Background: Expression and activation of subtype-3 muscarinic receptors (M3R) plays an
important role in the progression of colorectal neoplasia.
Method: Herein, we describe the role of muscarinic receptors in colon cancer, focusing specifically
on M3R, illustrate how M3R over-expression and activation of post-receptor signaling pathways potentiates
tumor progression, and explore the efficacy and safety of a variety of therapeutic approaches
that can target the molecules involved.
Results: Colon cancers overexpress M3R mRNA (CHRM3) and protein, and post-M3R signaling
stimulates cell proliferation. Post-M3R signal transduction is complex, involving interplay between
epidermal growth factor receptors (EGFR)/ERK and protein kinase C (PKC)/p38 mitogen-activated
protein (MAP) kinase signaling pathways. In particular, the development of an invasive and metastatic
phenotype requires that these signaling interactions augment cellular release of a key collagenase,
matrix metalloproteinase-1 (MMP1). Blocking either M3R activation or post-M3R signaling attenuates
MMP1 release and colon cancer invasiveness.
Conclusion: Parsing the complexities of these signaling interactions is important, not only to understand
these mechanisms of cancer initiation and progression, but also to develop novel treatment modalities.
Since the vast majority of persons with colon cancer die from disseminated disease, preventing
or reversing metastatic spread of cancer cells by targeting M3R, post-M3R signaling, or MMP1
has therapeutic potential.