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    Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells

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    Author
    Bapat, Aditi A.
    Munoz, Ruben M.
    Von Hoff, Daniel D.
    Han, Haiyong cc
    Affiliation
    Univ Arizona, Coll Med Phoenix, Dept Basic Med Sci
    Issue Date
    2016-10-28
    
    Metadata
    Show full item record
    Publisher
    PUBLIC LIBRARY SCIENCE
    Citation
    Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells 2016, 11 (10):e0165586 PLOS ONE
    Journal
    PLOS ONE
    Rights
    © 2016 Bapat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, pancreatic cancer cells migrate towards dorsal root ganglia (DRG) in a co-culture assay, indicating a paracrine NGF signaling between the DRGs and pancreatic cancer cells. Knocking down the expression of NGF pathway proteins or inhibiting the activity of TRKA by GW441756 reduced the migratory ability of Mia PaCa2 towards the DRGs. Finally, blocking NGF signaling by NGF neutralizing antibodies or GW441756 inhibited the neurite formation in PC-12 cells in response to conditioned media from pancreatic cancer cells, indicating a reciprocal signaling pathway between the pancreatic cancer cells and nerves. Our results indicate that NGF signaling pathway provides a potential target for developing molecularly targeted therapies to decrease PNI and reduce pain generation. Since there are several TRKA antagonists currently in early clinical trials they could now be tested in the clinical situation of pancreatic cancer induced pain.
    Note
    Open Access Journal.
    ISSN
    1932-6203
    DOI
    10.1371/journal.pone.0165586
    Version
    Final published version
    Sponsors
    National Cancer Institute (NCI), National Institute of Health (NIH) [CA140924]; Hearst Foundation
    Additional Links
    http://dx.plos.org/10.1371/journal.pone.0165586
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0165586
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