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Radiation-induced dormancy of intracerebral melanoma: endotoxin inflammation leads to both shortened tumor dormancy and long-term survival with localized senescence

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Abstract

Radiation therapy (RT) treats approximately half of all cancers and most brain cancers. RT is variably effective at inducing a dormant tumor state i.e. the time between RT and clinical recurrence of tumor growth. Interventions that significantly lengthen tumor dormancy would improve long-term outcomes. Inflammation can promote the escape of experimental tumors from metastatic dormancy in the lung. Previously we showed intracerebral B16F10 melanoma dormancy varied with RT dose; 20.5 Gy induced dormancy lasted ~ 2 to 4 weeks—sufficient time to study escape from dormancy. Tumors were followed over time using bioluminescence. Surprisingly, some tumors in endotoxin-treated mice exited from dormancy slower; a large fraction of the mice survived more than 1-year. A cohort of mice also experienced an accelerated exit from dormancy and increased mortality indicating there might be variation within the tumor or inflammatory microenvironment that leads to both an early deleterious effect and a longer-term protective effect of inflammation. Some of the melanin containing cells at the site of the original tumor were positive for senescent markers p16, p21 and βGal. Changes in some cytokine/chemokine levels in blood were also detected. Follow-up studies are needed to identify cytokines/chemokines or other mechanisms that promote long-term dormancy after RT.

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Acknowledgements

This work was supported by Connecticut Brain Tumor Alliance and University of Connecticut Seed Grants to Henry Smilowitz. We wish to thank BM Marin for her help with some of these experiments.

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Authors and Affiliations

  1. University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, 06030, USA

    Sharif M. Ridwan, Rose Emlein, Andrew Annabi & Henry M. Smilowitz

  2. 6G Research and Innovation Lab, School of Science, Computing and Engineering Technologies, Swinburne University of Technology, Melbourne, Australia

    Asghar Mesbahi

  3. Nanoprobes, Inc, 95 Horseblock Road, Yaphank, NY, 11980, USA

    James F. Hainfeld

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  1. Sharif M. Ridwan
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Correspondence to Henry M. Smilowitz.

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All the work and study protocols were performed were approved by the University of Connecticut Health Center Animal Care and Use Committee.

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262_2023_3481_MOESM1_ESM.tif

Supplementary Figure 1. A-B. B16 melanoma bearing mouse brain coronal section showing Controls for P16 staining. A. Secondary antibody only control, B. No antibody control. Dapi (blue) = nuclei, Green p16 fluorescence (Alexa-488) is absent. White bar = 100 µm. (TIF 791 kb)

262_2023_3481_MOESM2_ESM.tif

Supplementary Figure 2. A-B. B16 melanoma bearing mouse brain coronal section showing Controls for P21 staining. A. Secondary antibody only control, B. No antibody control. Dapi (blue) = nuclei, Green p21 fluorescence (Alexa-488) is absent. White bar = 100 um. (TIF 1019 kb)

262_2023_3481_MOESM3_ESM.tif

Supplementary Figure 3. Ki67 positive cells on the edge of the residual tumor remnant. A-C. B16 melanoma bearing mouse brain coronal section showing Ki67 staining. Dapi (blue) = nuclei, Green = Ki67, Red arrows = co-localization of Ki67 and nuclei stains. White bar = 100 µm. (TIF 2718 kb)

262_2023_3481_MOESM4_ESM.tif

Supplementary Figure 4: Ki67 staining is localized to the nucleus. A-C, Red box in Supplementary Figure 3 enlarged. Fluorescence localized to the nucleus. A. Green, Ki67 fluorescence, Blue, nuclei (DAPI stain); B. Green, Ki67 fluorescence only; C. Blue, Nuclei only. (TIF 2014 kb)

262_2023_3481_MOESM5_ESM.tif

Supplementary Figure 5: A-B. B16 melanoma bearing mouse brain coronal section showing Controls for Ki67 staining. A. Secondary antibody only control, B. No antibody control. Dapi (blue) = nuclei, Green Ki67 fluorescence (Alexa-488) is absent. White bar = 100 um. (TIF 970 kb)

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Ridwan, S.M., Emlein, R., Mesbahi, A. et al. Radiation-induced dormancy of intracerebral melanoma: endotoxin inflammation leads to both shortened tumor dormancy and long-term survival with localized senescence. Cancer Immunol Immunother 72, 3851–3859 (2023). https://doi.org/10.1007/s00262-023-03481-9

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