LKB1-deficient tumors grew more rapidly and spread more frequently than tumors with abnormal p53 or Ink4a/Arf.
A team of scientists believe that they have validated a new tumor suppressor gene called LKB1. They found that in mice, mutations of this gene result in tumors that are more aggressive and more likely to spread throughout the body.
Collaborating scientists in Boston and North Carolina say that 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. Noninherited mutations of the gene have been found in some lung cancers as well.
The investigators decided to study the role of LKB1 and 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 compared disease development in animals with mutated LKB1 to mice with abnormalities in either p53 or Ink4a/Arf (also known as Cdkn2a), both well-known tumor suppressors.
They found that while Kras cooperated more strongly with mutated LKB1 than mutated p53 or Ink4a/Arf, LKB1-deficient tumors demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous, and large-cell carcinoma), and more frequent metastasis compared to tumors lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of LKB1.
“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,” explains senior author, Kwok-Kin Wong, M.D., Ph.D., of Dana-Farber, one of three institutions, along with Massachusetts General Hospital and the University of North Carolina School of Medicine, leading the work.
The researchers went on to examine human non-small-cell lung tissue. They found that of the 144 samples analyzed, 34% of the lung adenocarcinomas and 19% of the squamous cell carcinomas contained abnormal versions of the gene.
Expression profiling in human lung cancer cell lines and mouse lung tumors identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC, and CD24, as targets of LKB1 repression in lung cancer, the authors wrote, in their study published online in Nature on August 5.