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Gene & Protein in Disease MOR in cancer

Figure 7. A model of the mechanism by which endogenous NO affects tumor angiogenesis. The binding of VEGF or other vasoactive
substances to receptors on the cell membrane can promote the production of endogenous NO, which in turn promotes the
production of cGMP and the activation of PKG/MAPK, thereby promoting the expression of uPA and affecting tumor angiogenesis.
cGMP: Cyclic guanosine monophosphate; ec-NOS: Endothelial constitutive NO synthetase; FGF-2: Fibroblast growth factor 2; MAPK: Mitogen-activated
protein kinase; MMPs: Matrix metalloproteinases; NO: Nitric oxide; PKG: Protein kinase G; sGC: Soluble guanylyl cyclase; uPA: Urokinase plasminogen
activator; VEGF: Vascular endothelial growth factor. Image created with BioRender.com.

role in regulating inflammation and tumors: inhibiting 3.4. Cancer therapy
inflammatory response and tumor growth and allowing As one of the drugs commonly used in cancer patients,
tumors to escape attacks from the immune system [102] . opioids, in addition to analgesic effect, have multifaceted
Koodie et al. [103] suggested that morphine could change the impact on the occurrence and development of tumors [107] .
cell adhesion molecules on white blood cells and endothelial Many recent tumor immunotherapies are associated with
cells in LCC by activating MOR, thereby inhibiting the MOR [102] . Methylnaltrexone (MNTX), an antagonist of
migration and recruitment of white blood cells to reduce MOR, has been widely used in clinical trials to improve
angiogenesis and tumor growth. Jiang et al. [104] isolated T survival in patients with advanced cancer . Gorur
[46]
cells from peripheral blood mononuclear cells (PMBCs) et al. [108] demonstrated that MNTX strongly inhibited
using anti-CD3 magnetic beads in patients with cervical the proliferation, invasion, and migration of FaDu and
cancer (CC); the in vitro experiment demonstrated that MDA686Tu cells (head and neck squamous cell carcinoma
the combination of morphine and ketamine may suppress cell lines) but had no effect on UMSCC47 cells (one cell
immune function in CC progression by reducing CD4 line). Similarly, Singleton et al. [109] showed that the infusion
+
percentage, CD4 /CD8 ratio, and the levels of interferon of peripheral MOR antagonist MNTX significantly
+
+
gamma (IFNγ), IL-2, and IL-17 through the Janus kinase attenuated tumor growth. Therefore, MOR may be a
3/signal transducer and activator of transcription 5 (JAK3/ promising potential target for chemotherapeutic agents.
STAT5) pathway.
Recently, tumor immunotherapy has been extensively
Zielinska et al. [105] used P-317, a cyclic analog of studied, and its applications in clinical practice has
morphiceptin, to stimulate opioid receptors to induce expanded [110] . For example, antibodies against the
an anti-inflammatory response. In a colitis-associated immune checkpoint programmed cell death-1 (PD-1),
CRC model, a significant difference in colorectal tumor programmed death-ligand 1 (PD-L1), and cytotoxic
development was observed between vehicle- and P-317- T-lymphocyte-associated protein 4 (CTLA4) have been
treated mice. P-317 reduced TNF-α expression and approved for the treatment of certain types of cancer, such
inflammatory responses in mice as well as the total number as NSCLC, bladder cancer, HCC, and melanoma, and have
of colorectal tumors [105] . Boehncke et al. [106] showed that demonstrated improved efficacy [111,112] . However, the role of
µ-opioid peptides may play a major role in melanoma PD-1 signaling in neurons remains unclear. Chen et al. [113]
progression by activating MOR and modulating immune observed attenuated morphine-induced analgesia in PD-1-
response. knockout mice and decreased morphine action through
Based on the studies on the effect of MOR activation the inhibition of PD-1 effect by nivolumab injection. In
on tumor immunity, we speculate that the signaling dorsal root ganglion (DRG) neurons, PD-1 and MOR
pathway associated with immune response following MOR receptors are co-expressed. When PD-1 is knocked down,
activation may serve as a new target for the treatment of the inhibitory effect of morphine on calcium channels
certain cancers. is attenuated. In the spinal dorsal horn, morphine

Volume 2 Issue 2 (2023) 11 https://doi.org/10.36922/gpd.282