Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

Salivary glands sustain collateral damage following radiotherapy (RT) to treat cancers of the head and neck, leading to complications, including mucositis, xerostomia and hyposalivation. Despite salivary gland-sparing techniques and modified dosing strategies, long-term hypofunction remains a significant problem. Current therapeutic interventions provide temporary symptom relief, but do not address irreversible glandular damage. In this review, we summarize the current understanding of mechanisms involved in RT-induced hyposalivation and provide a framework for future mechanistic studies. One glaring gap in published studies investigating RT-induced mechanisms of salivary gland dysfunction concerns the effect of irradiation on adjacent non-irradiated tissue via paracrine, autocrine and direct cell–cell interactions, coined the bystander effect in other models of RT-induced damage. We hypothesize that purinergic receptor signaling involving P2 nucleotide receptors may play a key role in mediating the bystander effect. We also discuss promising new therapeutic approaches to prevent salivary gland damage due to RT.

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The evolving definition of salivary gland stem cells

npj Regenerative Medicine ◽

10.1038/s41536-020-00115-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Cecilia Rocchi ◽

Lara Barazzuol ◽

Rob P. Coppes

Keyword(s):

Stem Cells ◽

Salivary Gland ◽

Adult Stem Cell ◽

Cell Types ◽

Research Field ◽

New Therapeutic Approaches ◽

Recent Developments ◽

Radiation Induced ◽

Definition Of

AbstractDysfunction of the salivary gland and irreversible hyposalivation are the main side effects of radiotherapy treatment for head and neck cancer leading to a drastic decrease of the quality of life of the patients. Approaches aimed at regenerating damaged salivary glands have been proposed as means to provide long-term restoration of tissue function in the affected patients. In studies to elucidate salivary gland regenerative mechanisms, more and more evidence suggests that salivary gland stem/progenitor cell behavior, like many other adult tissues, does not follow that of the hard-wired professional stem cells of the hematopoietic system. In this review, we provide evidence showing that several cell types within the salivary gland epithelium can serve as stem/progenitor-like cells. While these cell populations seem to function mostly as lineage-restricted progenitors during homeostasis, we indicate that upon damage specific plasticity mechanisms might be activated to take part in regeneration of the tissue. In light of these insights, we provide an overview of how recent developments in the adult stem cell research field are changing our thinking of the definition of salivary gland stem cells and their potential plasticity upon damage. These new perspectives may have important implications on the development of new therapeutic approaches to rescue radiation-induced hyposalivation.

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The protective efficacy of basic fibroblast growth factor in radiation-induced salivary gland dysfunction in mice

The Laryngoscope ◽

10.1002/lary.21873 ◽

2011 ◽

Vol 121 (9) ◽

pp. 1870-1875 ◽

Cited By ~ 20

Author(s):

Tsuyoshi Kojima ◽

Shin-ichi Kanemaru ◽

Shigeru Hirano ◽

Ichiro Tateya ◽

Atsushi Suehiro ◽

...

Keyword(s):

Salivary Gland ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Protective Efficacy ◽

Fibroblast Growth ◽

Salivary Gland Dysfunction ◽

Radiation Induced

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Effect of Cevimeline on Radiation-Induced Salivary Gland Dysfunction and AQP5 in Submandibular Gland in Mice

The Bulletin of Tokyo Dental College ◽

10.2209/tdcpublication.48.47 ◽

2007 ◽

Vol 48 (2) ◽

pp. 47-56 ◽

Cited By ~ 10

Author(s):

Katsuhiro Takakura ◽

Sachiko Takaki ◽

Ienaka Takeda ◽

Nobuyuki Hanaue ◽

Yasuhiro Kizu ◽

...

Keyword(s):

Salivary Gland ◽

Submandibular Gland ◽

Salivary Gland Dysfunction ◽

Radiation Induced

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1083 POSTER The Effects of Heparan Sulfate Mimetic RGTA-OTR4120 on Radiation-induced Salivary Gland Dysfunction in Mice

European Journal of Cancer ◽

10.1016/s0959-8049(11)70726-2 ◽

2011 ◽

Vol 47 ◽

pp. S119-S120

Author(s):

L. Spiegelberg ◽

U.M. Djasim ◽

J.W. van Neck ◽

E.B. Wolvius ◽

K.G.H. van der Wal

Keyword(s):

Salivary Gland ◽

Heparan Sulfate ◽

Salivary Gland Dysfunction ◽

Radiation Induced

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IGF1 prevents radiation‐induced salivary gland dysfunction which does not affect survival of head and neck tumors

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.930.3 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Kerton R Victory ◽

Kirsten H Limesand

Keyword(s):

Salivary Gland ◽

Head And Neck ◽

Head And Neck Tumors ◽

Salivary Gland Dysfunction ◽

Neck Tumors ◽

Radiation Induced

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Simvastatin attenuates radiation-induced salivary gland dysfunction in mice

Drug Design Development and Therapy ◽

10.2147/dddt.s105809 ◽

2016 ◽

Vol Volume 10 ◽

pp. 2271-2278 ◽

Cited By ~ 3

Author(s):

Xinchen Sun ◽

Xi Yang ◽

Jiayan Chen ◽

Xiao-Lin Ge ◽

Qin Qin ◽

...

Keyword(s):

Salivary Gland ◽

Salivary Gland Dysfunction ◽

Radiation Induced

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Peroxynitrite formation in radiation-induced salivary gland dysfunction in mice

Biomedical Research ◽

10.2220/biomedres.28.147 ◽

2007 ◽

Vol 28 (3) ◽

pp. 147-151 ◽

Cited By ~ 16

Author(s):

Nobuaki HANAUE ◽

Ienaka TAKEDA ◽

Yasuhiro KIZU ◽

Morio TONOGI ◽

Gen-yuki YAMANE

Keyword(s):

Salivary Gland ◽

Salivary Gland Dysfunction ◽

Radiation Induced

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Integration of metabolomics and transcriptomics reveals convergent pathways driving radiation-induced salivary gland dysfunction

Physiological Genomics ◽

10.1152/physiolgenomics.00127.2020 ◽

2021 ◽

Author(s):

Lauren Gayle Meeks ◽

Diogo De Oliveira Pessoa ◽

Jessica Anne Martinez ◽

Kirsten H. Limesand ◽

Megha Padi

Keyword(s):

Salivary Gland ◽

Energy Metabolism ◽

Head And Neck ◽

Salivary Glands ◽

Metabolic Phenotype ◽

Glutathione Metabolism ◽

Metabolic Reaction ◽

Salivary Gland Dysfunction ◽

Damage Response ◽

Radiation Induced

Radiation therapy for head and neck cancer causes damage to the surrounding salivary glands, resulting in salivary gland hypofunction and xerostomia. Current treatments do not provide lasting restoration of salivary gland function following radiation; therefore, a new mechanistic understanding of the radiation-induced damage response is necessary for identifying therapeutic targets. The purpose of the present study was to investigate the metabolic phenotype of radiation-induced damage in parotid salivary glands by integrating transcriptomic and metabolomic data. Integrated data were then analyzed to identify significant gene-metabolite interactions. Mice received a single 5 Gy dose of targeted head and neck radiation. Parotid tissue samples were collected 5 days following treatment for RNA sequencing and metabolomics analysis. Altered metabolites and transcripts significantly converged on a specific region in the metabolic reaction network. Both integrative pathway enrichment using rank-based statistics and network analysis highlighted significantly coordinated changes in glutathione metabolism, energy metabolism (TCA cycle and thermogenesis), peroxisomal lipid metabolism, and bile acid production with radiation. Integrated changes observed in energy metabolism suggest that radiation induces a mitochondrial dysfunction phenotype. These findings validated previous pathways involved in the radiation-damage response, such as altered energy metabolism, and identified robust signatures in salivary glands, such as reduced glutathione metabolism, that may be driving salivary gland dysfunction.

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