Oxygen plays role in cancer aggressiveness.

Oxygen plays role in cancer aggressiveness

Oxygen-starved cancer cells from mice increase their deadlines when flooded with oxygen in the lab and then injected into healthy mice, according to a new study. The finding raises safety questions about proposed anticancer treatments that aim to kill tumors by shutting off their blood supply.

Previous research has shown that placing cultured cancer cells in a low-oxygen environment and then reoxygenating them boosts their ability to spread and to survive harsh treatment with anticancer drugs. Those studies hinted that tumor cells robbed of oxygen in the body might also develop aggressive qualities when reoxygenated.

Now, a Canadian research team has tested that idea in mice, using two skin cancers and a connective tissue cancer. They found that tumor cells located far from blood vessels -- and thus from the oxygen supply -- show a greater tendency to metastasize to distant parts of the body after reoxygenation than tumor cells situated close to the blood supply.

Richard P. Hill and S. D. Young of the Ontario Cancer Institute in Toronto injected a fluorescent dye into the blood of cancer-afflicted mice and removed tumor tissue. They sorted the cells by the amount of oxygen each received in the body: Cells close to the blood supply glowed more than distant ones because they picked up more dye. Hill and young then exposed all the cancer cells to oxygen for up to 10 days and injected the cells into the tail veins of healthy mice. After 20 days, the researchers counted the number of lung tumors that had developed in these mice, a measure of how aggressively the injected cells proliferated and migrated to distant body sites.

Hill and Young found that the tumor cells originally derived from the most oxygen-starved sites in vivo showed double the metastatic efficiency of cells from well-oxygenated regions. That finding, detailed in the March 7 JOURNAL OF THE NATIONAL CANCER INSTITUTE, prompts questions about experimental attempts to kill tumor cells by interfering with their blood supply. Last year, for example, a New Zealand research team reported killing cancer cells in mice by using an experimental anticancer drug, flavone acetic acid, to restrict blood flow to the tumor.

The success of that work led to hopes that a similar treatment might benefit human cancer patients. But the Canadian study suggests such an approach could backfire if some cancer cells survived the drug assault. If Hill and Young's findings are correct, says J. Martin Brown of the Stanford University School of Medicine, any remaining oxygen-deprived cells might show a heightened ability to seed new cancer growths when their blood supply is restored. Brown wrote an editorial accompanying the Canadian research report.

The Canadian team's results seem to contradict earlier reports that oxygen-deprived tumor cells show extra resistance to standard chemotherapy. Hill and Young found that oxygen-deprived tumor cells removed from mice and reoxygenated were just as sensitive to the anti-cancer drugs methotrexate and doxorubicin as well-oxygenated tumor cells. However, Hill told SCIENCE NEWS he won't rule out the notion that oxygen-deprived tumor cells are more drug-resistant. The methods used in his study, he says, may not have been able to detect very small numbers of drug-resistant cancer cells that could nevertheless spread malignancy though the body.

Scientists don't know why the oxygen deprivation/reoxygenation sequence seems to produce such aggressive tumor cells. Hill speculates that it increases expression of genes that regulate the cells' ability to proliferate. The new study revealed that the most aggressive cancer cells--those from the poorly oxygenated sites--contained "excess" DNA in comparison with tumor cells from well-oxygenated areas, he notes. In future research, Hill says, the team will seek a connection between this overabundance of DNA and specific genes that may be involved in cancer spread.