Role of sensory neurons, neuroimmune pathways, and transient receptor potential vanilloid 1 (TRPV1) channels in a murine model of breast cancer metastasis
Sensory nerves sensitive to capsaicin are afferent nerve fibers which contain TRPV1 channels. Activation of these channels induces release of neuropeptides which regulate local blood flow and immune response. Inactivation of sensory neurons either with high-dose capsaicin treatment or local ablation of vagal sensory nerve activity markedly increases metastasis of breast carcinoma formed by 4T1 derivative cells. These cancer cells also induce an extensive systemic inflammatory response. Further findings have documented that lack of local sensory neuromediators alters phenotype of cancer cells within primary tumor leading to overgrowth of metastatic subsets. This might be due to decreases in local and systemic immune response to growing tumor. Specifically, Substance P, one of the most abundant sensory neuropeptides, enhances anti-tumoral immune response evoked by radiotherapy under in vivo conditions. These findings further suggest that activation of TRPV1 channels on sensory neurons may induce an anti-tumoral immune response. We are testing this hypothesis. Our initial results as reported here demonstrate anti-inflammatory consequences of low-dose systemic capsaicin treatment. In conclusion, sensory nerve fibers sensitive to capsaicin have important roles in defense against metastatic breast carcinoma; hence, controlled activation of these neural pathways might be effective in cancer therapy. Specifically, activation of sensory fibers of left vagus nerve using a perineuronal stimulation may inhibit metastasis of breast carcinoma. Likewise, pharmacological modulators of TRPV1 channels may induce anti-tumoral immune response. Exact players of this newly explored defense system are, however, only partly validated, and further studies are required.
KeywordsMetastasis Breast cancer Vagus Immune Capsaicin CITIM 2019
A disintegrin and metalloprotease 10
Autonomous nervous system
Neurokinin 1 receptors
Newly described results on TRPV1 channels and on perivagal capsaicin treatment were from studies supported by funds from The Scientific and Technological Research Council of Turkey (TÜBİTAK), Project Nos: 115S943 and 104S492, respectively.
Compliance with ethical standards
Conflict of interest
The author declares that she has no conflict of interest.
Ethical approval and ethical standards
All animal experimentation was performed following the guidelines of an accredited animal care committee of Akdeniz University. Ethical approval from the Akdeniz University Ethics Committee was given to Nuray Erin (Protocol No. 70904504). All protocols described in Figs. 1 and 2 were approved and performed under the supervision of the Akdeniz University Institutional Animal Care and Use Committee.
Wild-type (WT) female BALB/c mice were purchased from Kobay Research Animal Laboratory, Ankara Turkey.
Cell line authentication
4T1 cells were a gift from Dr. Danny Welch who was a faculty member of the Gittlen Cancer Center, Hershey Medical School, Hershey PA in 2001. The 4TBM cell line, established by Nuray Erin, was derived from brain metastasis of the 4T1 cells. The 4TBM cell line, kept in liquid nitrogen, forms primary tumors when injected into the mammary pad of BALB/c mice even after 50 passages.
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