Lack of Oxygen May Not Halt Cancer's Spread

Study casts doubt on theory of starving tumors

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HealthDay Reporter

THURSDAY, Sept. 18, 2003 (HealthDayNews) -- A sad fact of cancer is that some tumor cells spread, signaling a worse prognosis for the patient, while others don't. An enduring question in cancer research has been, "Why?"

"If you look at the public health problem of cancer, it's mostly due to cancer that has spread," says Dr. Max Sung, medical director of the Ruttenberg Cancer Treatment Center at the Mount Sinai Medical Center in New York City. "If there's a mechanism by which these cancer cells that have spread can be destroyed, that would be wonderful. The next best thing is to see if we could prevent the primary tumor from spreading in the first place."

An article appearing in the Sept. 18 issue of Nature looks into just this issue: why tumor cells spread and how that deadly process can be prevented.

Scientists already knew tumor cells that don't have enough oxygen, a condition known as hypoxia, have a greater tendency to spread than those with a regular supply of oxygen.

Now scientists have shown that tumor cells that are deprived of oxygen also seem to have the ability to zoom in on certain organs, which explains why certain types of cancer tend to spread to certain parts of the body. Breast cancer, for instance, has a preference for bone marrow, lungs and the liver.

"This adds a novel dimension to our insight. It has shown that, not only do tumor cells acquire the ability to spread, but they also acquire the ability to home in on certain organs," says Rene Bernards, author of an accompanying article in the journal and a professor of molecular carcinogenesis at The Netherlands Cancer Institute in Amsterdam.

When faced with hypoxia, tumor cells respond by increasing production of a protein called hypoxia-inducible factor (HIF), which in turn binds to and activates different genes.

The von Hippel-Lindau (VHL) tumor suppressor gene produces proteins that prevent cells from becoming malignant. It is also part of the oxygen-sensing machinery of the cell that controls the levels of the HIF.

"The question is 'What is the relationship of this gene to the tumor cells spreading?'" Sung says.

In this study, the researchers introduced VHL into kidney cancer cells (which normally lack a copy of this gene) and then looked for changes in the activity of thousands of other genes under conditions of adequate oxygen. To their surprise, they found that VHL reduced the production of a receptor protein called CXCR4, which is known to be over-expressed in those breast cancer cells that spread to the bone. The CXCR4 acts as a sort of homing system.

"Now it turns out that if tumor cells become starved of oxygen, that they begin to express CXCR4, which allows tumor cells to migrate specifically to other organs," Bernards explains.

The findings do open up the possibility of gene therapy to correct the situation sometime in the future.

At the same time, the results cast doubt on the concept of angiogenesis, which posits that cutting off blood supply to a tumor will shrink or kill it. Oxygen is carried via the bloodstream. "Although the concept that oxygen deprivation promotes tumor metastasis is not altogether novel, this is still an interesting and important study," says Charles Graham, assistant professor of anatomy and cell biology at Queen's University in Ontario. "The idea of using angiogenesis inhibitors to deprive tumors of their blood [and hence oxygen] supply as a therapeutic approach has been around for quite a while. However, this and other studies. . . indicate that reducing the blood supply to a tumor may have unintended consequences, as it may promote the spread of malignant cells."

There are other unresolved issues. "A key question that follows is whether these changes have already taken place in the primary tumor, allowing it to spread to a specific secondary site, or whether primary tumor cells that are carried to secondary organs undergo these changes after they have been exposed to the new environment," Bernards writes in his commentary.

The current results seem to suggest the changes leading to this deadly cascade happen early on.

This supports research that Bernards and his colleagues previously conducted that was also published in Nature. "We showed that breast cancer comes in two flavors even if they are small primary tumors, either of good prognosis or bad prognosis. Even if the primary tumor is still small, it has either already decided very early in its life that it will become malignant and aggressive and metastatic or has started out on a relatively benign path," he says. "In a way, that is good news for cancer patients because you can determine up front whether a cancer is likely to metastasize to other parts of the body or not, and we can adjust the chemotherapy requirements to this insight."

More information

The American Cancer Society and the National Cancer Institute have information on metastatic cancer.

SOURCES: Rene Bernards, Ph.D., professor, molecular carcinogenesis, The Netherlands Cancer Institute, Amsterdam; Max Sung, M.D., assistant professor, hematology/oncology, and medical director, Ruttenberg Cancer Treatment Center, Mount Sinai Medical Center, New York City; Charles Graham, Ph.D., assistant professor, anatomy and cell biology, Queen's University, Ontario; Sept. 18, 2003, Nature

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