COLD SPRING HARBOR, N.Y., Dec. 14 (UPI) -- Independent research groups from Memorial Sloan-Kettering Cancer Center in New York City and the Massachusetts Institute of Technology in Cambridge, Mass., have developed mouse models of human lung cancer that can control the timing and extent of the disease.
The research, which could lead to better drug therapies, is published in the Friday issue of Genes & Development.
"It's an important development, lung cancer is the leading cause of cancer death in the United States and the world -- 1 million deaths per year and we still have only a 15 percent survival rate after five years -- very little on that score has changed in the last 20 years," Robert Dubinette, professor of medicine and director of the University of California-Los Angeles Lung Cancer Research Program, told United Press International.
"We need to understand the disease on the most basic molecular level," he said.
Of the 157,400 people projected to die of lung cancer in the United States this year, more than 40 percent 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 percent.
The role of K-Ras in cancer development is one of the most actively pursued cancer research topics.
Dr. Tyler Jacks of MIT and Dr. Harold Varmus of Sloan-Kettering have generated two different conditional mouse models of human lung adenocarcinoma.
"In an earlier model we were unable to control the timing and extent of the disease but what makes this model unique is that we can imitate infected animals," Jacks told UPI. "We can control the timing and the extent of the disease and control the tumor progression which makes it easier to target treatment."
The models are termed conditional because they allow the researcher to turn-on K-Ras gene expression at will and induce tumorigenesis.
"In an earlier model, we were unable to control the extent of the tumors and too many tumors were formed and the animal would die not from lung cancer but because it could not breathe," Jacks said. "The new model allows us to determine the amount of tumors and their progression."
The two models differ, though, in their regulatory agent and their ability to turn-off K-Ras expression. Jacks and colleagues developed a mouse strain that expresses K-Ras upon infection with a genetically engineered virus.
The ability to control the timing, location and multiplicity of tumors affords an unprecedented view into the initial cellular changes associated with pulmonary adenocarcinoma.
Using this model, Jacks and colleagues have discovered a new cell type that is involved in the development of lung cancer.
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. He found when K-Ras expression was activated, the mice develop full-blown lung cancer within two months.
However, when K-Ras expression is terminated, the tumors regressed and were undetectable within one month. Similar results were obtained in mice lacking established tumor suppresser genes, such as p53.
Varmus and colleagues therefore concluded continued expression of K-Ras was necessary for lung adenocarcinoma progression.
Both conditional models are advantageous because they better show 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.
Most existing mouse models involve the injection or surgical implantation of cancers which then grow and can be treated using experimental drugs, according to Dr. William W. Li, medical director of the Angiogenesis Foundation, a nonprofit research and education institute in Cambridge, Mass.
Angiogenesis is the growth of new blood vessels in the body, a process used to maintain health and one that is hijacked by diseases like cancer to recruit their own private blood supply.
"However, these are 'artificial' models that are actually quite unlike the cancers that grow, spontaneously, in human patients with their behavior controlled by genetic mutations," Li told UPI. "The identification of specific oncogenes has enabled us to pinpoint some of the culprit genes linked to specific cancers."
K-Ras is one of those oncogenes, and it is associated with abnormal cell division or tumor growth in a number cancer types, especially lung cancer.
It also controls production of vascular endothelial growth factor, a potent protein that tumors use to recruit blood supply through angiogenesis. Tumors remain small and growth is restricted to about 2 millimeters in diameter, but once angiogenesis takes place, a tumor can grow up to 16,000 times in volume in only 14 days, according to Li.
"Therefore, the new mouse models of K-Ras developed by Jacks and Varmus enable us to study the 'switch' between early tumors without a blood supply and aggressive tumors with a blood supply, in a precise and genetically controllable fashion to better understand antiangiogenic drugs which cut off the tumor's blood supply to starve it," Li said. "The Jacks and Varmus model represents a turnkey solution to a challenge facing these drugs."
(Reporting by Alex Cukan in Albany, N.Y.)
