Wednesday 16 April, 2014

Genetic change helps lung tumors spread to other parts of the body

Published On: Thu, Apr 7th, 2011 | Lung Cancer | By BioNews

Scientists have identified a genetic change that makes lung tumors more likely to spread to other parts of the body.

The findings offers new insight into how lung cancers metastasize and could help identify drug targets to combat metastatic tumors, which account for 90 percent of cancer deaths.

The researchers, led by Tyler Jacks, director of the David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, found the alteration while studying a mouse model of lung cancer.

They then compared their mouse data to genetic profiles of human lung tumors and found that reduced activity of the same gene, NKX2-1, is associated with higher death rates for lung-cancer patients.

Lead author Monte Winslow and his colleagues at the Koch Institute studied mice that are genetically programmed to develop lung tumors.

The mice”s lung cells can be induced to express an activated form of the cancer-causing gene Kras, and the tumor suppressor gene p53 is deleted.

While all of those mice develop lung tumors, only a subset of those tumors metastasizes, suggesting that additional changes are required for the cancer to spread.

The researchers analyzed the genomes of metastatic and non-metastatic tumors in hopes of finding some genetic differences that would account for the discrepancy. The absence of NKX2-1 activity in metastatic tumors was the most striking difference, said Winslow.

The NKX2-1 gene codes for a transcription factor — a protein that controls expression of other genes. Its normal function is to control development of the lung, as well as the thyroid and some parts of the brain.

When cancerous cells turn down the expression of the gene, they appear to revert to an immature state and gain the ability to detach from the lungs and spread through the body, seeding new tumors.

Once the researchers identified NKX2-1 as a gene important to metastasis, they started to look into the effects of the genes that it regulates.

They zeroed in on a gene called HMGA2, which had been previously implicated in other types of cancer. It appears that NKX2-1 represses HMGA2 in adult tissues. When NKX2-1 is shut off in cancer cells, HMGA2 turns back on and helps the tumor to become more aggressive.

They also found that human tumors with NKX2-1 missing and HMGA turned on tended to be metastatic, though not all metastatic tumors fit that profile.

The study is to be published in the April 6 online issue of Nature.

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