Article Figures & Data
Figures
- Figure 1.
Molecular basis and functional impact of tumor innervation. The outgrowth of nerves in the tumor microenvironment (axonogenesis) is driven by the secretion of neurotrophic factors (NTF) by cancer cells and takes place from peripheral nerves in the surrounding tissues that emerge from the CNS and associated neural ganglia. In return, nerve endings in the tumor microenvironment, which can be of adrenergic, cholinergic, or sensory origin, release neurotransmitters (NT) that stimulate corresponding receptors in stromal cells, immune cells, and cancer stem cells, resulting in the regulation of cancer growth and metastasis. Therefore, the stimulation of cancer cell growth can be direct and indirect through the stimulation of other cell types in the tumor microenvironment. Of note, the stimulation of endothelial cells by noradrenalin (NA) released from adrenergic nerves induces an angiogenic switch that fuels tumor growth and metastasis. The presence of sensory nerves in the tumor microenvironment can also participate in cancer pain.
- Figure 2.
Yin–yang type of neural regulation in pancreatic cancer. In pancreatic cancer cells, sensory (9, 14) and sympathetic (10) nerves activate the growth of pancreatic cancer cells through the liberation of substance P (SP) and noradrenaline (NA), and the subsequent activation of the neurokinin-1 receptor (NK1R) as well as the adrenergic receptor beta 2 (ADRβ2), respectively. Sympathetic nerves also activate the release of NGF by cancer cells that activates the corresponding receptor tyrosine kinase (RTK) in neurons, leading to more axonogenesis in the tumor microenvironment (10). In contrast to sensory and sympathetic nerves, parasympathetic nerves inhibit pancreatic cancer cell growth via the liberation of acetylcholine (ACh) and the activation of cholinergic muscarinic receptor 1 (CHRM1), leading to the inhibition of PI3K/AKT and EGFR/ERK (11). Cholinergic signaling also leads to the suppression of the cancer stem cell compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver (11). This opposite impact of sensory and sympathetic vs. parasympathetic nerves suggests that the development of pancreatic cancer is regulated through a balance of neural innervation.
Tables
- Table 1.
Evidence for neural regulation in cancer and cancer cell–induced axonogenesis
Cancer type Finding Ref. Prostate Adrenergic and cholinergic nerves stimulate tumor progression (5) Adrenergic nerves activate an angiogenic switch (38) Botulinum toxin–based denervation induces cancer cell apoptosis (74) Neurogenic expression in stem cells (51) Neurotrophic factors drive tumor axonogenesis (26, 27) Cancer incidence is lower in spinal cord injuries (6) Gastric Vagus nerve stimulates cancer initiation and progression (8) Cholinergic signaling stimulates cancer stem cell growth (8, 28) Cholinergic signaling induces NGF secretion that in turn drives tumor axonogenesis (28) Pancreatic Sensory nerves stimulate tumor progression (9) Sympathetic nerve/NGF feed-forward loop promotes cancer progression (10) Parasympathetic nerves suppress tumorigenesis and cancer stemness (11) Neuronal cross-talk promotes tumorigenesis (13, 14, 29) Skin Sensory innervation is necessary to tumor initiation and cancer stem cell growth (15) Breast Axonogenesis is associated with tumor aggressiveness and driven by NGF (30, 31) Colon Nerve infiltration is associated with tumor aggressiveness (33, 34) Neuroimmune regulation of cancer progression (62) Ovary Tumor axonogenesis is driven by BDNF (71) Head and neck Axonogenesis is stimulated by cancer cell–released exosomes containing Ephrin B1 (73) Glioma Neurons stimulate cancer cell growth through the release of neuroligin-3 and pleiotropin (16, 17) NOTE: Nerves can stimulate cancer cells directly or indirectly through the tumor microenvironment.
Volume 9, Issue 6
Jump to section
- Article
- Abstract
- Introduction
- Denervation and the Discovery of Nerve Involvement in Tumorigenesis
- Tumor Axonogenesis: An Emerging Hallmark of Cancer
- Sympathetic Nerves Drive Tumor Angiogenesis
- Nerve–Cancer Stem Cell Connection: Toward a Yin–Yang Type of Neural Regulation
- A Higher Regulation Level of Cancer Development
- Clinical Implications of Tumor Axonogenesis
- Conclusion
- Disclosure of Potential Conflicts of Interest
- Acknowledgments
- Footnotes
- References
- Figures & Data
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