Navigation Links
Genetic pathways to curable and incurable forms of pancreatic cancer identified

Pancreatic ductal adenocarcinoma is an almost uniformly fatal disease regardless of the stage at time of diagnosis. However, a small percentage of patients develop a form of ductal adenocarcinoma associated with cystic lesions that can be detected earlier, is less aggressive and has a 50 percent long-term survival rate. Why cystic ductal pancreatic cancer behaves differently, despite carrying the same basic genetic mutations as the more common and deadly type of ductal pancreatic cancer, has long been a mystery. Now researchers at Fred Hutchinson Cancer Research Center have unlocked the genetic reason why.

Using unique mouse models to mimic the progression of both forms of human pancreatic cancer, researchers have discovered that a specific sequence of otherwise common genetic mutations is responsible for sending cells down the less-traveled path toward cystic pancreatic cancer versus the well-traveled route to the more fatal form of ductal pancreatic cancer.

Sunil Hingorani, M.D., assistant member of the Hutchinson Center's Clinical Research and Public Health Sciences divisions, led a study to be published in the March 12 issue of the journal Cancer Cell that explains this sequence and details why the cells behave differently.

"Although at their end stage the two different routes to ductal pancreatic cancer can look very much the same under the microscope, involve the same constellation of genetic events, and culminate in invasive and metastatic disease that can ultimately kill patients, one route is 100 percent fatal while the other is 50 percent curable," Hingorani said. "Until now we didn't understand why. What these studies suggest is that it's not just the total complement of mutations that determines the behavior of these cancers but also the sequence in which the mutations arise."

About 5 percent of all primary tumors of the pancreas, out of 40,000 annual new cases in the United States, arise from cystic tumors.

The findings reported in the journal by Hingorani and colleagues represent an accidental discovery. The researchers started out studying the common genetic pathways to pancreatic ductal adenocarcinoma in hopes of finding clues to developing early detection biomarkers and possible treatments to halt the progression of the disease. The work involved activating the pancreatic cancer oncogene called Kras and then selectively mutating tumor-suppressor genes such as p53, p16 and Dpc4 in different combinations.

In the mouse model, which Hingorani first developed while at the University of Pennsylvania, the combination of Kras and p53 led to the more deadly form of pancreatic ductal adenocarcinoma. Earlier studies by researchers in Boston also found the same association between Kras and p16. From studies of human cancers, it is known that mutations in Dpc4 can also occur, but they do so late in the course of disease progression. The current study showed that the combination of Kras and an early mutation of Dcp4, in which one copy of the suppressor gene is eliminated, lead to cancer by a different path, beginning with the creation of a distinct class of precancerous lesions in the ductal epithelium called mucinous cystic neoplasms (MCN). This initiates a process that results in the rarer but far less deadly cystic pancreatic cancer.

MCN lesions often are large enough to be detected early by MRI or CT scan and also to cause symptoms. The cells in this cancer also react differently to a key signaling protein, TGFb, which can induce cancer cells to change shape and become more mobile and invasive. It turns out that the cystic pancreatic cancer cells are resistant to these effects of TGFb and these types of cancers are also less likely to invade surrounding tissues and to metastasize, or spread, to other organs. These properties likely contribute to the improved survival seen with this form of the cancer, Hingorani said.

Conversely, the initial lesions that lead to the more common and deadly form of pancreatic ductal adenocarcinoma, called pancreatic epithelial neoplasms, are tiny enough to be undetectable until the disease has progressed to the point where survival is almost nil. Moreover, these cells appear to be highly sensitive to the tumor-promoting properties of TGFb and thereby manifest a more aggressive behavior.

"With accurate animal models of both forms of pancreatic ductal cancers now in hand, it should be possible to unravel the detailed mechanisms behind their distinct behavior and hopefully identify points of vulnerability in the more fatal form to improve survival," Hingorani said.


'"/>

Source:Fred Hutchinson Cancer Research Center


Related biology news :

1. Novel Asthma Study Shows Multiple Genetic Input Required; Single-gene Solution Shot Down
2. Genetically modified natural killer immune cells attack, kill leukemia cells
3. Ants Genetic Engineering Leads To Species Interdependency
4. Genetic Variation Visualization - From EMBL
5. Genetically modified rice in China benefits farmers health, study finds
6. Infants With Rare Genetic Disease Saved by Cord Blood Stem Cells
7. Genetically Modified Natural Killer Immune Cells Attack, Kill Leukemia Cells
8. Genetic defects give the immune system the green light to attack the pancreas
9. Maine Researchers Find Exceptions to Old Rules of Genetic Inheritance
10. Genetic therapy reverses nervous system damage in animal model of inherited human disease
11. Infants with Rare Genetic Disease Saved By Cord Blood Stem Cells
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:2/1/2016)... -- Rising sales of consumer electronics coupled ... gesture control market size through ... electronics coupled with new technological advancements to drive global ... through 2020   --> Rising ... to drive global touchfree intuitive gesture control market ...
(Date:2/1/2016)... ( www.wocketwallet.com ) announces the launch of a new video featuring singer, ... Las Vegas , where Joey appeared at the Wocket booth to ... , where Joey appeared at the Wocket booth to meet and greet ... the Consumer Electronics Show (CES2016) in Las Vegas , ... --> --> The video is ...
(Date:1/27/2016)... 2016  Rite Track, Inc. a leading semiconductor equipment ... Chester, Ohio announced today the acquisition of PLUS ... in Austin, Texas , will significantly ... modifications, installations and technical support offerings for TEL Track ... commented, "PLUS has provided world class service including refurbishment, ...
Breaking Biology News(10 mins):
(Date:2/8/2016)... (PRWEB) , ... February 08, 2016 , ... ... a wide range of loose, bulk foods at various stages of the production ... also used to inspect large bulk products post packaging such as sacks of ...
(Date:2/8/2016)... , February 8, 2016 ... ("Atlas Genetics" or the "Company"), the ultra-rapid Point-Of-Care (POC) molecular ... CE Mark its Chlamydia trachomatis (CT) test to be launched ... the IVD Directive (98/79/EC), the CT test is now cleared ... --> The launch of the io® CT ...
(Date:2/5/2016)... , Feb. 5, 2016 On Thursday, ... trusted information source for community, health and disaster services, ... will integrate to enhance care coordination and service ... the services they need and to better connect service ... care.   San Diego has ...
(Date:2/4/2016)... Calif. , Feb. 4, 2016  Sangamo BioSciences, ... genome editing, announced today that Edward Lanphier , ... update on the progress of Sangamo,s ZFP Therapeutic ® ... business strategy at 2:40 pm ET on Thursday, February ... Annual Global Healthcare Conference. The conference is being held ...
Breaking Biology Technology: