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    Overcoming Obstacles to Targeting Muscarinic Receptor Signaling in Colorectal Cancer.

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    Author
    Ali, Osman
    Tolaymat, Mazen
    Hu, Shien
    Xie, Guofeng
    Raufman, Jean-Pierre
    Date
    2021-01-13
    Journal
    International Journal of Molecular Sciences
    Publisher
    MDPI AG
    Type
    Article
    Other
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/ijms22020716
    Abstract
    Despite great advances in our understanding of the pathobiology of colorectal cancer and the genetic and environmental factors that mitigate its onset and progression, a paucity of effective treatments persists. The five-year survival for advanced, stage IV disease remains substantially less than 20%. This review examines a relatively untapped reservoir of potential therapies to target muscarinic receptor expression, activation, and signaling in colorectal cancer. Most colorectal cancers overexpress M3 muscarinic receptors (M3R), and both in vitro and in vivo studies have shown that activating these receptors stimulates cellular programs that result in colon cancer growth, survival, and spread. In vivo studies using mouse models of intestinal neoplasia have shown that using either genetic or pharmacological approaches to block M3R expression and activation, respectively, attenuates the development and progression of colon cancer. Moreover, both in vitro and in vivo studies have shown that blocking the activity of matrix metalloproteinases (MMPs) that are induced selectively by M3R activation, i.e., MMP1 and MMP7, also impedes colon cancer growth and progression. Nonetheless, the widespread expression of muscarinic receptors and MMPs and their importance for many cellular functions raises important concerns about off-target effects and the safety of employing similar strategies in humans. As we highlight in this review, highly selective approaches can overcome these obstacles and permit clinicians to exploit the reliance of colon cancer cells on muscarinic receptors and their downstream signal transduction pathways for therapeutic purposes.
    Keyword
    acetylcholine
    colorectal cancer
    epidermal growth factor receptors
    matrix metalloproteinases
    muscarinic receptors
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14399
    ae974a485f413a2113503eed53cd6c53
    10.3390/ijms22020716
    Scopus Count
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