A cellular pathway called Sonic Hedgehog (for a cartoon character) that is activated to repair smoking-induced damage may cause up to 99 percent of small cell lung cancers when it is inappropriately activated over a prolonged period, according to an article in the March 5th issue of Nature.

"We believe chronic injury to the lungs by cigarette smoking reactivates genes in the Hedgehog pathway to repair cell damage in the lining of the lungs. The ongoing and regular assault to the lungs by cigarettes causes the usually dormant pathway to be stuck in activation mode making too many new cells, ultimately resulting in cancer," explained Neil Watkins, Ph.D., lead author of the study.

The Sonic Hedgehog pathway has been well studied for its role in the normal development of mammalian embryonic cells, and more recently, for its relationship to cancer. The research group involved in the current study is testing drugs in mice that block the pathway. Human clinical trials are not planned at this time and may be 3 to 4 years away.

In the current work, investigators analyzed tissue samples and tumor cell lines from patients with small cell lung cancer and non-small cell lung cancer. Of 10 small cell tumor samples studied, 5 showed activation of the Hedgehog pathway and increased expression of one of a target gene called Gli1. The researchers confirmed these findings by looking at small cell lung cancer cell lines: Of the 7 lines studied, 5 showed similar activation of the pathway and Gli1 gene. Only limited activation of the pathway was found in non-small cell lung cancer samples.

"This study represents one of the first attempts to therapeutically manipulate this cell pathway, and it's a perfect example of how basic developmental science can have clinical implications in a relatively short period of time," said coauthor Stephen B. Baylin, M.D.

Watkins added, "As cigarette smoking persists among young people, we expect to be dealing with this disease for years to come. As a result, the search for potential new therapies is key to controlling this disease."