Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP

Authors

  • Nicole Nemetz,

    1. Department of Laboratory Animal Medicine, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
    Current affiliation:
    1. Department of Animal Care and Technology, Arizona State University, AZ
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  • Catalina Abad,

    1. Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
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  • Greg Lawson,

    1. Department of Laboratory Animal Medicine, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
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  • Hiroko Nobuta,

    1. Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
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  • Seririthanar Chhith,

    1. Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
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  • Lucy Duong,

    1. Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
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    • Lucy Duong was a recipient of a Student Research Fellowship Award from the Crohn's and Colitis Foundation of America.

  • Gary Tse,

    1. Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
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  • Jonathan Braun,

    1. Department of Pathology and Laboratory Medicine, University of California at Los Angeles, CA
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  • James A. Waschek

    Corresponding author
    1. Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Mental Retardation Research Center, University of California at Los Angeles, CA
    • 635 Charles E. Young Dr. South, Room NRB345, Los Angeles, CA 90095
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    • Fax: +310-206-5061


Abstract

Pituitary adenylyl cyclase activating peptide (PACAP) is expressed in central, sensory, autonomic, and enteric neurons. Although it classically acts as a neurotransmitter/neuromodulator, recent studies indicate that PACAP can also regulate immune function. To this effect, PACAP has been shown to reduce clinical symptoms and inflammation in mouse models of human immune-based diseases such as rheumatoid arthritis, Crohn's Disease, septic shock and multiple sclerosis. Despite these findings, the role of the endogenous peptide in regulating immune function is unknown. To determine if endogenous PACAP plays a protective role in inflammatory bowel disease (IBD) and IBD-associated colorectal cancer in mice, PACAP-deficient (KO) mice were subjected to 3 cycles of dextran sulfate sodium (DSS) in drinking water over 2 months, an established mouse model for colitis. Compared to wild type (WT) controls, PACAP KO mice exhibited more severe clinical symptoms of colitis and had significantly higher colonic inflammation on pathological examination. Moreover, 60% of the PACAP KO mice developed colorectal tumors with an aggressive-appearing pathology. Consistent with published data, DSS-treated WT mice did not develop such tumors. The results demonstrate a new mouse model which rapidly develops inflammation-associated colorectal cancer in the absence of a carcinogen. © 2007 Wiley-Liss, Inc.

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