Table 1:
Preclinical and early clinical functional evidence of tumour-nerve interactions
| Tumour type | Therapeutic avenue | Mechanism and target* | Contribution to cancer | |
|---|---|---|---|---|
|
| ||||
| 1 | Prostate cancer | Tumour growth | Adrenergic signalling | Sympathetic neurogenesis and an increase in the density of β-adrenergic nerves promotes early stages of tumorigenesis (eg, low-to-high-grade prostatic intraepithelial neoplasia).16,17 |
| 2 | Prostate cancer | Tumour growth | Adrenergic signalling (ADRB2) | Adrenergic nerves promote a metabolic shift in endothelial cells towards aerobic glycolysis that triggers angiogenesis and malignant growth.16 |
| 3 | Pancreatic cancer | Tumour growth | Sensory neuron input | Dorsal root ganglion sensory neurons convey inflammatory signals from pancreatic cancer tumours to the CNS in a Kras-induced genetically engineered mouse model, contributing to tumour initiation and growth.18 |
| 4 | Pancreatic cancer | Tumour growth | Cholinergic signalling | Cholinergic signalling suppresses pancreatic cancer growth through stimulation of muscarinic receptors.19 |
| 5 | Pancreatic cancer | Tumour growth | Catecholamine signalling (ADRB2, NGF) | Catecholamines bind to ADRB2 and increase nerve density and neurotrophin secretion, creating a feedforward loop that promotes tumour development in a mouse model of pancreatic cancer.20 |
| 6 | Basal cell carcinoma | Tumour growth | Sensory neuron input (Hedgehog pathway) | Cutaneous innervation activates Hedgehog signalling in stem-cell niches within the skin to promote tumorigenesis.21 |
| 7 | Medulloblastoma | Tumour growth | Neurochemical signalling (mGluR4) | Activation of mGluR4 receptors prevents development of medulloblastoma in mouse models.22 |
| 8 | Gastric cancer | Tumour growth | Cholinergic signalling (NGF, Wnt pathway) | Vagal innervation results in NGF secretion via acetylcholine signalling, thereby promoting gastric tumorigenesis through Wnt activation.23 |
| 9 | Pancreatic cancer | Tumour growth | Protein signalling (ARTN) | The neurotrophic factor ARTN contributes to perineural invasion in pancreatic cancer.24 |
| 10 | Glioma | Tumour growth | Protein signalling (BDNF) | BDNF is secreted in an activity-dependent manner and binds to the receptorTrkB, promoting glioma growth.25 |
| 11 | Pancreatic cancer | Tumour growth | Protein signalling (GDNF/RET) | GDNF secretion and its interactions with its receptor RET promote perineural invasion in pancreatic cancer.26 |
| 12 | Glioma | Tumour growth | Protein signalling (NLGN3, ADAM10) | The synaptic adhesion protein NLGN3 is released from neighbouring non-glioma neurons and cleaved by the protease ADAM10 in a neuron activity-dependent manner. The resultant secreted form of NLGN3 promotes growth through a PI3K-mTOR-dependent pathway.27–30 |
| 13 | Multiple myeloma | Tumour growth, immune remodelling | Protein signalling (NNT-1) | NNT-1 is a neurotrophic factor that demonstrates B cell-stimulating capability and promotes growth and survival in myeloma.31 |
| 14 | Multiple myeloma | Tumour growth | Protein signalling (BDNF) | BDNF promotes tumour survival in multiple myeloma through binding to the receptorTrkB, thereby activating MAPK and PI3K/Akt signalling cascades.32 |
| 15 | Thyroid carcinoma (NRTC), NSCLC | Tumour growth | Neurotrophic-tropomyosin receptor kinase (NTRK) rearrangement | NTRK gene fusions can produce chimeric oncoproteins with constitutively activated kinase function (TrkA, TrkB, andTrkC), resulting in proliferation through the RAS–RAF–MAPK pathway.33,34 |
| 16 | Glioma | Tumour growth, electrical hyperactivity and seizures | Direct synapse formation (AMPAR) | Nerves form direct glutamatergic synapses onto glioma cells and modulate tumour microtube-mediated invasion in gliomas.29,35 |
| 17 | Glioma | Electrical hyperactivity and seizures | Glutamate signalling (AMPAR) | Gliomas release high amounts of glutamate to surrounding tissue and also exhibit glutamate-response growth via Ca2+-permeable AMPA receptors, establishing a positive feedback loop of nerve–tumour hyperactivity and tumour proliferation.29,35–37 |
| 18 | Glioma | Tumour growth, electrical hyperactivity and seizures | Neurochemical signalling (GABA) | GABA receptors are present on low-grade astrocytomas and oligodendrogliomas, and GABA currents have also been evoked in glioblastoma.38,39 |
| 19 | Glioma | Tumour growth, electrical hyperactivity and seizures | Neurochemical signalling (DRD4, DRD2) | Blockade of DRD4 has been shown to inhibit glioblastoma proliferation via disruption of autophagy, and blockade of DRD2 alone or in combination with EGFR blockade might have therapeutic potential.40,41 |
| 20 | Glioma | Tumour growth, electrical hyperactivity and seizures | Neurochemical signalling (GABA) | Gliomas downregulate inhibitory GABA currents in the surrounding tumour microenvironment.42 |
| 21 | Brain metastases | Metastasis | Neurochemical signalling (GABA) | Breast cancer brain metastases upregulate GABA receptors and GABA catabolism.43 |
| 22 | Brain metastases | Metastasis, electrical hyperactivity and seizures | Direct synapse formation (NMDAR) | Breast cancer cells form astrocyte-like synapses (pseudo-tripartite synapses) to access glutamate secreted from neurons, which activates the NMDAR pathway and promotes brain colonisation.44 |
| 23 | Metastatic tumours | Metastasis | Anoikis resistance (TrkB) | TrkB is a neurotrophic receptor that is shown to suppress anoikis, contributing to metastatic spread through supporting circulation of cancerous cells.45 |
| 24 | Prostate cancer | Metastasis | Parasympathetic signalling (CHRM1) | Parasympathetic innervation of cholinergic fibres stimulates prostate cancer dissemination at later stages.17 |
| 25 | Brain metastases | Metastasis, immune remodelling | Adrenergic signalling (ADRB2) | β2-adrenergic signalling facilitated breast cancer metastases by recruiting macrophages and inducing a pro-metastatic and immunosuppressive M2 state. Treatment with propranolol reversed this response in animals.46 |
| 26 | Glioma | Tumour growth, electrical hyperactivity and seizures | Neuronal hyperexcitability (GPC3) | Subsets of glioblastoma driven by PIK3CA secrete GPC3, which drives hyperexcitability and glioma growth.47 |
| 27 | Glioma | Electrical hyperactivity and seizures, stress adaptation | Microtube formation (Connexin 43 gap junctions) | Glioma cells form microtubes that facilitate direct communication with surrounding glioma and non-gliomatous cells via Connexin 43-mediated gap junctions, allowing for propagation of calcium waves that have been implicated as a cause of treatment resistance.48 |
| 28 | Pancreatic cancer | Neuropathic pain | Neurotrophin signalling (NGF) | Cancer cells, fibroblasts, and immune cells can release NGF to recruit and activate sensory neurons by way of the receptor TrkA. Elevated expression of NGF–TrkA in pancreatic cancer tissues is thought to be associated with increased perineural invasion and pain.49 |
| 29 | Pancreatic cancer | Neuropathic pain | Neurotrophin signalling (TRPV1) | NGF and other neurotrophins can activate the receptor TRPV1, a cation channel that facilitates nociception in sensory neurons. TRPV1 activation can trigger sensory neuronal membrane depolarisation and the release of substance P or CGRP to transmit pain signals.50 |
| 30 | Glioma | Stress adaptation | Dopamine signalling | Combination treatment with the dopamine antagonist quetiapine, atorvastatin, and radiation prolonged survival in glioblastoma xenografts.51 |
| 31 | Pancreatic cancer | Stress adaptation | Decreased apoptosis (MALT1, TRAF) | In-vitro co-cultures of mouse dorsal root ganglia and human pancreatic cancer cells demonstrated that pro-survival (MALT1, TRAF) genes are upregulated in neoplastic cells.52 |
| 32 | Prostate cancer | Stress adaptation | Decreased apoptosis (NFκB) | Prostate cancer cells exhibiting perineural invasion demonstrate increased proliferation and decreased apoptosis through a NFκB-dependent mechanism.53 |
| 33 | Ovarian cancer | Stress adaptation | Neurotrophin signalling (BDNF) | Activation of the BDNF–TrkB pathway inhibits apoptosis, and knockdown of TrkB enhances apoptosis.54 |
| 34 | Pancreatic cancer | Stress adaptation, tumour growth | Axonal recruitment (NGF) | Starved pancreatic cancer cells in nutrient-poor, serine-deprived desmoplastic environments increase production of NGF, which promotes axonal recruitment as a means of L-serine acquisition. Treatment with theTrk–NGF inhibitor larotrectinib decreased pancreatic cancer tumour growth.55 |
| 35 | Breast cancer | Stress adaptation, metastasis | β-adrenergic signalling | Chronically stressed mice exhibited 38-times higher frequency of distant metastases relative to unstressed mice. Propranolol blocked metastases in chronically stressed animals but had no effect on metastatic burden in unstressed mice.46 |
| 36 | Melanoma | Immune remodelling | β-adrenergic signalling (ADRB2) | Concurrent β-blockade and immunotherapy is associated with improved survival in metastatic melanoma and might be mediated by the ADRB2 receptor.56,57 |
| 37 | Colon cancer, melanoma, and breast cancer | Immune remodelling | β-adrenergic signalling | Addition of β2-adrenergic blockade improved local control and abscopal effects at distant metastatic sites following irradiation.58 |
| 38 | HPV E6+ and E7+ tumours | Immune remodelling | β-adrenergic signalling | Propranolol improved efficacy of an anti-tumour vaccine via enhancement of CD8+ T lymphocyte tumour infiltration.59 |
| 39 | Lung cancer | Immune remodelling | CD8+ T-cell infiltration | Depletion of tumour-associated macrophages in combination with anti-PD-1 immunotherapy restores cytotoxic T-cell migration and infiltration.60,61 |
| 40 | Melanoma | Immune remodelling | Tumour innervation (Schwann cells) | Melanoma cells activate Schwann cells in the tumour microenvironment that promote tumour growth.62 |
| 41 | Pancreatic cancer | Immune remodelling | Cholinergic signalling (acetylcholine) | Acetylcholine impairs the recruitment of CD8+ by pancreatic adenocarcinoma cells and favours T-helper-2 (Th2) cells. Subdiaphragmatic vagotomy in tumour-bearing mice was associated with increased CD8+ concentrations, elevated Th1:Th2 ratio, and improved survival.63 |
GABA=γ-aminobutyric-acid. HPV=human papillomavirus. NGF=nerve growth factor. NSCLC=non-small cell lung cancer. NRTC=NTRK-rearranged thyroid carcinoma. TRAF=TNF receptor associated factors.
*
Targets are provided in parentheses where available.