New model to aid pancreatic cancer research

Results from the genetically-engineered mice, published online Nov. 14 in the journal Genes and Development, suggest that the mice could provide new opportunities to investigate targeted chemotherapeutics and screening methods for one of the most deadly cancers.

With a 5-year survival rate of less than 5 percent, pancreatic cancer is one of the most lethal cancers. “Most cases are diagnosed at a late stage when it is incurable,” said Hal Moses, M.D., the Hortense B. Ingram Professor of Molecular Oncology, professor of Cancer Biology and senior author on the study.

If appropriate, surgery is the most successful treatment option. However, surgery is usually unable to help patients with advanced disease, and there is currently no effective chemotherapy regimen.

Developing an animal model of pancreatic cancer is essential to identifying new treatment and screening options, but progress has been slow. The first realistic pancreatic cancer model, reported in 2003, involved a mutation in a single gene, called Kras. A mutation in this gene is among the earliest genetic changes observed in human pancreatic cancers. Yet the model does not mimic human disease closely.

“Kras mutation alone is not a very good model because it mainly gives a precursor condition,” said Moses. This precursor condition called PanIN (pancreatic intraepithelial neoplasia) rarely progresses to the tumor type seen in humans, called PDAC (pancreatic ductal adenocarcinoma).

Kras mutation is considered a “tumor-initiating” event, but additional mutations in other genes are probably required for progression to a clinically relevant tumor. For the past few years, researchers have been searching for a combination of genetic mutations that recapitulates human pancreatic cancer in animals.

To hopefully improve upon previous models, Moses and colleagues have combined the Kras mutation with a “knock out” of the type II TGFƒÒ receptor (TGFBR2), a component of a signaling pathway that inhibits cell growth. Loss of TGFƒÒ signaling could remove the molecular “checks and balances” on cell growth, allowing unrestrained cell proliferation and tumor formation.

The researchers used a genetic manipulation that allowed them to control these genetic changes in pancreatic cells only. The resulting tumors were localized to the pancreas, with no extraneous tumor formation in other tissues ¡V a problem that has complicated previous models.

“Our model is more aggressive in terms of survival time,” said Hideaki Ijichi, M.D., Ph.D., research fellow and lead author on the study. The mice survive approximately two months, reflecting the aggressiveness of human pancreatic tumors.

Also, the microscopic appearance of tumors in the new model more closely resembles that of human tumors.

“Combining the Kras mutation with the TGFBR2 knock-out resulted in 100 percent penetrance in developing tumors that histologically and clinically looks very much like human disease,” said Moses.

“A certain percentage (of the previous models) have a sarcomatoid histology, which is very rare in humans,” Ijichi said. “Our model has almost no sarcomatoid histology.”

Ijichi and Moses are planning to use the new model to test targeted drug therapies and identify possible screening methods that could be used for early detection of pancreatic cancer ¡V something that is sorely lacking for humans.

Progress is indeed picking up in the field. Publishing in the same issue of the journal, a research group from Harvard University reports the development of another pancreatic cancer mouse model. Ronald DePinho, M.D., and colleagues combined the same Kras mutation with a “knockout” of a downstream component of the TGFƒÒ pathway, called Smad4.

While the Smad4 mutations are more commonly found in humans than mutations in the TGFBR2, the mice developed by DePinho and colleagues did not show the PDAC histology observed in Moses' mice.

Just why a mutation that is more common clinically would induce tumors that are unlike human cancers is unclear, Moses said.

“We really want to know the underlying mechanism of pancreatic carcinogenesis,” said Ijichi. And these new animal models now provide researchers with two additional tools with which to investigate this problem.