© 2003 Cold Spring Harbor Laboratory Press
Early stage pancreatic lesions in Pdx1-Cre; LSL-Kras; Ink/Arf
Aquiet killer, pancreatic cancer often eludes detection until it has progressed to late-stage metastatic disease. This is largely due to the organ's location in the body, which makes it difficult for physicians to evaluate. "You can't feel it with your hands, you can't palpitate it on an examination. There is no pap smear or mammogram for the pancreas, or PSA test. ... So when people present with pancreatic cancer, usually their symptoms are very nonspecific," says David Tuveson, assistant professor of hematology and oncology at the University of Pennsylvania.
Two new mouse models of the disease may represent steps toward early detection.12 Tuveson and colleagues at Penn's Abramson Cancer Center and Ronald DePinho and colleagues at the Dana-Far-ber Cancer Institute in Boston developed models by tinkering with expression of the genes
Nabeel Bardeesy, a postdoc in the DePinho lab, explains that previous mouse models used transgenic technology and employed promoters specific to acinar or islet cells; these generated acinar- or islet-type tumor cells, which are less common than ductal tumors in humans, he says. In contrast, the two current models use Cre/
DePinho's group knocked out a stopper element to activate the
Tuveson and colleagues targeted only
Both research groups showed that the models mirror the histological progression of human pancreatic cancer. "It's as good as one gets in terms of having a nice capitulation of the human situation," says DePinho. Several growth-factor receptors activated in human pancreatic ductal tumors were also activated in the mouse tumors, which Bardeesy says further demonstrates recapitulation.
Tuveson and coworkers also identified a serum proteomic signature in mice with early pancreatic cancer, a finding that may aid in the development of human diagnostics. While it's too soon to determine if the mouse markers resemble those found in humans, "the demonstration that there's this proteomic signature is an important proof of principle that one can use these mouse models to look for an early detection test," says Ralph Hruban of Johns Hopkins University School of Medicine, Baltimore.
Berns, who has used conditional mutations to model lung cancer in mice, says that a "major move" into using such systems has pushed the technology further with time-specific and sporadic switches that mimic tumorigenesis more closely. "There might be very substantial difference between a whole tissue [that] expresses
Aileen Constans can be contacted at