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Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
Published on: April 24, 2021
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Tumor innervation is triggered by endoplasmic reticulum stress
Chen Chen Jiang1,2,3, Mark Marsland1,2, Yufang Wang4
1Cancer Neurobiology Group, School of Biomedical Sciences & Pharmacy, The University of Newcastle, Callaghan, NSW, 2308, Australia.
Oncogene
|November 17, 2021
Summary
Cancer cell endoplasmic reticulum (ER) stress triggers nerve growth by releasing pro-brain-derived neurotrophic factor (proBDNF). Targeting this proBDNF pathway may offer new cancer therapies to reduce tumor innervation and progression.
Area of Science:
- Oncology
- Neuroscience
- Molecular Biology
Background:
- Tumor innervation promotes cancer progression but its initiation mechanisms are unclear.
- Nerve infiltration in the tumor microenvironment is a potential therapeutic target.
Purpose of the Study:
- To elucidate the mechanisms by which cancer cells initiate tumor innervation.
- To investigate the role of endoplasmic reticulum (ER) stress in tumor innervation.
Main Methods:
- Induction of ER stress in human cancer cells and analysis of proBDNF release.
- Investigated the role of X-box binding protein 1 (XBP1) in proBDNF synthesis.
- Utilized orthotopic tumor xenograft models and next-generation sequencing.
- Administered anti-proBDNF antibody and 5-Fluorouracil (5-FU) in vivo.
- Analyzed human tumor tissues for XBP1, proBDNF, and EGLN3 expression.
Main Results:
- ER stress in cancer cells induces XBP1-dependent proBDNF release, stimulating neurite outgrowth.
- c-MYC-mediated EGLN3 expression is necessary for proBDNF-induced neurite outgrowth.
- ER stress promotes tumor innervation and cancer progression, which is inhibited by anti-proBDNF antibody.
- The chemotherapeutic 5-FU induces ER stress and tumor innervation, counteracted by anti-proBDNF antibody.
- Human tumors with nerve infiltration show high XBP1 and proBDNF, with upregulated EGLN3 in nerves.
Conclusions:
- ER stress in cancer cells drives tumor innervation via proBDNF signaling.
- Targeting the ER stress-proBDNF pathway presents a novel therapeutic strategy against cancer progression and innervation.
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