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Table 1 Neurotransmitters influencing tumor metastasis

From: Role of the nervous system in cancer metastasis

Neurotransmitters Receptor Type of cancer Model Mechanism/pathway Ref.
NE β2-AR Pancreatic cancer CFPAC1, MiaPaCa2 Panc1, and IMIM-PC2 cells NE treatment reduces migratory activity of pancreatic cancer cells. NE mediates inhibitory effect via imbalanced activation of PKC/PLC signaling pathway → to activation of anti-migratory cAMP/PKA signalling. [155]
Prostate cancer Subcutaneous injection of PC-3 cells in BALB/c nude mice ↑ NE leads to lumbar lymph node metastasis in an animal model. [156, 157]
DA DR1 & DR5 HCC Tumor and non-tumor adjacent tissues from patients; LM3, Huh7 and SNU449 cells;
subcutaneous injection of LM3 cells in BALB/c nude mice
DR5 is upregulated in tumor tissue and DR1 is upregulated in non-tumor human tissues.
Dopamine ↑ cell proliferation in SNU449 cells.
Administration of DR antagonist (thioridazine) inhibits cell proliferation in vitro and in and cell migration through EMT → ↓ tumor metastasis
[120]
GABA GABAA HCC Human primary and adjacent non-tumor tissues, and Orthotopic inoculation of SMMC-7721 cells into the liver of BALB/c nude mice GABAAreceptor subunit ε1 expression is lower in human HCC tissues than in non-tumor liver tissues.
GABA inhibits invasion and migration of human liver cancer cells in vitro.
In mice, inoculation of SMMC-7721 cells pretreated with GABA ↓ tumor metastasis.
[128]
GABAB PLC/PRF/5 and Huh cells Administration of GABAB agonist (baclofen) ↓ cell migration associated with ↓ in intracellular cAMP levels. [132]
Breast cancer Human tissues, 4 T1 and MCF-7 cells Administration of GABAB agonist (baclofen) promotes invasion and migration of breast cancer cells in vitro and metastasis in vivo via ERK1/2 and MMP-2signaling pathway. [107]
Prostate cancer Human prostate and lymph node tissues, C4–2 cells ↑ Expression of GABA → cell invasion in vitro and lymph node metastasis in patients mediated by activation of MMPs signalling. [158]
HCC Human primary and adjacent non-tumor tissues The mRNA levels of GABAB R1.2 and GABAB R1.4 are higher in HCC tissues than in non-tumor liver tissues [128]
ACh AR HCC SNU-449 cells ACh activates AR receptors → ↑ invasion and migration of SNU-449 cells via activation of AKT and STAT3 signaling pathways. [133]
α7-nAChR Pancreatic cancer CD18/HPAF, Capan1, FG/Colo357 cells in vitro and orthotopically implanted CD18/HPAF cells in immunodeficient mice Nicotine treatment stimulates the expression of α7-nAChR and MUC4 in vitro. In the in vivo model, exposure to low and high cigarette smoking increases the tumor metastasis and MUC4 expression compared to sham controls.
Nicotine induces tumor metastasis by upregulating MUC4 via α7-nAChR-mediated JAK2/STAT3 signaling in collaboration with Ras/Raf/MEK/ERK1/2 signalling pathway.
[135]
Lung cancer Line 1 cells in vitro, and subcutaneous injection of Line 1 cells in BALB/c mice Intraperitoneal injection of nicotine ↑ tumor growth and metastasis through change in gene expression via nAChR signalling pathway. [159]
nAChR β2 Lung cancer B16 cells intravenous injection in C57BL/6 mice ↑ Nicotine exposure → activation of nAChR β2 on NK cells mediates metastasis [160]
α9-nAChR Breast cancer MDA-MB-231 and MCF-7 cells Nicotine treatment enhances the migratory abilities of both cells by activating α9-nAChR through elevated expression of EMT markers [134]
mAChR Colon cancer Hh508 and SNU-C4 cells Administration of muscarinic inhibitor (atropine) → ↓ cell invasion and migration.
ACh binding to M3R mediates cell migration via the activation of post-ERBB1, ERK and PI3K-dependent RhoA pathway.
[138, 139]
NSCLC Human tissues, micA549, PC9, SPC-A1, GLC82, L78 and HLF cells M3R expression correlates with clinical stage and poor survival in patients.
M3R stimulation by ACh enhances in vitro cell invasion and migration via PI3K/AKt pathway.
[136, 137]
Prostate cancer Human tissues,
Hi-Myc transgenic mice-bearing PC-3
Presences of cholinergic nerve fibers associate with poor clinical outcome in human patients.
Pharmacological blockade or genetic disruption of the M1R inhibit metastasis leading to improved survival of the mice
[93]
SP NK-1R Pancreatic cancer MiaPaCa-2, BxPC-3, CFPAC-1, HAPC, Panc-1, and SW1990 cells Binding of SP to NK-1R promotes cell invasion and migratory potential which is mediated by expression of MMP-2. SP also increases cell migration and neurite outgrowth toward DRG demonstrating important role in metastasis and PNI. [146, 161]
NPY   Ewing sarcoma Human serum,
SCID/beige mice bearing SK-ES1 cells
Enhanced level of systemic NPY associate with metastatic tumors.
In the xenograft model, NPY expression associate with bone metastases.
[149, 150]
Y5 Breast cancer 4 T1 cell line NPY mediates metastatic effect via the activation of Y5 receptor. [148]
Neurotensin NTSR1 Breast cancer Human tissues The expression of NTSR1 associates with lymph node metastasis. [151]
  1. Ach acetylcholine, AR androgen receptor, β2-AR β2-adrenergic receptor, cAMP cyclic adenosine monophosphate, DA dopamine, DR dopamine receptor, DRG dorsal root ganglia, ERBB1 epidermal growth factor receptor 1, EMT epithelial–mesenchymal transition, ERK 1/2 extracellular signal-regulated kinase, GABA gamma-aminobutyric acid, GABA A&B gamma-aminobutyric acid receptor A&B, HCC, hepatocellular carcinoma, JAK2 janus kinase 2, MEK MAPK/ERK kinase, MMP matrix metallopeptidase, RAF mitogen activated protein kinase, RAS mitogen activated protein kinase, MUC4 mucin 4, mAChRs muscarinic acetylcholine receptors, M3R muscarinic receptors 3, NK natural killer cells, NK-1R neurokinin-1 receptor, nAChR nicotinic acetylcholine receptor, NSCLC non-small cell lung cancer, NE norepinephrine, PNI perineural invasion, PLC phospholipase C, PI3K phosphoinositide 3-kinase, PKA protein kinase A, PKC protein kinase C, RhoA Ras homolog gene family member A, AKT serine/threonine kinase or protein kinase B, STAT3 signal transducer and activator of transcription 3, SP substance P