Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients

Heijden, Martijn van der; Jong, Monique C. de; Verhagen, Caroline V.M.; Roest, Reinout H. de; Sanduleanu, Sebastian; Hoebers, Frank; Leemans, C. René; Brakenhoff, Ruud H.; Vens, Conchita; Verheij, Marcel; Brekel, Michiel W. M. van den

doi:10.3390/cancers11040583

Cited by 15 publications

(18 citation statements)

References 48 publications

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“…The comparison of LRC with DM further helped to discern a more radiation response specific role from a role in metastasis. Our data here and those reported by us and others do indeed confirm the role of hypoxia in determining radiation response as reflected by the LRC rates (25,27,29). In addition, hypoxia has been also implicated in tumor cell invasiveness, facilitating dissemination, and has been therefore associated with metastasis formation, a role that is also evident from our DM analyses.…”

Section: Discussionsupporting

confidence: 90%

“…Within their own category, stem cell related markers, CD44 and SLC3A2 (r = 0.57, p < 0.001), and the immune cell related markers correlate with each other. While the correlation of acute and chronic hypoxia is significant, it is fairly weak (R = 0.26, p < 0.001) and was in line with previous reports (29). EGFR expression and the proliferation score are correlated to some extent (r = 0.26, p < 0.01).…”

Section: Tumor Biology Assessment and (In)dependence In Hpv-negative supporting

confidence: 91%

“…Confirming its role above marking poor prognosis patients, hypoxia biomarkers also predict response to hypoxia modification therapy (25,(30)(31)(32)(33). Elaborating on a gene expression profile that captures the cellular changes caused by acute hypoxia, we recently showed the relevance of acute hypoxia in addition to chronic hypoxia (29). As predicted by the process they capture, these two classifications did not necessarily overlap in the samples and also reveal different outcome associations in HNSCC that result from a prominent role of acute hypoxia.…”

Section: Introductionmentioning

confidence: 72%

“…HPV and hypoxia are indeed the best studied biology related prognostic markers in HNSCC. Within the HPVnegative patients, tumor hypoxia marks patients with a poor prognosis (25)(26)(27)(28)(29). Confirming its role above marking poor prognosis patients, hypoxia biomarkers also predict response to hypoxia modification therapy (25,(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 85%

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Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8 + T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). van der Heijden et al. HNSCC Biology Impacting Chemo-Radiotherapy Outcomes Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8 + T-cells: HR = 2.2, p < 0.05; CD8 + T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8 + Tcell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.

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Section: Discussionsupporting

confidence: 90%

Section: Tumor Biology Assessment and (In)dependence In Hpv-negative supporting

confidence: 91%

Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 85%

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Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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“…Several studies have aimed at comparing the published gene signatures (126)(127)(128)(129), but with the constraint that common analyzing methods have been used, such as the two-class k-means clustering, and not the validated analysis method, which for some of the gene signatures include cutoff values.…”

Section: Molecular Hypoxia Biomarkersmentioning

confidence: 99%

Tumor Hypoxia: Impact on Radiation Therapy and Molecular Pathways

2020

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Tumor hypoxia is a common feature of the microenvironment in solid tumors, primarily due to an inadequate, and heterogeneous vascular network. It is associated with resistance to radiotherapy and results in a poorer clinical outcome. The presence of hypoxia in tumors can be identified by various invasive and non-invasive techniques, and there are a number of approaches by which hypoxia can be modified to improve outcome. However, despite these factors and the ongoing extensive pre-clinical studies, the clinical focus on hypoxia is still to a large extent lacking. Hypoxia is a major cellular stress factor and affects a wide range of molecular pathways, and further understanding of the molecular processes involved may lead to greater clinical applicability of hypoxic modifiers. This review is a discussion of the characteristics of tumor hypoxia, hypoxia-related molecular pathways, and the role of hypoxia in treatment resistance. Understanding the molecular aspects of hypoxia will improve our ability to clinically monitor hypoxia and to predict and modify the therapeutic response.

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Hypoxia‐induced SENP3 promotes chemosensitivity and mitochondrial fission via deSUMOylation of Drp1

Mao,

Liu,

Yang

et al. 2024

Head & Neck

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ObjectiveThe study aimed to investigate the effect of the SUMOylation status of Drp1 on mitochondrial fission in CDDP‐treated HNSCC cells cultured under hypoxic conditions.Materials and methodsThe effect of hypoxia on the chemosensitivity of HNCC cells was evaluated by flow cytometry and CCK‐8 assays. The biological function of SUMO‐specific peptidase 3 (SENP3) was evaluated by loss‐of‐function assays both in vitro and in vivo. SENP3‐regulated deSUMOylation of Drp1 were performed with co‐IP assays.ResultsSENP3 expression correlated with chemosensitivity in clinical HNSCC samples subjected to hypoxic conditions. Hypoxia‐induced ROS increased HIF‐1α/SENP3 expression and mitochondrial fission in CDDP‐treated HNSCC cells, and these effects were reversed by NAC treatment. SENP3 knockdown reversed hypoxia‐induced mitochondrial fission and inhibited HNSCC cell apoptosis, which decreased CDDP sensitivity. Furthermore, hypoxia‐induced SENP3 deconjugated SUMO2 from Drp1.ConclusionOur findings revealed that hypoxia‐induced SENP3 facilitates CDDP sensitivity and mitochondrial fission via deSUMOylation of Drp1.

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Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients

Cited by 15 publications

References 48 publications

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Tumor Hypoxia: Impact on Radiation Therapy and Molecular Pathways

Hypoxia‐induced SENP3 promotes chemosensitivity and mitochondrial fission via deSUMOylation of Drp1

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