‘Sonic Hedgehog’ Holds Clue to Lung Cancer

‘Sonic Hedgehog’ Holds Clue to Lung Cancer

Source: HealthScoutNews

By Amanda Gardner

HealthScoutNews Reporter

Certain cancer tumors appear to proliferate by hijacking a process that, under normal circumstances, is involved in forming and repairing cells.

Blocking this process may stop tumor growth in its tracks, scientists say in a new study.

Specifically, the findings may hold promise for small-cell lung cancer (SCLC), the deadliest form of lung cancer that is closely tied to smoking. The authors of the article, appearing in the March 5 issue of Nature, already have a compound that successfully blocked tumor growth in mice with human cancers.

“Knowing what are the key molecules that are causing this process is really exciting,” says Myung Shin, associate member of the Fox Chase Cancer Center in Philadelphia. “They demonstrate that this pathway is being turned on in cancer cells and that they can block it.”

Something seems to go wrong at a very fundamental, molecular level.

In certain normal cells, the so-called “embryonic pathways” that repair cells and help them turn over are on all the time. “In adult organisms, the skin, bone marrow and gut all have cells which are constantly growing and turning over and replacing lost cells,” says study author Dr. D. Neil Watkins, a research associate with the Kimmel Cancer Center at Johns Hopkins University in Baltimore.

That’s normal. What is not normal is when these pathways start working on behalf of tumor cells. In other words, they’re on when they’re not supposed to be.

Lung cells represent a case in point. “In a normal adult lung, everything is quiet,” Watkins says. There is no hustle and bustle of repairing and replicating activity unless you’re a smoker. In people who smoke, injured airways signal repair crews to patch them up so they’ll continue to perform the work of breathing.

This is still a normal process, as long as the pathway goes back to sleep as soon as the repair is finished. The authors found, however, that when an SCLC tumor is present, a signaling molecule called the “Sonic hedgehog” pathway (after the cartoon character) stays on. The Sonic hedgehog (Shh) pathway is also essential for the formation of the lungs in embryos.

“The cells are regenerating and they don’t know when to stop. They’re bypassing the normal process,” Shin explains.

The Shh pathway seems to be involved both in repairing lungs and in fueling specific types of cancer.

Although it’s not clear exactly why this is so, the Nature authors speculate the normal cells involved in repair, called “progenitor” cells, are vulnerable to mutations that cause them to transform into cancer cells.

As it turns out, the Shh pathway was also turned on in certain samples of human tissue that had been taken from lung tumors. So this pathway is essentially the Achilles heel of the cancer.

“The more interesting — and, in some ways, more unexpected — finding is that although SCLC cells harbor many mutations and many abnormal pathways which permit the cell to replicate endlessly, it’s still dependent on the pathway for growth,” Watkins says. “Although it’s a very aggressive malignant tumor, it’s extremely vulnerable to having the pathway silenced.”

Watkins and his team may already have a way to target this Achilles heel. A naturally occurring plant compound called cyclopamine did, in fact, block that pathways in mice so the cells didn’t grow. “Mice that have human tumors respond to treatment with this drug,” Watkins says.

Cyclopamine originally drew interest because it prevented birth defects related to the Shh pathway in sheep. (Study co-author Philip Beachy discovered its ability to block the hedgehog pathway.)

“This is not conventional chemotherapy. It does nothing else [to the body],” Watkins says. “It’s potentially a very exciting finding because this may be a way of highly specifically treating certain types of cancer without affecting the rest of body.”

And while the compound seems to work in sheep and mice, it’ll be years before it’s ready for human cancer patients.

More information

For more on lung cancer, including small-cell lung cancer, visit the National Cancer Institute or the American Lung Association.

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