Abstract
The effects of autonomic innervation of tumors on tumor growth remain unclear. Here we developed a series of genetic techniques to manipulate autonomic innervation in a tumor- and fiber-type-specific manner in mice with human breast cancer xenografts and in rats with chemically induced breast tumors. Breast cancer growth and progression were accelerated following stimulation of sympathetic nerves in tumors, but were reduced following stimulation of parasympathetic nerves. Tumor-specific sympathetic denervation suppressed tumor growth and downregulated the expression of immune checkpoint molecules (programed death-1 (PD-1), programed death ligand-1 (PD-L1), and FOXP3) to a greater extent than with pharmacological α- or β-adrenergic receptor blockers. Genetically induced simulation of parasympathetic innervation of tumors decreased PD-1 and PD-L1 expression. In humans, a retrospective analysis of breast cancer specimens from 29 patients revealed that increased sympathetic and decreased parasympathetic nerve density in tumors were associated with poor clinical outcomes and correlated with higher expression of immune checkpoint molecules. These findings suggest that autonomic innervation of tumors regulates breast cancer progression.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Code availability
No custom code was generated for this study.
References
Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A. & Sood, A. K. Sympathetic nervous system regulation of the tumour microenvironment. Nat. Rev. Cancer 15, 563–572 (2015).
Hanoun, M., Maryanovich, M., Arnal-Estape, A. & Frenette, P. S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360–373 (2015).
Chida, Y., Hamer, M., Wardle, J. & Steptoe, A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat. Clin. Pract. Oncol. 5, 466–475 (2008).
Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med 12, 939–944 (2006).
Schuller, H. M., Al-Wadei, H. A., Ullah, M. F. & Plummer, H. K. III. Regulation of pancreatic cancer by neuropsychological stress responses: a novel target for intervention. Carcinogenesis 33, 191–196 (2011).
Sloan, E. K. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042–7052 (2010).
Barron, T. I., Connolly, R. M., Sharp, L., Bennett, K. & Visvanathan, K. Beta blockers and breast cancer mortality: a population- based study. J. Clin. Oncol. 29, 2635–2644 (2011).
Cardwell, C. R., Coleman, H. G., Murray, L. J., Entschladen, F. & Powe, D. G. Beta-blocker usage and breast cancer survival: a nested case-control study within a UK clinical practice research datalink cohort. Int. J. Epidemiol. 42, 1852–1861 (2014).
Melhem-Bertrandt, A. et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 29, 2645–2652 (2011).
Shaashua, L. et al. Perioperative COX-2 and beta-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin. Cancer Res. 23, 4651–4661 (2017).
Grytli, H. H., Fagerland, M. W., Fossa, S. D. & Tasken, K. A. Association between use of beta-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur. Urol. 65, 635–641 (2013).
Sorensen, G. V. et al. Use of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and risk of breast cancer recurrence: a Danish nationwide prospective cohort study. J. Clin. Oncol. 31, 2265–2272 (2013).
Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
Bellinger, D. L. & Lorton, D. Autonomic regulation of cellular immune function. Auton. Neurosci. 182, 15–41 (2014).
Chen, L. & Han, X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. Clin. Invest. 125, 3384–3391 (2015).
Tanaka, A. & Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Cell Res. 27, 109–118 (2016).
Felten, D. L., Hall, P. V., Campbell, R. L. & Kalsbeck, J. E. A histochemical investigation of catecholamines in spinal cord injury. J. Neural. Transm. 39, 209–221 (1976).
Hollis, E. R. 2nd, Kadoya, K., Hirsch, M., Samulski, R. J. & Tuszynski, M. H. Efficient retrograde neuronal transduction utilizing self-complementary AAV1. Mol. Ther. 16, 296–301 (2008).
Pirozzi, M. et al. Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia. J. Clin. Invest. 116, 202–208 (2006).
Irie, K. et al. Comparative study of the gating motif and C-type inactivation in prokaryotic voltage-gated sodium channels. J. Biol. Chem. 285, 3685–3694 (2009).
Ren, D. et al. A prokaryotic voltage-gated sodium channel. Science 294, 2372–2375 (2001).
Lin, C. W. et al. Genetically increased cell-intrinsic excitability enhances neuronal integration into adult brain circuits. Neuron 65, 32–39 (2010).
Sakamoto, M. et al. Continuous neurogenesis in the adult forebrain is required for innate olfactory responses. Proc. Natl Acad. Sci. USA 108, 8479–8484 (2011).
Ubil, E. et al. Mesenchymal–endothelial transition contributes to cardiac neovascularization. Nature 514, 585–590 (2014).
Kinoshita, M. et al. Genetic dissection of the circuit for hand dexterity in primates. Nature 487, 235–238 (2012).
Lamkin, D. M. et al. Alpha2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression. Psychoneuroendocrinology 51, 262–270 (2014).
Kamiya, A., Kawada, T., Shimizu, S. & Sugimachi, M. Closed-loop spontaneous baroreflex transfer function is inappropriate for system identification of neural arc but partly accurate for peripheral arc: predictability analysis. J. Physiol. 589, 1769–1790 (2011).
Struyker-Boudier, H. A., van Essen, H., Nievelstein, H. M. & Smits, J. F. Role of baroreflex activation in the regional hemodynamic effects of the beta-blockers tertatolol and propranolol in conscious spontaneously hypertensive rats. Am. J. Nephrol. 6 (Suppl. 2), 25–29 (1986).
Kennedy, J. D., Pierce, C. W. & Lake, J. P. Extrathymic T cell maturation. Phenotypic analysis of T cell subsets in nude mice as a function of age. J. Immunol. 148, 1620–1629 (1992).
Nakajima, C. et al. A role of interferon-gamma (IFN-gamma) in tumor immunity: T cells with the capacity to reject tumor cells are generated but fail to migrate to tumor sites in IFN-gamma-deficient mice. Cancer Res. 61, 3399–3405 (2001).
Zanetti, M. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics. J. Immunol. 194, 2049–2056 (2015).
Bhat, P., Leggatt, G., Waterhouse, N. & Frazer, I. H. Interferon-gamma derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis. 8, e2836 (2017).
Ligocki, A. J., Brown, J. R. & Niederkorn, J. Y. Role of interferon-gamma and cytotoxic T lymphocytes in intraocular tumor rejection. J. Leukoc. Biol. 99, 735–747 (2016).
Zhou, J., Ma, P., Li, J., Cui, X. & Song, W. Improvement of the cytotoxic T lymphocyte response against hepatocellular carcinoma by transduction of cancer cells with an adeno-associated virus carrying the interferon-gamma gene. Mol. Med. Rep. 13, 3197–3205 (2016).
Asamoto, M. et al. Transgenic rats carrying human c-Ha-ras proto-oncogenes are highly susceptible to N-methyl-N-nitrosourea mammary carcinogenesis. Carcinogenesis 21, 243–249 (2000).
Zhou, X., Vink, M., Klaver, B., Berkhout, B. & Das, A. T. Optimization of the Tet-On system for regulated gene expression through viral evolution. Gene Ther. 13, 1382–1390 (2006).
Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl Acad. Sci. USA 89, 5547–5551 (1992).
Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell Biol. 12, 954–961 (1992).
Bucsek, M. J. et al. Beta-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy. Cancer Res. 77, 5639–5651 (2017).
Perron, L., Bairati, I., Harel, F. & Meyer, F. Antihypertensive drug use and the risk of prostate cancer (Canada). Cancer Causes Control 15, 535–541 (2004).
Powe, D. G. et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1, 628–638 (2010).
Hicks, B. M., Murray, L. J., Powe, D. G., Hughes, C. M. & Cardwell, C. R. Beta-blocker usage and colorectal cancer mortality: a nested case-control study in the UK Clinical Practice Research Datalink cohort. Ann. Oncol. 24, 3100–3106 (2013).
McCourt, C. et al. Beta-blocker usage after malignant melanoma diagnosis and survival: a population-based nested case-control study. Br. J. Dermatol. 170, 930–938 (2014).
Hayakawa, Y. et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 31, 21–34 (2017).
Zhao, C. M. et al. Denervation suppresses gastric tumorigenesis. Sci. Transl Med. 6, 250ra115 (2014).
Zahalka, A. H. et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 358, 321–326 (2017).
Oh, M. S., Hong, S. J., Huh, Y. & Kim, K. S. Expression of transgenes in midbrain dopamine neurons using the tyrosine hydroxylase promoter. Gene Ther. 16, 437–440 (2009).
Eto, K. et al. Enhanced GABAergic activity in the mouse primary somatosensory cortex is insufficient to alleviate chronic pain behavior with reduced expression of neuronal potassium-chloride cotransporter. J. Neurosci. 32, 16552–16559 (2012).
Borg, M. L. et al. Hypothalamic neurogenesis is not required for the improved insulin sensitivity following exercise training. Diabetes 63, 3647–3658 (2014).
Sobin, L. H. & Fleming, I. D. Review of TNM classification of malignant tumors, fifth edition. Cancer 80, 1803–1804 (1997).
Acknowledgements
This study was supported by a research project promoted by the Grants-in-Aid for Scientific Research promoted by the Ministry of Education, Culture, Sports, Science, and Technology in Japan (17H04365, 18K19950, and 18H04707, received by A.K.) and the Japan Agency for Medical Research and Development (AMED-PRIME, received by A.K.).
Author information
Authors and Affiliations
Contributions
A.K. designed the study, conducted the experiments, and wrote the paper, with assistance from A.S. and T.O. Y.H. conducted the analyses. S.K. and K.K generated some of the viral vectors and rats. R.K. and Y.Y. generated some of the rats. T.S. and K.I. generated the NaChBac mutant and conducted the in vitro electrophysiological experiments.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests except the patent (patent applicant: Asunori Kamiya; name of inventor: Asunori Kamiya; application number: PCT/JP2017/25468; status of application: international migration; specific aspect of manuscript covered in patent application: the genetic engineering of local nerves including tumoral autonomic nerves; the concept of genetic engineering of local nerves for treatment of variable diseases including cancers; the viral vectors and their constructions to control, stimulate and delete sympathetic nerves; and the viral vectors and their constructions to control, stimulate and delete parasympathetic nerves).
Additional information
Peer review information: Nature Neuroscience thanks Paul Frenette and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1038/s41593-024-01628-0
Supplementary information
About this article
Cite this article
Kamiya, A., Hayama, Y., Kato, S. et al. RETRACTED ARTICLE: Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression. Nat Neurosci 22, 1289–1305 (2019). https://doi.org/10.1038/s41593-019-0430-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41593-019-0430-3
This article is cited by
-
cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment
Journal of Hematology & Oncology (2024)
-
Metabolic heterogeneity in cancer
Nature Metabolism (2024)
-
The cancer-immune dialogue in the context of stress
Nature Reviews Immunology (2024)
-
Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis
Signal Transduction and Targeted Therapy (2024)
-
Chronic stress in solid tumor development: from mechanisms to interventions
Journal of Biomedical Science (2023)