Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists announce long-sought mouse model of human pancreatic cancer

10.12.2003


Could yield advances in early diagnosis, treatment of lethal disease



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.

Contact: Richard Saltus, 617-632-5357.

Bill Schaller | EurekAlert!
Further information:
http://www.dfci.harvard.edu/

More articles from Health and Medicine:

nachricht Team discovers how bacteria exploit a chink in the body's armor
20.01.2017 | University of Illinois at Urbana-Champaign

nachricht Rabies viruses reveal wiring in transparent brains
19.01.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>