Molecular Targeting of the Peripheral Nerve–Tumor Axis in Extracranial Solid Cancers: Eight Signaling Systems, One Effect—Systematic Review and Multilevel Meta-Analysis
9 affiliations
- 1Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania
- 2Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- 3Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- 4Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- 5Department of Gynecology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania
- 6Experimental Research Centre for Normal and Pathological Aging, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania
- 7Department of Neurology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania
- 8Department of Cardiology, University of Medicine and Pharmacy of Craiova, 2 Petru Rares Street, 200349 Craiova, Romania
- 9Department of Surgical Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Abstract
The peripheral nerves that innervate solid tumors communicate with the malignant cells through a restricted set of molecular signaling systems: adrenergic and muscarinic receptors, sensory neuropeptides, neurotrophins and their tyrosine kinase receptors, axon guidance molecules, and nociceptor ion channels. Each has been proposed separately as a therapeutic target but never quantitatively compared with the others. The question is whether one of them dominates—or whether the real target is the axis as a system. We systematically searched PubMed, Scopus, and Web of Science, with four query modules per database, without year or language restriction. We included in vivo studies in mammals, on extracranial solid cancers, with an intervention that modulated tumor innervation, peripheral nerve activity, or neural signaling, and with at least one tumor burden outcome. Of 16,649 unique records, 362 were included, with 1291 experiments and 1437 effects. Blockade of the peripheral nerve–tumor axis reduced tumor burden by −44.8%. In the prespecified primary analysis, on established tumors, the reduction was −52.0% with no significant difference from preventive interventions (p = 0.17). All eight molecular signaling systems responded to blockade, with estimates ranging from −34.3% for TRP channels to −70.2% for glutamatergic signaling. Interventions that activate the axis produced the opposite effect, with a 52.1% increase (95% CI: 32.1 to 75.1) across 253 effects, and bidirectionality was demonstrated within the same molecular system for the adrenergic compartment (−42.8% for blockade vs. 58.1% for activation), axon guidance molecules, and TRP channels. Egger’s test indicated marked small-study effects (slope −1.12; p < 0.001); the estimate remained stable when low-confidence digitized values were excluded (−42.6%). Eight distinct molecular signaling systems, disrupted by methods with nothing in common, produce reductions of a similar magnitude in tumor burden, and stimulation of three of them produces the opposite effect.
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BibTeX
@article{tudorașcu2026molecular,
title = {{Molecular Targeting of the Peripheral Nerve–Tumor Axis in Extracranial Solid Cancers: Eight Signaling Systems, One Effect—Systematic Review and Multilevel Meta-Analysis}},
author = {Diana-Rodica Tudorașcu and Cristin Constantin Vere and Mihai Petrescu and Ana-Maria Ciurea and Răzvan-Cosmin Pană and Alexandra Oltea Dan and Elena-Anca Târtea and Andrei Greșiță and Diana-Ruxandra Hădăreanu and Cosmin Vasile Obleagă and Georgică Târtea},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209090},
url = {https://www.mdpi.com/1422-0067/27/20/9090},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Molecular Targeting of the Peripheral Nerve–Tumor Axis in Extracranial Solid Cancers: Eight Signaling Systems, One Effect—Systematic Review and Multilevel Meta-Analysis
AU - Diana-Rodica Tudorașcu
AU - Cristin Constantin Vere
AU - Mihai Petrescu
AU - Ana-Maria Ciurea
AU - Răzvan-Cosmin Pană
AU - Alexandra Oltea Dan
AU - Elena-Anca Târtea
AU - Andrei Greșiță
AU - Diana-Ruxandra Hădăreanu
AU - Cosmin Vasile Obleagă
AU - Georgică Târtea
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209090
UR - https://www.mdpi.com/1422-0067/27/20/9090
AB - The peripheral nerves that innervate solid tumors communicate with the malignant cells through a restricted set of molecular signaling systems: adrenergic and muscarinic receptors, sensory neuropeptides, neurotrophins and their tyrosine kinase receptors, axon guidance molecules, and nociceptor ion channels. Each has been proposed separately as a therapeutic target but never quantitatively compared with the others. The question is whether one of them dominates—or whether the real target is the axis as a system. We systematically searched PubMed, Scopus, and Web of Science, with four query modules per database, without year or language restriction. We included in vivo studies in mammals, on extracranial solid cancers, with an intervention that modulated tumor innervation, peripheral nerve activity, or neural signaling, and with at least one tumor burden outcome. Of 16,649 unique records, 362 were included, with 1291 experiments and 1437 effects. Blockade of the peripheral nerve–tumor axis reduced tumor burden by −44.8%. In the prespecified primary analysis, on established tumors, the reduction was −52.0% with no significant difference from preventive interventions (p = 0.17). All eight molecular signaling systems responded to blockade, with estimates ranging from −34.3% for TRP channels to −70.2% for glutamatergic signaling. Interventions that activate the axis produced the opposite effect, with a 52.1% increase (95% CI: 32.1 to 75.1) across 253 effects, and bidirectionality was demonstrated within the same molecular system for the adrenergic compartment (−42.8% for blockade vs. 58.1% for activation), axon guidance molecules, and TRP channels. Egger’s test indicated marked small-study effects (slope −1.12; p < 0.001); the estimate remained stable when low-confidence digitized values were excluded (−42.6%). Eight distinct molecular signaling systems, disrupted by methods with nothing in common, produce reductions of a similar magnitude in tumor burden, and stimulation of three of them produces the opposite effect.
SN - 1422-0067
ER -