Radiation-Induced Fibrosis in Patients with Head and Neck Cancer: A Review of Pathogenesis and Clinical Outcomes

Ramia, Paul; Bodgi, Larry; Mahmoud, Dima; Mohammad, Mohammad Ali; Youssef, Bassem; Kopek, Neil; Al-Shamsi, Humaid O.; Dagher, Mona; Abu‐Gheida, Ibrahim

doi:10.1177/11795549211036898

Cited by 28 publications

(16 citation statements)

References 84 publications

(126 reference statements)

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“…Therefore, the decrease in CBT-induced myogenic potential and increase in skeletal muscle fibrosis, indicates the increased proliferation capacity of fibroblasts. Radiation-induced acceleration of fibrosis has been reported frequently in human clinical cases in various tissues, such as the lungs [6,23], kidneys [24], and skin [25]. This has also been observed previously in animal models [26][27][28].…”

Section: Discussionsupporting

confidence: 66%

Quantitative Evaluation of the Reduced Capacity of Skeletal Muscle Hypertrophy after Total Body Irradiation in Relation to Stem/Progenitor Cells

Fukuzawa

Natsume

Tamaki

et al. 2022

JCM

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The effects of total body irradiation (TBI) to the capacity of skeletal muscle hypertrophy were quantified using the compensatory muscle hypertrophy model. We additionally assessed the responses of stem and/or progenitor cells in the muscles. A single TBI of 9.0, 5.0 and 2.5 Gy was delivered to C57BL/6 mice. Bone marrow stromal cells were obtained from GFP-Tg mice, and were injected into the tail vein of the recipient mice (1 × 106 cells/mouse), for bone marrow transplantation (BMT). Five weeks after TBI, the mean GFP-chimerism in the blood was 96 ± 0.8% in the 9 Gy, 83 ± 3.9% in the 5 Gy, and 8.4 ± 3.4% in the 2.5 Gy groups. This implied that the impact of 2.5 Gy is quite low and unavailable as the BMT treatment. Six weeks after the TBI/BMT procedure, muscle hypertrophy was induced in the right plantaris muscle by surgical ablation (SA) of the synergist muscles (gastrocnemius and soleus), and the contralateral left side was preserved as a control. The muscle hypertrophy capacity significantly decreased by 95% in the 9 Gy, 48% in the 5 Gy, and 36% in the 2.5 Gy groups. Furthermore, stem/progenitor cells in the muscle were enzymatically isolated and fractionated into non-sorted bulk cells, CD45-/34-/29+ (Sk-DN), and CD45-/34+ (Sk-34) cells, and myogenic capacity was confirmed by the presence of Pax7+ and MyoD+ cells in culture. Myogenic capacity also declined significantly in the Bulk and Sk-DN cell groups in all three TBI conditions, possibly implying that skeletal muscles are more susceptible to TBI than bone marrow. However, interstitial Sk-34 cells were insusceptible to TBI, retaining their myogenic/proliferative capacity.

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Section: Discussionsupporting

confidence: 66%

Quantitative Evaluation of the Reduced Capacity of Skeletal Muscle Hypertrophy after Total Body Irradiation in Relation to Stem/Progenitor Cells

Fukuzawa

Natsume

Tamaki

et al. 2022

JCM

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“…Higher prevalence of dysphagia was found in this study (31%) compared to the previously reported prevalence of 14% at 2 years [56]. This may be due to development of soft tissue fibrosis, which tend to progress over time [31,57]. The finding of this study is of great importance as literature on long-term patient-reported dysphagia is scarce.…”

Section: Discussioncontrasting

confidence: 45%

“…Cytokines such as interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF) have been linked to oral mucositis, and possibly xerostomia, during RT, manifested by elevated levels in saliva immediately after treatment in HNC patients [29,30]. Chronic inflammation may further cause fibrosis, one of the key pathological features in radiation-induced late effects such as dysphagia [4,31]. Transforming growth factor beta (TGF-β) and TNF are involved in the formation of fibrosis in irradiated tissue, predominantly found in lung cancer studies [4,[32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Associations between patient-reported late effects and systemic cytokines in long-term survivors of head and neck cancer treated with radiotherapy

et al. 2022

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Purpose Head and neck cancer (HNC) treatment may lead to late effects and impaired health-related quality of life of survivors. Knowledge on long-term late effects after radiotherapy (RT) and potential underlying biological mechanisms is lacking. We assessed the prevalence of xerostomia, dysphagia, and chronic fatigue (CF) in HNC survivors ≥ 5 years post-RT, and examined associations between pro-inflammatory cytokines and late effects. Methods In a cross-sectional study, 263 HNC survivors treated between 2007 and 2013 were enrolled. They completed validated questionnaires assessing xerostomia and dysphagia (the EORTC QLQ-H&N35), and CF (the Fatigue Questionnaire), and underwent blood sampling and clinical examination. Pro-inflammatory cytokines were analyzed in 262 survivors and 100 healthy age- and gender-matched controls. Results Median time since treatment was 8.5 years. The proportions of survivors reporting xerostomia, dysphagia, and CF were 58%, 31%, and 33%, respectively, with a preponderance of females. We found no significant associations between IL-6, IL-8, IP-10, TARC, TNF, or ENA-78 and the three late effects. The odds of having elevated levels of IL-6 and IP-10 were significantly higher in the survivors compared to the controls. Conclusions More than one-third of long-term HNC survivors experienced xerostomia, dysphagia, and CF. Persistent inflammation, with elevated systemic cytokines, was not associated with these late effects, although HNC survivors had higher levels of some cytokines than the controls. Implications for Cancer Survivors This study provides new knowledge on late effects that can serve as grounds for informing patients with HNC about risk of late effects more than 5 years after RT.

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“…65,66 A most potent impact of radiotherapy is on the TME fibroblasts, subsequently to vascular damage and leakage of serum proteases, leading to extracellular matrix remodeling, fibroblast activation, and fibrosis. 67 Activated fibroblasts produce and organize large amounts of collagen in dense fibrillary tissue with opposing actions on residual tumor survival: increased hypoxia and decreased access to nutrients versus increased cancer cell survival due to integrin 1 signaling and TGF-1 release. 67 Antibody-mediated TGF-β neutralization during radiation therapy effectively generated carcinomas regression in mice and in humans, provided co-administration of anti-PD-1 and anti-CD137 (TNF receptor superfamily member 9) immunostimulatory monoclonal antibodies.…”

Section: Stroma and Microenvironment Impact On Radiation-treated Tumorsmentioning

confidence: 99%

“…67 Activated fibroblasts produce and organize large amounts of collagen in dense fibrillary tissue with opposing actions on residual tumor survival: increased hypoxia and decreased access to nutrients versus increased cancer cell survival due to integrin 1 signaling and TGF-1 release. 67 Antibody-mediated TGF-β neutralization during radiation therapy effectively generated carcinomas regression in mice and in humans, provided co-administration of anti-PD-1 and anti-CD137 (TNF receptor superfamily member 9) immunostimulatory monoclonal antibodies. [68][69][70] However, several clinical trials concluded that patients eventually relapse, and that all these treatments ended by being ineffective.…”

Section: Stroma and Microenvironment Impact On Radiation-treated Tumorsmentioning

confidence: 99%

The Stroma and Tumor Microenvironment Are Not the Most Instrumental Players in Tumor Cells Immune Evasion, Growth, and Resistance to Therapy

Tallima¹,

Ridi²

2022

Preprint

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The central reason behind emergence of clinically-detectable tumors is evasion from immune surveillance due to lack of cancer cells surface membrane expression of tumor-specific peptides in association with MHC class I molecules, concealment of natural killer cells-activating molecules, and absence of inflammation resulting from inefficient stimulation of innate immunity receptors and co-stimulatory molecules. The tumor microenvironment (TME) also contributes to tumor initiation, progression and resistance to therapeutic interventions because of its dense, fibrogenic, barrier-like composition, aberrant vasculature, and production of cytokines and chemokines responsible for recruitment of immune suppressive cells, notably myeloid-derived suppressor cells, M2 macrophages, regulatory T cells, extracellular trap-forming neutrophils, and cancer-associated fibroblasts. We herein show that the relentless efforts and strategies to overcome the TME elusive tumor-promoting impact produced contrasting, opposed, controversial effects, characterized by limited efficacy and proven adversity, and most importantly deterred from attempts to discover and counteract the fundamental inherent mechanisms initiating, and not consequent to, carcinogenesis.

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Radiation-Induced Fibrosis in Patients with Head and Neck Cancer: A Review of Pathogenesis and Clinical Outcomes

Cited by 28 publications

References 84 publications

Quantitative Evaluation of the Reduced Capacity of Skeletal Muscle Hypertrophy after Total Body Irradiation in Relation to Stem/Progenitor Cells

Quantitative Evaluation of the Reduced Capacity of Skeletal Muscle Hypertrophy after Total Body Irradiation in Relation to Stem/Progenitor Cells

Associations between patient-reported late effects and systemic cytokines in long-term survivors of head and neck cancer treated with radiotherapy

The Stroma and Tumor Microenvironment Are Not the Most Instrumental Players in Tumor Cells Immune Evasion, Growth, and Resistance to Therapy

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