (UCSF), is the first to show that low oxygen levels regulate cell proliferation in early pregnancy, controlling the development of the vital bridge between mother and baby.

The finding also sheds light on cancer, says co-author John Ludlow, associate professor at the University of Rochester Cancer Center, since hypoxia, or low oxygen level, also plays a role in cancerous growth -- a process remarkably similar to placental development.

The study grew out of Fisher's longstanding interest in fetal and placental development. A few clinical ultrasound studies, including some at Rochester under the direction of obstetrician Richard Jaffe, have indicated that low oxygen levels play an important role in the first trimester, so Fisher decided to measure the effects of hypoxia on the developing placenta, the structure in mammals that develops and serves as a bridge between mother and baby during pregnancy.

The team studied cytotrophoblasts, the cells from the placenta that form the connection between mother and fetus by attaching to the uterus. These cells eventually evolve into tumor-like cells that invade the mother's uterus and establish blood flow to the fetus, giving it access to the nutrients in the mother's blood.

The team found that the amount of oxygen in blood directly regulates how the placenta forms. Under the low-oxygen conditions typically found in the placenta during the first 10 weeks of pregnancy, the cells proliferate but don't invade the uterus. Later in pregnancy, when oxygen levels increase, the cells stop dividing and instead invade the uterus.

"We've shown that hypoxia is necessary for the early development of the human placenta and fetus," says author Olga Genbacev, research professor at UCSF. "Hypoxia is necessary at a certain stage, and normal oxygen levels are needed at a later stage. We believe that if the transition from hypoxia to normal oxygen levels is not made properly, a mother can suffer serious consequences, such as a spontaneous abortion or preeclampsia."

The way a placenta's cells invade the uterus bears a remarkable resemblance to how a cancerous tumor invades healthy tissue, says Ludlow, but the reaction of cancer cells to hypoxia is reversed. Ludlow's laboratory has shown that when facing low- oxygen conditions, ovarian cancer cells stop proliferating but still invade healthy tissue.

"In both systems cells invade tissue, but the effects of a lack of oxygen are exactly the opposite," says Ludlow. "By comparing the two cell types, maybe we can figure out how these cells detect and respond to changes in oxygen levels."

Understanding why cells respond like they do to hypoxia would help scientists develop more effective cancer treatments. It bodes poorly when cancer cells in patients stop proliferating under low-oxygen conditions, like those found deep inside a large tumor, because radiation and anti-cancer drugs target cells that are dividing. Scientists like Ludlow someday hope to break down this protective hypoxic barrier and make these cells more vulnerable to treatment.

Ludlow's work is sponsored by the National Institutes of Health (NIH) and the Sally Edelman and Harry Gardner Cancer Research Foundation of Hilton. The UCSF team, which also included researcher Yan Zhou, is sponsored by NIH.

University of Rochester

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