BOSTON - Researchers at Dana-Farber Cancer Institute have created bioengineered mice that develop aggressive, fatal pancreatic cancer through the same genetic mishaps that cause the disease in humans. The findings are being posted online today by the journal Genes and Development.
Because the mouse-model cancers start and progress along a path that closely resembles the disease's course in humans, the scientists believe it will be particularly useful in searching for telltale substances, or biomarkers, in the animals. These biomarkers could lead to a blood or urine screening test to catch the disease in an early and potentially curable stage in the mice and, ultimately, in humans.
Currently, nearly all the 30,000 cases of pancreatic cancer diagnosed annually are fatal within a matter of months because they are too advanced to remove surgically by the time they cause symptoms. Moreover, the standard treatments of chemotherapy and radiation are largely ineffective, for reasons that may become clearer as researchers study the biology of the disease in mice.
"This model shows great promise as a platform for rapid and efficient testing of novel therapeutic agents, and for the discovery of tumor stage-specific markers - both critical, unmet needs for the fourth-leading cause of cancer death in the United States," said Ronald A. DePinho, M.D., a senior author of the paper. The report, whose lead authors are Andrew J. Aguirre and Nabeel M. Bardeesy, Ph.D., will appear in the Dec. 15 print issue of Genes and Development.
DePinho, who is also a professor of medicine at Harvard Medical School, added that the new mouse model is the first to contain the two "critical lesions," or mutations, common to the human disease and "which faithfully recapitulates the rapid onset and lethal progression of the disease."
As in other solid tumors such as colon cancer, a series of genetic mutations underlies the conversion of normal cells in the pancreatic ducts to a precancerous series of stages termed PanIN-1, 2 and 3, and, finally, full-fledged, invasive cancer called adenocarcinoma. Only after the tumor has become a life-threatening adenocarcinoma does it cause symptoms by blocking bile ducts, causing jaundice and symptoms of pain, nausea and weight loss.
The genes mutate for various reasons: carcinogens such as tobacco smoke (smoking is a risk factor for pancreatic cancer), possibly dietary components and advancing age (mistakes in the DNA code of genes pile up and the body's DNA repair mechanisms fail to keep pace). Several particular mutations have been identified in tissues taken from pancreatic cancer patients. Among them are KRAS - a growth signal stuck in the "on" position, resulting in unchecked cell growth - and several genes that normally suppress tumor formation, including INK4a/Arf, p53, and SMAD4.
Because the basic mechanisms of pancreatic cancer are so poorly understood, scientists have been trying for more than 15 years to create a mouse model that would mimic the human disease but which could be studied and used to identify potential drug targets. However, none of the models to date had produced cancer in mice that faithfully replicated what occurs in humans.
The team headed by Aguirre and Bardeesy used sophisticated bioengineering methods to control the activities of mutant genes in the pancreas. One, a mutant KRAS gene, was activated and kept switched on continuously as the mouse pancreas developed in the fetus. The other mutation inactivated the normally functional INK4a/Arf tumor suppressor gene. These two "signature mutations," the researchers showed, are both needed to convert normal cells into premalignant and then fully invasive pancreatic tumors. Mice that were given either of the mutations alone did not develop invasive cancers.
Bardeesy said that because the cancer-prone mice are all genetically identical and raised in a standard environment, it is possible to identify the biomarkers associated with early and late stages of the cancer. This will provide an entry point for the discovery of equivalent molecules useful in screening humans.
The research was supported by the Lustgarten Foundation for Pancreatic Research, which was established in the name of Marc Lustgarten, Vice Chairman of Cablevision Systems Corp. of New York, who died of the disease.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
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