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Mutated Kras spins a molecular loop that launches pancreatic cancer
Date:1/26/2012

n and regulates a number of inflammation-promoting genes, including IL-1α.
  • IL-1α and another protein called p62 activate NF-κB which in turn cycles back to perpetuate the loop by activating its activators.

    "It's a vicious cycle," Chiao said. The overactive NF-κB fuels pancreatic cancer by activating genes that promote inflammation, the growth of new blood vessels and block programmed cell death.

    Chiao has three research grants from the National Cancer Institute to study pancreatic cancer. "We study signaling transduction pathways to try to find out why it's such a bad disease and to find a weak point for targeted therapy," he said.

    In the Cancer Cell paper, the authors conclude: "Our findings suggest that the prime mover responsible for cancer-related inflammatory response and the development of pancreatic intraepithelial neoplasia (precancerous lesions) and pancreatic ductal adenocarcinoma is the mutant Kras-initiated constitutive activation of NF-κB."

    This process, they further noted, creates a pro-tumor microenvironment by promoting inflammation, creation of new blood vessels and tissue repair that is similar to conditions found in inherited pancreatitis, inflammation of the pancreas that is linked to the development of cancer.

    Kras mutation, IL-1α, NF-κB go together with poor survival

    The team analyzed mouse and human tumors and mouse strains with mutated Kras expressed in their pancreases. In a series of experiments they found:

    • Active IKK2/ the activator of NF-κB was required for the Kras-mutated mice to develop either pancreatic cancer or precancerous legions.
    • Deletion of IKK2/Beta interrupted Kras-stimulated inflammation and cell proliferation, suggesting that chronic inflammation is a key factor in promoting pancreatic cancer development.
    • Microarray profiles of gene expression showed that several NF-κB-regu
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    Contact: Scott Merville
    smerville@mdanderson.org
    713-792-0661
    University of Texas M. D. Anderson Cancer Center
    Source:Eurekalert  

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