Mice Model a Silent Killer

EARLY LESIONS:© 2003 Cold Spring Harbor Laboratory PressEarly stage pancreatic lesions in Pdx1-Cre; LSL-Kras; Ink/Arflox/lox animals. (A) A low-grade PanIN lesion. (B) A low-grade preinvasive ductal lesion. (C) A high-grade preinvasive ductal lesion. (D) Early focus of pancreatic adenocarci-noma with both ductal and anaplastic components. (E) A high-grade PanIN lesion with no adenocarcinoma foci. (F) A high-grade PanIN lesion (asterisk) surrounded by anaplastic tumor cells.Aquiet killer, pa

Mar 29, 2004
Aileen Constans
<p>EARLY LESIONS:</p>

© 2003 Cold Spring Harbor Laboratory Press

Early stage pancreatic lesions in Pdx1-Cre; LSL-Kras; Ink/Arflox/lox animals. (A) A low-grade PanIN lesion. (B) A low-grade preinvasive ductal lesion. (C) A high-grade preinvasive ductal lesion. (D) Early focus of pancreatic adenocarci-noma with both ductal and anaplastic components. (E) A high-grade PanIN lesion with no adenocarcinoma foci. (F) A high-grade PanIN lesion (asterisk) surrounded by anaplastic tumor cells.

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 Ink4a/Arf and KRAS, which have been implicated in human ductal pancreatic adenocarcinoma. "I think these models are going to be extremely important to not only understand the whole tumor development, but also to design rational approaches to interfere, and to identify early markers," says Anton Berns, director of research, Netherlands Cancer Institute, Amsterdam.

KNOCKOUT PUNCH

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/lox-mediated conditional knockout technology to precisely target pancreatic expression using native promoters.

DePinho's group knocked out a stopper element to activate the KRAS gene alone, resulting in a premalignant condition known as pancreatic interepithelial neopla-sia, or PanIN, which did not progress to a metastatic stage. Deletion of the Ink4a/Arf locus alone did not result in any disease. "But when we combined the two deletions, we saw a greatly enhanced progression of these premalignant lesions to very advanced states and also to the emergence of a very aggressive malignant and metastatic disease," says Bardeesy. The researchers concluded that KRAS initiates pancreatic ductal neoplasia while the Ink4a/Arf gene acts as a checkpoint against further disease progression.

Tuveson and colleagues targeted only KRAS expression to mouse pancreatic progenitor cells to study in detail the preinvasive PanIN lesions. Over time, he says, "Some of these mice will actually develop invasive and advanced pancreatic cancer, including spread or metastasis."

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.

SIGNATURE MOVES

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 RAS, or a few cells that express RAS, in an environment where most cells are normal, and where there is a normal signaling," he explains. Bardeesy says that future studies will further develop Cre-mediated mutation technology by adding more gene knockouts and knockins to the mix. "The availability of different tumor suppressor gene knockouts that we can also add to our model ... will allow us to actually compare the onset and the clinical presentation of these tumors, and to pinpoint the roles of these in causing the different biological features of the disease," says Bardeesy.

Aileen Constans can be contacted at aconstans@the-scientist.com.