Kwok-Kin Wong, MD, PhD
Collaborating scientists in Boston and North Carolina have found that
a particular gene can block key steps of the lung cancer process in
mice. The researchers report in the journal Nature that LKB1
is not only a "tumor-suppressor" gene for non-small cell lung cancer in
mice, it also may be more powerful than other, better-known
suppressors. The study will be published on the journal's Web site on
Aug. 5 and later in a print version.
If further research shows LKB1 has a
similar effect in human lung cells, it could influence the way non-small
cell lung cancer is diagnosed and treated, says the study's senior
author, Kwok-Kin Wong, MD, PhD, of Dana-Farber, one of three
institutions, along with Massachusetts General Hospital and the
University of North Carolina School of Medicine, leading the work. If
tumors with LKB1 mutations are found to be
especially fast-growing, for example, patients with such tumors might be
candidates for more aggressive therapy.
People born with defective versions of LKB1
often develop Peutz-Jeghers syndrome, which is marked by intestinal
growths and an increased risk for certain cancers. Non-inherited
mutations of the gene have been found in some lung cancers. This
suggested that LKB1 normally thwarts tumors from forming. Mutated versions may be unable to act as a brake on cancer.
To find out, the investigators ran a series of experiments in mice with a defective form of a gene called Kras, which drives the formation and growth of lung cancer. They tracked the development of lung cancer in animals with mutated LKB1 and compared it to the experience of animals with abnormalities in either of two well-known tumor-suppressor genes.
They found that while Kras "cooperated" with the mutated tumor-suppressor genes to produce lung cancer, it cooperated even more strongly with mutated LKB1. "The LKB1-deficient
tumors grew more rapidly and spread more frequently than the others,
and comprised all three types of non-small cell lung cancer — squamous
cell carcinoma, large-cell carcinoma, and adenocarcinoma – rather than
just one or two," Wong says. "This suggests that LKB1
plays a role at major stages of the tumors' development: initiation,
differentiation of normal lung cells into cancer cells, and metastasis."
An examination of human non-small-cell lung tissue suggests LKB1
mutations play a role there as well. Of 144 samples analyzed, 34
percent of the lung adenocarcinomas and 19 percent of the squamous cell
carcinomas contained abnormal versions of the gene, researchers report.
"We were surprised at how significant a role LKB1
mutations play in non-small cell lung cancer development in mice," say
Wong, who is also an assistant professor of medicine at Harvard Medical
School. "This suggests there may be additional lung tumor-suppressor
genes yet to be discovered. We're currently examining whether these
results apply to human lung cancers as well and, if so, how such
information can improve treatment."
The lead author of the study was Hongbin Ji, PhD, of Dana-Farber. Other Dana-Farber co-authors include Dongpo
Cai, PhD, Liang Chen, PhD, Pasi Janne, MD, PhD, Bruce Johnson, MD,
Jussi Koivunen, MD, PhD, Danan Li, Mei-Chih Liang, PhD, Kate McNamara,
Matthew Meyerson, MD, PhD, Samanthi Perera, PhD, Geoffrey Shapiro, MD,
PhD, and Takeshi Shimamura, PhD. Other authors
were based at Children's Hospital Boston, Brigham and Women's Hospital,
Broad Institute of Harvard University and Massachusetts Institute of
Technology, University of Tennessee Health Science Center, and the
University of Texas Southwestern Medical Center.
The research was supported by the National Institutes of Health, the
Sidney Kimmel Foundation for Cancer Research, the American Federation of
Aging, the Joan Scarangello Foundation to Conquer Lung Cancer, the
Flight Attendant Medical Research Institute, the Waxman Foundation, the
Harvard Stem Cell Institute, and the Linda Verville Foundation.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National