School of Medicine researchers have tentatively linked two mouse genes to the increased creation and the growth of lung tumor cells — a finding that may aid the search for genes with similar effects in humans.
“Most people regard lung cancer in humans as something primarily caused by tobacco smoke,” said Ming You, M.D., Ph.D., professor of surgery and a researcher at the Siteman Cancer Center. “But there is epidemiological evidence implying that even among heavy smokers, a genetic component puts some people more at risk for lung cancer than others.”
According to You, the findings are the first major advance in a decade in the search for lung tumor susceptibility genes in mouse models or humans. Researchers have already identified genes in human DNA similar to the two mouse genes, lung adenoma susceptibility gene 1 (Las-1) and Kirstin rat sarcoma oncogene 2 (Kras2).
You’s team and his collaborators at the University of Michigan published the findings in the Oct. 28 issue of the Proceedings of the National Academy of Sciences.
Lung cancer kills more patients than any other cancer, You said, and the patients’ high and rapid mortality rates make it challenging to gather blood samples for studies of the genetics of human lung cancer susceptibility.
When researchers began modeling the disease in mice more than a half-century ago, they found a wide spectrum of susceptibility: Most types of mice are highly resistant to lung tumors, but a minority can develop lung tumors when exposed to carcinogens and a few can even develop spontaneous lung tumors.
To identify susceptibility genes, researchers in You’s laboratory repeatedly crossbred a strain of mice with maximum resistance to lung cancer and a strain of mice highly susceptible to lung cancer. They tested reactions of each of the resulting mouse strains to carcinogens and began searching DNA from those that developed the most tumors.
Previous studies had linked lung tumor susceptibility to a region on mouse chromosome 6, and with data from their new lines of mice, You’s group was able to focus the search on a smaller area within that region.
“This section has about 12 genes, but only four of them have changes in the DNA that could potentially change the function of the protein produced from the gene,” You said.
Researchers took copies of the four genes from the mouse strains and inserted them in cell lines used to test cell growth, comparing the effects of genes from cancer-susceptible mice with the effects of genes from cancer-resistant mice.
Only one gene produced a difference in the tests, a gene that You’s group named Las-1. Cells with Las-1 from cancer-susceptible mice had high rates of cell division and growth, but cells given the same gene from cancer-resistant mice were normal.
Next, they took the cell lines and grafted them onto the backs of mice. Grafts carrying the Las-1 gene from susceptible mice became large tumors in a few weeks, while grafts with the gene from the resistant mice grew very little.
Another gene in the search area on mouse chromosome 6 caught the scientists’ eyes: Kras2, a gene involved in normal regulation of cell growth that is also linked to cancer development. There were no significant changes in the regions of the Kras2 gene that code for protein parts, but other areas of DNA that affect how often the gene’s protein is made did have changes.
Through a series of tests of the potential for levels of Kras2 protein to affect tumors, scientists gathered evidence suggesting the gene may be linked to cancer cells’ ability to grow.
Follow-up studies, including work to develop a mouse with both genes disabled at birth, are under way.
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