Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression

Atsunori Kamiya, Yohsuke Hayama, Shigeki Kato, Akihiko Shimomura, Takushi Shimomura, Katsumasa Irie, Ryosuke Kaneko, Yuchio Yanagawa, Kazuto Kobayashi, Takahiro Ochiya

Research output: Contribution to journalArticlepeer-review

130 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1289-1305
Number of pages17
JournalNature Neuroscience
Issue number8
Publication statusPublished - Aug 1 2019

ASJC Scopus subject areas

  • Neuroscience(all)


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