Products Cited in Publications Worldwide Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression

Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression

Hiroki Kobayashi; Tadashi Iida; Yosuke Ochiai; Ermanno Malagola; Xiaofei Zhi; Ruth A. White; Jin Qian; Feijing Wu; Quin T. Waterbury; Ruhong Tu; Biyun Zheng; Jonathan S. LaBella; Leah B. Zamechek; Atsushi Ogura; Susan L. Woods; Daniel L. Worthley; Atsushi Enomoto; Timothy C. Wang

DOI: PMID:

Abstract

Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have eachbeen shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGFfrom CAFs directly enhances CRC cell growth via the PI3K/AKT pathway. Treatment with a tropomyosinreceptor kinase (Trk) inhibitor decreased YAP and AKT activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk inhibitor may represent a potential therapeutic approach for CRC.

Keywords

colorectal cancer ; tumor microenvironment ; fibroblasts ; nerve growth factor ; sympathetic nerves

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