Acute radiotherapy-associated oral pain may promote tumor growth at distant sites

Constanza S Meneses; Emily M Gidcumb; Karen L Marcus; Yarines Gonzalez; Yen Hao Lai; Santosh K Mishra; B Duncan X Lascelles; Michael W Nolan

doi:10.3389/fonc.2023.1029108

Acute radiotherapy-associated oral pain may promote tumor growth at distant sites

Front Oncol. 2023 May 19:13:1029108. doi: 10.3389/fonc.2023.1029108. eCollection 2023.

Authors

Constanza S Meneses^{1

2

3}, Emily M Gidcumb⁴, Karen L Marcus¹, Yarines Gonzalez⁴, Yen Hao Lai¹, Santosh K Mishra^{2

5}, B Duncan X Lascelles^{1

2

3

6

7

8}, Michael W Nolan^{1

2

6

9}

Affiliations

¹ Department of Clinical Sciences College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
² Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
³ Translational Research in Pain, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
⁴ College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
⁵ Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
⁶ Comparative Pain Research and Education Center, North Carolina State University, Raleigh, NC, United States.
⁷ Thurston Arthritis Center, The University of North Carolina School of Medicine, Chapel Hill, NC, United States.
⁸ Center for Translational Pain Research, Department of Anesthesiology, Duke University, Durham, NC, United States.
⁹ Duke Cancer Institute, Duke University, Durham, NC, United States.

Abstract

Introduction: Patients developing acute radiotherapy induced dermatitis or oral mucositis commonly experience pain. When severe, this radiotherapy-associated pain (RAP) can necessitate treatment breaks; unfortunately, in a variety of cancers, prolongation of the radiotherapy course has been associated with early cancer relapse and/or death. This is often attributed to accelerated repopulation, but it is unknown whether pain or pain signaling constituents might alter tumor behavior and hasten metastatic disease progression. We studied this by testing the hypothesis that severe acute RAP at one site can hasten tumor growth at a distant site.

Methods: Mice underwent single fraction tongue irradiation (27 Gy, or 0 Gy "sham" control) to induce severe glossitis. At the time of maximal oral RAP, one of three luciferase-transfected tumor cell lines were injected via tail vein (4T1, B16F10, MOC2; each paired to their syngeneic host: BALB/c or C57BL/6); tumor burden was assessed via in vivo transthoracic bioluminescence imaging and ex vivo pulmonary nodule quantification. Survival was compared using Kaplan-Meier statistics.

Results: Tongue irradiation and resultant RAP promoted lung tumor growth of 4T1-Luc2 cells in BALB/c mice. This effect was not a result of off-target radiation, nor an artefact of environmental stress caused by standard (subthermoneutral) housing temperatures. RAP did not affect the growth of B16F10-Luc2 cells, however, C57BL/6 mice undergoing tail vein injection of MOC2-Luc2 cells at the time of maximal RAP experienced early lung tumor-attributable death. Lung tumor growth was normalized when RAP was reduced by treatment with resiniferatoxin (300 µg/kg, subcutaneously, once).

Discussion: This research points towards radiation-induced activation of capsaicin-responsive (TRPV1) neurons as the cause for accelerated growth of tumors at distant (unirradiated) sites.

Keywords: TRPV1; cancer; mouse; pain; radiotherapy; sensory nerves.

Grants and funding

In support of this work, MN and SM received research grant support from the American College of Veterinary Radiology, and MN, SM, and BL received research grant support from the NC State College of Veterinary Medicine. Neither grant has a grant number/identifier. Other support was provided by BL salary release. CM work was supported by the National Agency for Research and Development (ANID) (Chilean Scholarship Program/DOCTORADO BECAS CHILE/2017/72180112).