Published online 28 August 2008 | Nature | doi:10.1038/news.2008.1068

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When good cells turn bad

Non-cancerous mammary cells in mice can take up residence in the lungs and later form tumours.

cancer cellCan a normal cell migrate around the body before becoming a cancer cell?NATIONAL CANCER INSTITUTE / SCIENCE PHOTO, LIBRARY

Non-cancerous breast cells can migrate through the bloodstream and settle in the lungs, experiments in mice have shown. Once there, and if cancer-promoting genes become active, the cells can form tumours in their new location.

The findings, published today in Science1, could reveal a new and unexpected form of metastasis, the process by which cancer cells can migrate from one part of the body to another. This migration was generally thought to be a difficult feat, beyond the ability of most normal cells.

If this process is found in humans, it would be a big surprise for cancer researchers. "The key thing is that this work is provocative," says Ann Chambers, a cancer researcher at the University of Western Ontario in London, Canada, who was not affiliated with the study. "Does this ever happen clinically? This work will put that out as a hypothesis."

The idea that normal human cells are able to metastasize could provide an explanation for rare medical mysteries, in which physicians discover what appear to be secondary tumours – a breast cancer tumour growing in a lung, for example - yet no hint of the 'initial' tumour in the breast can be found.

But questions remain about how applicable this research is to humans. There might be key differences between mice and humans in how cancer develops and spreads. And the experimental set-up might also have played a role: the researchers injected the mammary cells into the tail veins of mice and then monitored where they travelled. Whether cells can actually break away from breast tissue and migrate to the lungs on their own is not yet known.

Hitting the cancer switch

For a cancer to spread to other parts of the body, tumour cells must leave their home, endure a harsh journey swept along by the swift currents of the bloodstream, exit the blood vessels, and set up shop in a foreign environment.

For years, researchers have been picking apart each step of the journey in hopes of finding out what allows cancer cells to survive the trip. The hope has been to discover new therapeutic targets that might interfere with metastasis. Indeed, primary tumours rarely kill cancer patients – their wandering offspring are more often to blame.

Katrina Podsypanina, a researcher in Harold Varmus's lab at Memorial Sloan-Kettering Cancer Center in New York, and her colleagues had created a new experimental system to study cancer in mice. The researchers made genetically engineered mice in which two cancer-promoting genes were placed under the control of a chemical switch. When mice were fed the chemical, the genes were activated in mammary tissue2.

Expression of two genes, Myc and a mutant form of the Kras gene, was enough to turn an innocent mammary cell into a cancer cell. In further experiments to see what happened if unswitched mammary cells from the engineered mice were injected into the bloodstream of non-engineered mice, Podsypanina and her colleagues found that some of these cells migrated to the lungs and took up residence there.

The cells remained dormant in the lungs until the cancer-causing genes were activated by feeding the mice a diet containing the chemical switch. Then they developed into tumours.

Cancer cells are not the only cells able to move throughout the body – specialized cells involved in wound repair, for example, also travel from one site to another. But Podyspanina's study shows that mammary cells need not be transformed into cancer cells in order to make the journey. "The underlying mechanisms may be already built into our biology," says Joan Massagué, a cancer researcher also at the Memorial Sloane-Kettering Cancer Center, who did not work on the study.

To ascertain if that is the case, Podyspanina and her colleagues must first determine whether the cell migration they have observed occurs naturally. "At present we don't know if these cells can spontaneously disseminate on their own," she says. The group already has experiments under way to address the question. 

  • References

    1. Podsypanina, K. et al. Science doi:10.1126/science.1161621 (2008).
    2. Podsypanina, K., Politi, K., Beverly, L.J. & Varmus, H.E. Proc. Natl Acad. Sci. USA 105, 5242–5247 (2008).
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