Modeling human lung cancer

December 14, 2001

Independent research groups from Sloan-Kettering and MIT have developed mouse models of human lung cancer that shed new light on the initiation and maintenance of the most prevalent form of this disease.

Lung cancer is the leading cause of cancer-related death in the United States. Of the 157,400 people projected to die of lung cancer in the U.S. in 2001, over 40% will be afflicted with pulmonary adenocarcinoma, the most common form of lung cancer. Of these cases, the oncogene K-Ras will be mutated to an active form in about 30%. Thus, the role of K-Ras in cancer development is one of the most actively pursued cancer research topics.

Drs. Tyler Jacks and Harold Varmus at MIT and Sloan-Kettering, respectively, have generated two different conditional mouse models of human lung adenocarcinoma. Both models present significant advantages over existing models. These models are termed conditional because they allow the researcher to turn-on K-Ras gene expression at will and induce tumorigenesis. The two models differ, though, in their regulatory agent and their ability to turn-off K-Ras expression.

Dr. Jacks and colleagues developed a mouse strain that expresses K-Ras upon infection with a genetically engineered virus. Their ability to control the timing, location and multiplicity of tumor initiation affords an unprecedented view into the initial cellular changes associated with pulmonary adenocarcinoma. Using this model, Dr. Jacks and colleagues have discovered a new cell type that is involved in the development of lung cancer.

Dr. Varmus and colleagues developed a mouse strain that expresses the K-Ras gene in a specific subset of lung cells under the control of the oral antibiotic, doxycycline. K-Ras expression is activated when doxycycline is put in their drinking water, and terminated when it is removed from the water.

Dr. Varmus found that when K-Ras expression is activated, the mice develop full-blown lung cancer within two months. Interestingly, when K-Ras expression is terminated, the tumors regress and are undetectable within one month. Similar results were obtained in mice lacking established tumor suppressor genes, like p53. Therefore, Dr. Varmus and colleagues conclude that the continued expression of K-Ras is necessary for lung adenocarcinoma progression in the presence or absence of tumor suppressor genes.

Both conditional models are advantageous because they better recapitulate the spontaneous mutations that underlie human lung cancer development. By allowing researchers to track the development and initial stages of cancer progression, these models will enable the design and testing of therapeutic agents.
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Cold Spring Harbor Laboratory

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