An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation
Abstract
:1. Introduction
2. Perineural Invasion and the Perineural Niche
3. The Sympathetic Nervous System and Adrenergic Signaling
4. The Parasympathetic Nervous System and Acetylcholine
5. The Tumor/Nervous Interface in the Central Nervous System Tumors and Electrochemical Communication
6. Molecules with a Widespread Activity in Various Types of Cancer: Neurotransmitters, Amino Acids, Growth Factors, Axon Guidance, and Synaptic Proteins
6.1. Dopamine
6.2. Gamma-Aminobutyric Acid
6.3. Serotonin
6.4. Glutamate
6.5. Serine
6.6. Neuropeptides
6.7. Nerve Growth Factor
6.8. Axon Guidance Molecules and Neuroligin
6.8.1. Axon Guidance Molecules
6.8.2. Neuroligins
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Family | Member | Cellular Receptor | Affected Intracellular Pathways | Refs |
---|---|---|---|---|
Neurotransmitters/amino acids | Norepinephrine (noradrenaline) | α-β adrenergic receptors | Gαs–cAMP, MAPK, PKA, EPAC ERK/cyclooxygenase 2 CREB1-miR-373 axis, Src PKA, VDCC, Hippo | [50,56,58,61,64] |
Dopamine | Dopamine 1–5 (D1–5) receptors | VEGFA-mediated ERK1/2 phosphorylation | [95,96] | |
Serotonin (5-hydroxytryptamine) | 5-HT1-7 receptors | Akt/Mtor, glycolysis, endothelial nitric oxide synthase, p-ERK1/2 | [130,131,133] | |
Acetylcholine | Muscarinic acetylcholine receptor, nicotinic acetylcholine receptor | Ca2+ flux, PKC/ERK1/2, COX2, PGE2, CREB, SRC, AKT, Ras-RAF1, MAPK, survivin, BCL-2, NF-κB, PI3K/AKT | [2,5,73,75,76,79] | |
Glutamate | Metabotropic glutamate receptor, NMDA receptor, Kainate receptor, AMPA receptor | PI3K (p110) | [144] | |
Gamma-aminobutyric acid | GABAB GABAA GABAc receptors | Ca2+ flux MAPK/ERK | [103,109] | |
Serine | Amino acid transporters | mRNA translation | [145] | |
Neuropeptides | Neuropeptide Y | NPY1R, NPY2R, PPYR1, NPY5R | PI3-K/pAkt microRNA-375 | [156] |
Substance P | NK1, NNK2, NNK3 | inositol 1,4,5-triphosphate (IP3) DAG, c-myc, mitogen-activated protein kinases, activator protein 1, extracellular signal-regulated kinases 1 and 2, glycogen breakdown | [149,152] | |
Growth factors | NGF | TrkA, p75NTR | PI3K, MAPK c-Jun N-terminal kinase | [157] |
Axon guidance | Netrin 1 | DCC, UNC5 | Netrin 1 is a target of NFkB and induces YAP. | [171,172] |
Ephrins | Ephs | Forward signaling: Src family kinases, Rho GTPases, Ephexins (GEFs that can activate Rho GTPases), ERK/MAPK pathway, which promote cell proliferation. Additionally, FAK and the JAK/STAT pathway interact with EPHs, which modifies cell adhesion. Reverse signaling: interactions between ephrins and Src, Erk, Rac, T, paxillin, p75, and integrin-dependent cell adhesion as well as with Src, Grb4, PTP-BL, and PDZ-RGS3, which controls a variety of actions, including cell adhesion, migration, and proliferation. | [175] | |
Semaphorins | Neuropilins, plexins | Sema3A: nrp1 PTEN/FOXO 3a-dependent MelCAM (CD146) expression. Sema3B binds to NRP1 and inhibits PI3K/Akt signaling. Full-length Sema3C NRP2 inhibits VEGF-C-dependent ERK1/2 and Akt signaling and suppresses lymphangiogenesis and metastasis. Cleaved Sema3C promotes cancer cell survival. Sema4D binds to plexin-B1 and activates ErbB2, phosphorylating plexin-B1. By activating RhoA GTPase, phosphorylated plexin-B1 promotes migration. Through ErbB2-dependent MAPK signaling, cleaved p61-Sema3E binds to plexin-D1 to promote metastasis. Sema3E binds to plexin-D1 and disrupts the interactions between plexin-D1 and NR4A, which is known to induce caspase-9-mediated apoptosis. | [188] | |
Synaptic proteins | Neuroligin 1 | - | Neuroligin 1 recruits APC to the plasma membrane, blocking beta catenin degradation and causing its transfer to the nucleus, where it promotes EMT-linked gene transcription. | [196] |
Neuroligin 1 | - | Neuroligin 1 synergizes with GDNF to induce cancer cell invasion of nerves and to activate the cytoskeleton-regulating protein cofilin. | [199] | |
Neuroligin 3 | - | NLGN3 extracellular domain shedding by ADAM10 into the tumor microenvironment promotes glioma growth. | [198] | |
For all other synaptic proteins, see [6]. | [6] |
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Arese, M.; Bussolino, F.; Pergolizzi, M.; Bizzozero, L. An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation. Int. J. Mol. Sci. 2022, 23, 14695. https://doi.org/10.3390/ijms232314695
Arese M, Bussolino F, Pergolizzi M, Bizzozero L. An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation. International Journal of Molecular Sciences. 2022; 23(23):14695. https://doi.org/10.3390/ijms232314695
Chicago/Turabian StyleArese, Marco, Federico Bussolino, Margherita Pergolizzi, and Laura Bizzozero. 2022. "An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation" International Journal of Molecular Sciences 23, no. 23: 14695. https://doi.org/10.3390/ijms232314695