From Our 2008 Archives

Study Suggests How Cancers Spread to Lungs

By Jeffrey Perkel
HealthDay Reporter

MONDAY, Sept. 29 (HealthDay News) -- Cancers typically spread -- or metastasize -- to specific, predictable locations. Now researchers have a deeper molecular understanding of why, at least for lung metastases in mice.

The finding might someday lead to drug therapies that curb lung cancer metastasis in humans, experts say.

Dr. Yoshiro Maru of the Tokyo Women's Medical University and colleagues report that primary tumors transmit a series of signals throughout the body to "prepare the soil" in the lungs to accept the "seed" of a metastatic cell from solid tumors located elsewhere.

The key players in this process are signaling proteins, which pass back and forth like text messages between the tumor and the premetastatic lung, and then from the premetastatic lung to the tumor and the bone marrow.

"I think the important part of the paper is that it's putting molecules on these pathways between different cells ... and between the primary tumor and the soil," said Mikala Egeblad, an assistant research anatomist at the University of California, San Francisco.

Just as important, the new study suggests that blocking these signaling interactions could inhibit the ability of tumors to metastasize to the lungs.

The findings were published online Sept. 28 in the journal Nature Cell Biology.

According to Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, much has been learned about what differentiates a benign growth from a more aggressive cancer, as well as the characteristics of cells that break off from a primary tumor and make their way to distant sites within the body -- that is, to metastasize. This study, however, examines how a tumor is able to colonize a particular tissue -- in this case, the lungs.

"This research takes a look at what allows the cancer cells to set up a home in the lungs of the mice," Lichtenfeld said. "By understanding that mechanism, they potentially could incorporate that theory into the treatment of patients and perhaps, by understanding those mechanisms, you may be able to take advantage of that to prevent that [metastasis] from happening."

Studying lung metastases in mice, Maru and his team investigated the cellular signals that accompany tumor migration to the lung. What they discovered was a sort of signaling cascade -- a series of protein messages flashing back and forth throughout the body.

According to their theory: Suppose a tumor in the colon or breast is preparing to metastasize. Before it does so, it sends out specific proteins called growth factors throughout the body.

In cancer-free lungs, local cells respond by producing a second signal: a pair of molecules called S100A8 and S100A9. Nearby lung monocytes respond to these messages by producing the third and final message, called SAA3. This causes immune cells called macrophages to amplify the signal even further, driving both immune cells and tumor cells to migrate to the lungs.

Both of those cell types express the receptor for SAA3 -- a protein called TLR4. According to Maru, "that's a big problem," because TLR4, in a healthier context, induces immune cells to get on the move. But in this case deadly cancer cells get moving, too.

In this way, "the tumor prepares the soil, the pre-metastatic site, prior to its settlement," Maru said.

According to Egeblad, this study suggests "how the tumor is preparing organs, and particularly lungs, so that when the cancer cells arrive, they have an easier time staying and growing."

Added Lichtenfeld, "If they can interfere with that mechanism, they can prevent that [metastasis] from happening, and this could then become an important part of cancer treatment in the future."

SOURCES: Yoshiro Maru, M.D., Ph.D., professor and chair, Department of Pharmacology, Tokyo Women's Medical University, Japan; Mikala Egeblad, Ph.D., assistant researcher, University of California, San Francisco; Len Lichtenfeld M.D., deputy chief medical officer, American Cancer Society, Atlanta; Sept. 28, 2008, Nature Cell Biology, online

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