Background & Aims

Clinical experience reveals that mechanical stimulation induces severe oral cancer pain[1, 2]. The transient receptor potential vanilloid-4 (TRPV4) is an ion channel that opens with mechanical stimulation[3-5]. Our multiplex immunohistochemistry assays demonstrate that TRPV4 is expressed on Schwann cells harvested from the lingual nerve innervating human oral cancer and Schwann cells harvested from the sciatic nerve innervating a mouse paw cancer generated with an oral cancer cell line. On the other hand, patch clamp recordings of mouse trigeminal neurons do not demonstrate functional TRPV4. We hypothesize that TRPV4 expression by Schwann cells mediates mechanical nociception in oral cancer. GSK2193874 is a selective TRPV4 antagonist that can be loaded into nanoparticles (NPs), which can facilitate drug delivery[6-8]. Therefore, we further hypothesize that delivery of GSK2193874 in NPs might yield a greater anti-nociceptive effect for a longer duration than free GSK2193874.

Methods

We generated a xenograft tongue cancer mouse model by inoculating human oral squamous cell carcinoma (HSC-3) into the tongue of BALB/c Foxn1nu mice. Facial mechanical withdrawal threshold assay with von Frey fibers were used to measure mechanical allodynia secondary to cancer in the tongue. After the mice developed cancer nociception, free GSK2193874 or GSK2193874-encapsulated NPs were locally injected into the cancer-affected tongue. We measured the anti-nociceptive effect at 1, 3, 6, 12, and 24 hour/s post-treatment. In an in vitro experiment, NPs tagged with rubrene (a fluorescent marker) were applied to cultured Schwann cells to study the uptake of NPs into Schwann cells.

Results

In facial mechanical withdrawal threshold assay, NP-encapsulated GSK2193874 yielded greater attenuation of oral cancer nociception than free GSK2193874 (1.7 ± 0.2 versus 1.0 ± 0.2, area under the curve, arbitrary unit) and the anti-nociceptive effect of the NP-encapsulated GSK2193874 lasted 3 hours longer. Schwann cells endocytosed the NPs as imaged with a high-resolution laser confocal microscope.

Conclusions

These results demonstrate that TRPV4 plays a role in oral cancer pain and that NP-encapsulated TRPV4 receptor antagonist delivery increases the anti-nociceptive efficacy of TRPV4 receptor antagonist. Future studies are planned to genetically delete TRPV4 on Schwann cells in an oral cancer mouse model to confirm the cell-specific effect of TRPV4 in oral cancer pain.

References

1.Kolokythas, A., S.T. Connelly, and B.L. Schmidt, Validation of the University of California San Francisco Oral Cancer Pain Questionnaire. J Pain, 2007. 8(12): p. 950-3.

2.Connelly, S.T. and B.L. Schmidt, Evaluation of pain in patients with oral squamous cell carcinoma. J Pain, 2004. 5(9): p. 505-10.

3.Veteto, A.B., et al., Transient receptor potential vanilloid-4 contributes to stretch-induced hypercontractility and time-dependent dysfunction in the aged heart. Cardiovasc Res, 2020. 116(11): p. 1887-1896.

4.Matthews, B.D., et al., Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. Integr Biol (Camb), 2010. 2(9): p. 435-42.

5.Mochizuki, T., et al., The TRPV4 cation channel mediates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures. J Biol Chem, 2009. 284(32): p. 21257-64.

6.Bahrami, B., et al., Nanoparticles and targeted drug delivery in cancer therapy. Immunol Lett, 2017. 190: p. 64-83.

7.Bhansali, D., et al., Nanotechnology for Pain Management: Current and Future Therapeutic Interventions. Nano Today, 2021. 39.

8.Mitchell, M.J., et al., Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov, 2021. 20(2): p. 101-124.

Presenting Author

Tu Huu Nguyen

Poster Authors

Tu Huu Nguyen

MD, PhD

NYU

Lead Author

E-mail

Kenji Inoue

New York University College of Dentistry

Lead Author

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Catherina Suh

NYU Dentistry, Translational Research Center.

Lead Author

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Varun Chokshi

NYU Dentistry, Translational Research Center.

Lead Author

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Jieun Kim

NYU Dentistry, Translational Research Center.

Lead Author

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Rachel Pollard

Translational Research Center, College of Dentistry, NYU

Lead Author

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Kiana Bahrami

NYU Tandon School of Engineering, Department of Chemical and Biomolecular Engineering.

Lead Author

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Nathalie Pinkerton

NYU Tandon School of Engineering, Department of Chemical and Biomolecular Engineering.

Lead Author

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Nigel Bunnett

Department of Molecular Pathobiology, Pain Research Center, NYU

Lead Author

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Brian Schmidt

NYU Dentistry, Translational Research Center

Lead Author

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Topics

  • Models: Oral/craniofacial