Neurobiology of Cancer Progression and Stress Response

The interplay between the nervous system and cancer has emerged as a fundamental determinant of tumour behaviour and patient outcome. Neural signals within the tumour microenvironment influence cancer cell proliferation, migration, stemness and metastatic potential, while systemic stress responses mediated by the sympathetic nervous system and hypothalamic–pituitary–adrenal axis can accelerate tumour progression and impair anti‐tumour immunity. Bidirectional communication among cancer cells, neurons and stromal elements fosters neurogenesis, perineural invasion and the remodelling of lymphatic and vascular networks, which together facilitate dissemination. Understanding these pathways reveals novel opportunities for intervention, including blockade of adrenergic signalling, inhibition of tumour‐induced neurogenesis, and modulation of stress hormone effects. Such strategies promise to complement existing therapies by disrupting the neural circuits that promote metastasis and therapy resistance, ultimately improving patient survival and quality of life.

Research from Nature Portfolio

Recent studies have demonstrated that chronic stress can drive cancer dissemination by reorganising tumour‐associated lymphatic vessels. In preclinical models, activation of the sympathetic nervous system induces cyclooxygenase‐mediated inflammation that stimulates vascular endothelial growth factor C production, leading to lymphatic remodelling and enhanced metastatic spread. Pharmacological blockade of β-adrenergic receptors reverses these effects and reduces lymphogenous dissemination in both animal models and patient samples. Another seminal finding has revealed that tumours actively recruit nerve fibres through the release of extracellular vesicles. These vesicles, rich in axon guidance molecules, induce sensory neurite outgrowth and establish dense innervation within the tumour mass. Genetic or pharmacological disruption of vesicle release significantly attenuates tumour innervation and concomitantly reduces metastatic burden, signalling a potential route to impede perineural invasion and tumour growth.

Neurobiology of Cancer Progression and Stress Response publication trend

The graph below shows the total number of articles in neurobiology of cancer progression and stress response across all publications each year (not limited to Nature Index journals).

Technical terms

Sympathetic nervous system (SNS): The branch of the autonomic nervous system that mediates ‘fight or flight’ responses via catecholamine release, influencing tumour biology.

cAMP-responsive element (CRE): A DNA sequence in gene promoters that binds transcription factors activated by cyclic adenosine monophosphate, linking neural signals to gene expression.

Exosome: A small extracellular vesicle secreted by cells, carrying proteins and nucleic acids that mediate intercellular communication, including tumour-induced neurite growth.

Perineural invasion: The process by which cancer cells infiltrate and spread along nerve sheaths, facilitating local and distant metastasis.

β2-adrenergic receptor (ADRB2): A G-protein-coupled receptor activated by epinephrine and norepinephrine, whose engagement on tumour cells promotes stress-mediated progression.

References

1. Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness. Signal Transduction and Targeted Therapy (2023).
2. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nature Communications (2016).
3. Cancer exosomes induce tumor innervation. Nature Communications (2018).
4. Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduction and Targeted Therapy (2020).
5. Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2. Cell Death & Disease (2019).