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Guo R, Zhang WW, Lv J, Lin JY, Xu C, Li J, Wu YL, Zhang XM, Tang LL, Sun Y, Ma J. Long-term Outcomes Following Individualized Primary Tumor Clinical Target Volume Delineation Based on Stepwise Spread Patterns of Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy. Int J Radiat Oncol Biol Phys 2025; 122:126-139. [PMID: 39701547 DOI: 10.1016/j.ijrobp.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 12/02/2024] [Accepted: 12/10/2024] [Indexed: 12/21/2024]
Abstract
PURPOSE Our institution has developed an individualized elective primary tumor clinical target volume (CTVp) delineation protocol for nasopharyngeal carcinoma (NPC) based on stepwise tumor spread patterns in intensity modulated radiation therapy for over 10 years. Herein, we report the long-term efficacy and toxicities in patients with NPC treated under this protocol. METHODS AND MATERIALS A total of 7262 patients with histologically proven nonmetastatic NPC treated with intensity modulated radiation therapy following this individualized delineation protocol were retrospectively evaluated. Survival rates were estimated using the Kaplan-Meier method. Dose-volume histogram parameters for patients with local relapse were compared with those of propensity score-matched without local relapse. Dosimetric comparisons of our delineation protocol with the 2018 International Guideline (2018-IG) were conducted on representative early- and advanced-stage NPC cases. RESULTS The 5-year local relapse-free survival, regional relapse-free survival, distant metastasis-free survival, progression-free survival, and overall survival were 93.6%, 94.4%, 86.8%, 77.8%, and 86.0%, respectively. 92.3% of local relapses and 86.0% of regional relapses occurred within the 95% isodose lines and were considered in-field failures. No significant differences in dose-volume histogram parameters were observed between the local relapse group and the propensity score-matched nonrelapse group. Compared with the 2018-IG, our contouring protocol resulted in a 58.4% and 48.3% reduction in PTV70, and an 80.8% and 62.8% reduction in PTV60 for early and advanced-stage diseases, respectively. Late grade 3 toxicities included ototoxicity (1.8%), xerostomia (0.2%), dysphagia (0.2%), temporal lobe injury (0.2%), and trismus (0.1%). CONCLUSIONS Individualized elective CTVp delineation based on the stepwise spread patterns of nasopharyngeal carcinoma achieved excellent long-term outcomes and reduced the irradiated volumes at equivalent dose levels compared with the 2018-IG.
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Affiliation(s)
- Rui Guo
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Wei-Wei Zhang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Jiawei Lv
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Jia-Yi Lin
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Cheng Xu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Jing Li
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Yan-Ling Wu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Xiao-Min Zhang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Ling-Long Tang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Ying Sun
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China
| | - Jun Ma
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, People's Republic of China.
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Di Giovannantonio M, Hartley F, Elshenawy B, Barberis A, Hudson D, Shafique HS, Allott VES, Harris DA, Lord SR, Haider S, Harris AL, Buffa FM, Harris BHL. Defining hypoxia in cancer: A landmark evaluation of hypoxia gene expression signatures. CELL GENOMICS 2025; 5:100764. [PMID: 39892389 PMCID: PMC11872601 DOI: 10.1016/j.xgen.2025.100764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/04/2024] [Accepted: 01/07/2025] [Indexed: 02/03/2025]
Abstract
Tumor hypoxia drives metabolic shifts, cancer progression, and therapeutic resistance. Challenges in quantifying hypoxia have hindered the exploitation of this potential "Achilles' heel." While gene expression signatures have shown promise as surrogate measures of hypoxia, signature usage is heterogeneous and debated. Here, we present a systematic pan-cancer evaluation of 70 hypoxia signatures and 14 summary scores in 104 cell lines and 5,407 tumor samples using 472 million length-matched random gene signatures. Signature and score choice strongly influenced the prediction of hypoxia in vitro and in vivo. In cell lines, the Tardon signature was highly accurate in both bulk and single-cell data (94% accuracy, interquartile mean). In tumors, the Buffa and Ragnum signatures demonstrated superior performance, with Buffa/mean and Ragnum/interquartile mean emerging as the most promising for prospective clinical trials. This work delivers recommendations for experimental hypoxia detection and patient stratification for hypoxia-targeting therapies, alongside a generalizable framework for signature evaluation.
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Affiliation(s)
- Matteo Di Giovannantonio
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Fiona Hartley
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Badran Elshenawy
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Alessandro Barberis
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Dan Hudson
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK; The Rosalind Franklin Institute, Didcot, UK
| | | | | | | | - Simon R Lord
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Syed Haider
- Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
| | - Adrian L Harris
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Francesca M Buffa
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK; CompBio Lab, Department of Computing Sciences, Bocconi University, Milan, Italy; AI and Systems Biology Lab, IFOM - Istituto Fondazione di Oncologia Molecolare ETS, Milan, Italy.
| | - Benjamin H L Harris
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK; St. Catherine's College, University of Oxford, Oxford, UK; Cutrale Perioperative and Ageing Group, Imperial College London, London, UK.
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Anderson RF, Qi W. Coenzyme Q 10 as an Inhibitor of Effector Release from One-Electron-Reduced Bioreductive Anticancer Prodrugs. Molecules 2025; 30:760. [PMID: 40005071 PMCID: PMC11858625 DOI: 10.3390/molecules30040760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/10/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
The kinetic parameters for the release of anticancer effectors from the radical anions of prodrugs through fragmentation have been measured under conditions that model the interfacial region where the enzymatic reduction in the prodrugs takes place. While the back-oxidation of the radical anions via O2 mainly occurs under normoxia, preventing radical anion fragmentation, this is not the case for the lower concentrations of O2 found in hypoxic regions of tumors. Rate-constant data show that O2 concentrations known to bring about a 50% decrease in the level of cell kill arising from the prodrugs in anoxia (the K-value) do not significantly inhibit the fragmentation of radical anions. Evidence is put forward suggesting that radical anions can undergo an electron transfer to ubiquinone (CoQ10, UQ) in competition with the fragmentation of the radical anions releasing effectors. The prior inhibition of the synthesis of UQ in cells is put forward as a possible approach to increase the effectiveness of such prodrugs in killing hypoxic tumor cells.
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Affiliation(s)
- Robert F. Anderson
- Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
- School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Wen Qi
- School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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Wang F, Song L, Xu Q, Jia A, Meng X, Jiang H, Zhang R. Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis. Eur J Med Chem 2025; 283:117155. [PMID: 39657461 DOI: 10.1016/j.ejmech.2024.117155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/04/2024] [Accepted: 12/06/2024] [Indexed: 12/12/2024]
Abstract
Hypoxia is a common feature of various solid tumors, which reduces the sensitivity of tumor cells to both radiotherapy and chemotherapy. However, hypoxia also presents an opportunity for tumor-selective therapy. The prodrug strategy, leveraging the hypoxic nature of the tumor microenvironment, shows significant potential for clinical application. Here we present CHD-1, a hypoxia-activated antitumor prodrug that activates in hypoxic environments, effectively inhibiting hypoxic tumor cells while exhibiting no toxicity to normoxic cells. CHD-1 impairs mitochondrial morphology and membrane potential of hypoxic tumor cells, further triggers excessive mitophagy and induces apoptosis. Moreover, prodrug CHD-1 significantly inhibits HeLa xenograft growth in vivo, and shows lower toxicity than parent molecule in an acute toxicity assessment in animal models. This study introduces a promising hypoxia-activated antitumor prodrug with strong potential for further development in hypoxic tumor therapy.
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Affiliation(s)
- Fangjie Wang
- Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou, Henan, 450018, China
| | - Lairong Song
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100071, China
| | - Qianqian Xu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China
| | - Ang Jia
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Xiangwei Meng
- Department of Drug Clinical Trials, Zibo Central Hospital, Zibo, 255036, China.
| | - Hongfei Jiang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.
| | - Renshuai Zhang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.
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Eggert D, Gaertner D, Rühm A, Sroka R, Arens C, Davaris N, Birkmeier K, Brodschelm A, Leisching P, Studier H, Becker W, König K, Betz CS. Differentiation of Tumors of the Upper Respiratory Tract Using Optical Metabolic Imaging. Lasers Surg Med 2025; 57:147-153. [PMID: 39682026 PMCID: PMC11844726 DOI: 10.1002/lsm.23870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 10/26/2024] [Accepted: 11/29/2024] [Indexed: 12/18/2024]
Abstract
OBJECTIVES With over 184,000 new cases and more than 99,000 deaths per year, malignancies of the larynx are a global health problem. Currently, a dedicated screening method enabling a direct onsite diagnosis is missing. This can lead to delayed diagnosis and worse outcomes of the patients. An endoscopic optical method enabling a direct distinction between healthy tissue, dysplastic tissue and cancerous tissue would be an ideal tool for the detection of tumors of the upper aerodigestive tract (UADT). Healthy and tumor cells differ significantly in their metabolic state due to the different metabolic pathways they use (more oxidative phosphorylation in healthy cells, more glycolysis in tumor cells). Optical metabolic imaging (OMI) measuring relative intracellular concentration of NAD(P)H and FAD redox pairs could be a promising approach for early tumor detection and differentiation of suspicious mucosal lesions. METHODS In this study, a specially designed endoscopic two-beam two-photon fluorescence lifetime imaging (FLIM) system was used to perform two-photon two-beam FLIM of NAD(P)H and FAD to image the metabolic state in different tissue samples of the UADT. FLIM data sets of 27 tissue samples from 16 patients were recorded directly after surgery ex vivo in a special tissue culture medium at 37°C on a dedicated microscope using multiphoton excitation. RESULTS Based on the FLIM measurements of NAD(P)H and FAD, six of the most common indices for the characterization of the cells' metabolism were calculated. Three of them, the ratio of the exponential coefficients (amplitudes) of the short and long lifetime components both for NAD(P)H and FAD (NAD(P)H a1/a2 ratio and FAD a1/a2 ratio) and the fluorescence lifetime redox ratio (FLIRR) enabled differentiation between healthy tissue, benign lesions, dysplastic tissue, and cancer tissue with statistical significance. CONCLUSIONS We showed by measurements on freshly collected tissue samples that mucosal lesions of the UADT can be differentiated using our newly designed endoscopic FLIM device. In vivo measurements in healthy volunteers were also possible. By means of this technology, differentiation of cancerous, pre-cancerous, and healthy tissue in the UADT by OMI could be possible. Of six indices used to characterize cell metabolism we calculated, the FLIRR showed the most significant differences between tissue types.
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Affiliation(s)
- Dennis Eggert
- Clinic and Polyclinic for Otolaryngology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - David Gaertner
- Clinic and Polyclinic for Otolaryngology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Adrian Rühm
- Department of UrologyLaser‐Forschungslabor, LIFE Center, University HospitalPlaneggGermany
| | - Ronald Sroka
- Department of UrologyLaser‐Forschungslabor, LIFE Center, University HospitalPlaneggGermany
| | - Christoph Arens
- University Clinic of Otolaryngology, Head and Neck SurgeryOtto von Guericke University MagdeburgMagdeburgGermany
- Clinic for Otolaryngology, University Hospital of Giessen and MarburgBaldingerstraßeGermany
| | - Nikolaos Davaris
- University Clinic of Otolaryngology, Head and Neck SurgeryOtto von Guericke University MagdeburgMagdeburgGermany
- Clinic for Otolaryngology, University Hospital of Giessen and MarburgBaldingerstraßeGermany
| | | | | | - Patrick Leisching
- TOPTICA Photonics AG Lochhamer SchlagGräfelfingGermany
- iThera Medical GmbHMünchenGermany
| | | | | | | | - Christan S. Betz
- Clinic and Polyclinic for Otolaryngology, University Medical Center Hamburg‐EppendorfHamburgGermany
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6
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Liao YH, Chen YF, Hsieh MS, Lin MC, Wang CW, Wang CP, Lou PJ, Chen TC. The Prognostic Importance of Radiologic Extranodal Extension in Hypopharyngeal Carcinoma. Head Neck 2025; 47:667-678. [PMID: 39497264 DOI: 10.1002/hed.27978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 09/10/2024] [Accepted: 10/14/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Extranodal extension (ENE) had been included in the latest cancer staging system in hypopharyngeal squamous cell carcinoma (HypoSCC). However, the impact of ENE on HypoSCC survival and treatment outcomes are still unclear. METHODS Records from all HypoSCC patients diagnosed at the National Taiwan University Hospital from January 2007 to December 2018 were reviewed. All patients were divided into two groups, with or without ENE. Clinical features, pathological factors, and survival rates between the two groups were reviewed. RESULTS We analyzed data from 388 HypoSCC patients, 125 (32.22%) with and 263 (67.78%) without ENE. The 5-year overall survival of the HypoSCC patients with radiological ENE, pathological ENE, and without ENE were 22.9%, 40.3%, and 55.5%. From the multivariate analysis, primary T3/T4 classification (p = 0.001) and radiological ENE (p < 0.001) were independent risk factors for disease-free and overall survival (OS). Finally, upfront neck dissection may significantly benefit disease-free survival (DFS) and neck nodal control in ENE+ (p = 0.002 and p = 0.007, respectively) or ENE- patients (p = 0.003 and p = 0.02, respectively). CONCLUSION More than one-third of HypoSCC patients have ENE, with significantly lower OS and DFS. The upfront neck dissection could provide better DFS and neck nodal control.
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Affiliation(s)
- Yu-Hao Liao
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ya-Fang Chen
- Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Min-Shu Hsieh
- Department of Pathology, National Taiwan University Hospital, National Taiwan University Cancer Center and National Taiwan University College of Medicine Taipei, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Mei-Chun Lin
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Wei Wang
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Cheng-Ping Wang
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jen Lou
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tseng-Cheng Chen
- Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Menozzi L, Vu T, Canning AJ, Rawtani H, Taboada C, Abi Antoun ME, Ma C, Delia J, Nguyen VT, Cho SW, Chen J, Charity T, Xu Y, Tran P, Xia J, Palmer GM, Vo-Dinh T, Feng L, Yao J. Three-dimensional diffractive acoustic tomography. Nat Commun 2025; 16:1149. [PMID: 39880853 PMCID: PMC11779832 DOI: 10.1038/s41467-025-56435-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 01/20/2025] [Indexed: 01/31/2025] Open
Abstract
Acoustically probing biological tissues with light or sound, photoacoustic and ultrasound imaging can provide anatomical, functional, and/or molecular information at depths far beyond the optical diffusion limit. However, most photoacoustic and ultrasound imaging systems rely on linear-array transducers with elevational focusing and are limited to two-dimensional imaging with anisotropic resolutions. Here, we present three-dimensional diffractive acoustic tomography (3D-DAT), which uses an off-the-shelf linear-array transducer with single-slit acoustic diffraction. Without jeopardizing its accessibility by general users, 3D-DAT has achieved simultaneous 3D photoacoustic and ultrasound imaging with optimal imaging performance in deep tissues, providing near-isotropic resolutions, high imaging speed, and a large field-of-view, as well as enhanced quantitative accuracy and detection sensitivity. Moreover, powered by the fast focal line volumetric reconstruction, 3D-DAT has achieved 50-fold faster reconstruction times than traditional photoacoustic imaging reconstruction. Using 3D-DAT on small animal models, we mapped the distribution of the biliverdin-binding serpin complex in glassfrogs, tracked gold nanoparticle accumulation in a mouse tumor model, imaged genetically-encoded photoswitchable tumors, and investigated polyfluoroalkyl substances exposure on developing embryos. With its enhanced imaging performance and high accessibility, 3D-DAT may find broad applications in fundamental life sciences and biomedical research.
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Affiliation(s)
- Luca Menozzi
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Tri Vu
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Aidan J Canning
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | | | - Carlos Taboada
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | | | - Chenshuo Ma
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Jesse Delia
- American Museum of Natural History, New York City, New York, USA
| | - Van Tu Nguyen
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Soon-Woo Cho
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Jianing Chen
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Theresa Charity
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, 27710, USA
- Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Yirui Xu
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Phuong Tran
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
- Department of Biomedical Engineering, North Carolina State University, Raleigh, NC, USA
| | - Jun Xia
- Department of Biomedical Engineering, University at Buffalo, Buffalo, New York, USA
| | - Gregory M Palmer
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, 27710, USA
- Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Tuan Vo-Dinh
- Department of Biomedical Engineering, Duke University, Durham, NC, USA.
- Department of Chemistry, Duke University, Durham, NC, 27708, USA.
| | - Liping Feng
- Duke University School of Medicine, Durham, NC, USA.
| | - Junjie Yao
- Department of Biomedical Engineering, Duke University, Durham, NC, USA.
- Department of Neurology, Duke University of School of Medicine, Durham, NC, 27710, USA.
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Qing L, Li Q, Yang Y, Xu W, Wang Y, Li R, You C, Dong Z. Hypoxia-mediated attenuation of EGLN2 inhibition of the NF-κB signaling pathway leads to the formation of a loop between HIF-1α and MUC1-C promoting chemoresistance in bladder cancer. Mol Carcinog 2024; 63:1303-1318. [PMID: 38634741 DOI: 10.1002/mc.23725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/30/2024] [Accepted: 03/29/2024] [Indexed: 04/19/2024]
Abstract
The expression pattern of MUC1-C in tumors is closely linked to tumor progression; however, its specific mechanism remains unclear. The expression of MUC1-C in cancer and adjacent normal tissues was detected using immunohistochemistry and Western blot. The IC50 of cells to gemcitabine was determined using the CCK8 assay. The effects of hypoxia and MUC1-C on the behavioral and metabolic characteristics of bladder cancer cells were investigated. Gene expression was assessed through Western blot and polymerase chain reaction. The relationship between the genes was analyzed by co-immunoprecipitation, immunofluorescence and Western blot. Finally, the role of the EGLN2 and NF-κB signaling pathways in the interaction between MUC1-C and hypoxia-inducible factor-1α (HIF-1α) was investigated. MUC1-C expression is significantly higher in bladder cancer tissues than in adjacent normal tissues, particularly in large-volume tumors, and is closely correlated with clinical features such as tumor grade. Tumor volume-mediated hypoxia resulted in increased expression of MUC1-C and HIF-1α in bladder cancer cells. Under stimulation of hypoxia, the inhibitory effect of EGLN2 on the NF-κB signaling pathway was weakened, allowing NF-κB to promote the positive feedback formation of MUC1-C and HIF-1α. Simultaneously, EGLN2-mediated degradation of HIF-1α was reduced. This ultimately led to elevated HIF-1α-mediated downstream gene expression, promoting increased glucose uptake and glycolysis, and ultimately resulting in heightened chemotherapy resistance and malignancy.
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Affiliation(s)
- Liangliang Qing
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Qingchao Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yongjin Yang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Wenbo Xu
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yanan Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Rongxing Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Chengyu You
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Zhilong Dong
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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9
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Makanai H, Kanda M, Harada S, Nishihara T, Tanabe K. Tracking and recording of intracellular oxygen concentration changes in cell organelles: preparation and function of azide-modified fluorescent probes. RSC Adv 2024; 14:19586-19591. [PMID: 38895527 PMCID: PMC11184654 DOI: 10.1039/d4ra01625d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/07/2024] [Indexed: 06/21/2024] Open
Abstract
Tracking hypoxic environments and changes in oxygen levels contribute to the elucidation of pathological mechanisms. In this study, we attempted to design molecular probes that can be activated to show fluorescence under hypoxic conditions and that can move to specific cell organelles. Considering that azide groups were selectively reduced to primary amines by reductases under hypoxic conditions, we prepared Hoechst and fluorophore Cy-5 derivatives with azide groups (Hoechst-N3 and Cy-N3) as hypoxia probes. Hoechst-N3 and Cy-N3 showed weak fluorescence, but once activated in the cytosol of hypoxic cells, they exhibited robust fluorescence and then moved to their target organelles, the cell nucleus and mitochondria. In addition, when these probes were administered to the cells in the proper sequence, each probe was activated in response to the intracellular oxygen concentration at that point and exhibited oxygen concentration-dependent fluorescence at the target organelle. By measuring the fluorescence intensity of the cell nucleus and mitochondria, we successfully traced the history of changes in intracellular oxygen levels. Thus, we achieved tracking and recording of oxygen status in the cells.
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Affiliation(s)
- Hiroki Makanai
- Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University 5-10-1 Fuchinobe, Chuo-ku Sagamihara 252-5258 Japan
| | - Miei Kanda
- Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University 5-10-1 Fuchinobe, Chuo-ku Sagamihara 252-5258 Japan
| | - Sae Harada
- Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University 5-10-1 Fuchinobe, Chuo-ku Sagamihara 252-5258 Japan
| | - Tatsuya Nishihara
- Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University 5-10-1 Fuchinobe, Chuo-ku Sagamihara 252-5258 Japan
| | - Kazuhito Tanabe
- Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University 5-10-1 Fuchinobe, Chuo-ku Sagamihara 252-5258 Japan
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10
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Koganemaru S, Fuchigami H, Yamashita H, Morizono C, Sunakawa H, Kawazoe A, Nakamura Y, Kuboki Y, Shitara K, Yano T, Doi T, Yasunaga M. Quantitative Analysis of the Concentration of Trifluridine in Tumor Hypoxic Regions Using a Novel Platform Combining Functional Endoscopy and Mass Spectrometry. Clin Pharmacol Ther 2024; 115:62-70. [PMID: 37803526 DOI: 10.1002/cpt.3066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 09/22/2023] [Indexed: 10/08/2023]
Abstract
Hypoxic regions in solid tumors are highly resistant to drugs and thus represents an obstacle in drug discovery. Currently, however, there are technical barriers in sampling human hypoxic tumors and examining drug delivery with high sensitivity and accuracy. Herein, we present a new platform combining functional endoscopy and highly sensitive liquid chromatography-mass spectrometry (LC-MS) to assess drug delivery to hypoxic regions. Because oxygen saturation endoscopic imaging (OXEI), a functional endoscopy, can evaluate lesions and hypoxia in real-time by simultaneously acquiring a pseudocolor map of oxygen saturation and conventional endoscopic images, this platform can be used to evaluate drug delivery with human samples from hypoxic regions. As the first clinical application of this platform, the relationship between hypoxic regions and the concentration of trifluridine (FTD) incorporated into DNA was evaluated in patients with advanced gastric cancer treated with FTD/tipiracil (FTD/TPI; n = 13) by obtaining and analysis of tissue samples by OXEI and LC-MS and vascular maturity index by CD31/α-SMA staining ex vivo. The results showed that the concentration of FTD was significantly higher in the normoxic region than in the hypoxic region (P < 0.05) and there were significantly more immature vessels in hypoxic regions than in normoxic regions (P < 0.05). These results indicate that the platform was sufficiently sensitive to evaluate differences in drug anabolism in different oxygenic regions of human tumor tissue. This new platform allows quantitative drug analysis in hypoxic regions and is expected to initiate a new era of drug discovery and development.
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Affiliation(s)
- Shigehiro Koganemaru
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hirobumi Fuchigami
- Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Hiroki Yamashita
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Chihiro Morizono
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
- Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Hironori Sunakawa
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yasutoshi Kuboki
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tomonori Yano
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan
| | - Toshihiko Doi
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masahiro Yasunaga
- Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
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11
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Beckers C, Pruschy M, Vetrugno I. Tumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities. Semin Cancer Biol 2024; 98:19-30. [PMID: 38040401 DOI: 10.1016/j.semcancer.2023.11.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 12/03/2023]
Abstract
Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute to a reduced sensitivity of hypoxic tumor cells to ionizing radiation and hypoxia-related treatment resistances. A conventional low-dose fractionated radiotherapy regimen exploits iterative reoxygenation in between the individual fractions, nevertheless tumor hypoxia still remains a major hurdle for successful treatment outcome. The technological advances achieved in image guidance and highly conformal dose delivery make it nowadays possible to prescribe larger doses to the tumor as part of single high-dose or hypofractionated radiotherapy, while keeping an acceptable level of normal tissue complication in the co-irradiated organs at risk. However, we insufficiently understand the impact of tumor hypoxia to single high-doses of RT and hypofractionated RT. So-called FLASH radiotherapy, which delivers ionizing radiation at ultrahigh dose rates (> 40 Gy/sec), has recently emerged as an important breakthrough in the radiotherapy field to reduce normal tissue toxicity compared to irradiation at conventional dose rates (few Gy/min). Not surprisingly, oxygen consumption and tumor hypoxia also seem to play an intriguing role for FLASH radiotherapy. Here we will discuss the role of tumor hypoxia for radiotherapy in general and in the context of novel radiotherapy treatment approaches.
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Affiliation(s)
- Claire Beckers
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Martin Pruschy
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
| | - Irene Vetrugno
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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12
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Koi L, Bitto V, Weise C, Möbius L, Linge A, Löck S, Yaromina A, Besso MJ, Valentini C, Pfeifer M, Overgaard J, Zips D, Kurth I, Krause M, Baumann M. Prognostic biomarkers for the response to the radiosensitizer nimorazole combined with RCTx: a pre-clinical trial in HNSCC xenografts. J Transl Med 2023; 21:576. [PMID: 37633930 PMCID: PMC10464469 DOI: 10.1186/s12967-023-04439-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/14/2023] [Indexed: 08/28/2023] Open
Abstract
BACKGROUND Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use. METHODS Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined. RESULTS Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC. CONCLUSIONS Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC.
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Affiliation(s)
- Lydia Koi
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
| | - Verena Bitto
- Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Division of Radiooncology / Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- HIDSS4Health - Helmholtz Information and Data Science School for Health, Karlsruhe/Heidelberg, Germany.
| | - Corina Weise
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Lisa Möbius
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Annett Linge
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
| | - Steffen Löck
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
| | - Ala Yaromina
- The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
| | - María José Besso
- Division of Radiooncology / Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Chiara Valentini
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Manuel Pfeifer
- Institute of Legal Medicine, Medizinische Fakultät, Technische Universität Dresden, Dresden, Germany
| | - Jens Overgaard
- Department of Radiation Oncology, University Hospital Aarhus, Aarhus, Denmark
| | - Daniel Zips
- Corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Department of Radiation Oncology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ina Kurth
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Division of Radiooncology / Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mechthild Krause
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany
| | - Michael Baumann
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, Helmholtz-Zentrum Dresden - Rossendorf, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Division of Radiooncology / Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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13
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Hu M, Coleman S, Fadlullah MZH, Spakowicz D, Chung CH, Tan AC. Deciphering the Tumor-Immune-Microbe Interactions in HPV-Negative Head and Neck Cancer. Genes (Basel) 2023; 14:1599. [PMID: 37628651 PMCID: PMC10454300 DOI: 10.3390/genes14081599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/01/2023] [Accepted: 08/06/2023] [Indexed: 08/27/2023] Open
Abstract
Patients with human papillomavirus-negative head and neck squamous cell carcinoma (HPV-negative HNSCC) have worse outcomes than HPV-positive HNSCC. In our study, we used a published dataset and investigated the microbes enriched in molecularly classified tumor groups. We showed that microbial signatures could distinguish Hypoxia/Immune phenotypes similar to the gene expression signatures. Furthermore, we identified three highly-correlated microbes with immune processes that are crucial for immunotherapy response. The survival of patients in a molecularly heterogenous group shows significant differences based on the co-abundance of the three microbes. Overall, we present evidence that tumor-associated microbiota are critical components of the tumor ecosystem that may impact tumor microenvironment and immunotherapy response. The results of our study warrant future investigation to experimentally validate the conclusions, which have significant impacts on clinical decision-making, such as treatment selection.
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Affiliation(s)
- Min Hu
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (M.H.); (S.C.); (M.Z.H.F.)
| | - Samuel Coleman
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (M.H.); (S.C.); (M.Z.H.F.)
| | | | - Daniel Spakowicz
- Pelotonia Institute for Immuno-Oncology and Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA;
| | - Christine H. Chung
- Department of Head and Neck Endocrine Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Aik Choon Tan
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; (M.H.); (S.C.); (M.Z.H.F.)
- Department of Biomedical Informatics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
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14
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Liew LP, Shome A, Wong WW, Hong CR, Hicks KO, Jamieson SMF, Hay MP. Design, Synthesis and Anticancer Evaluation of Nitroimidazole Radiosensitisers. Molecules 2023; 28:molecules28114457. [PMID: 37298933 DOI: 10.3390/molecules28114457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/29/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition.
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Affiliation(s)
- Lydia P Liew
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
| | - Avik Shome
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland 1023, New Zealand
- Department of Ophthalmology, The University of Auckland, Auckland 1023, New Zealand
| | - Way W Wong
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland 1023, New Zealand
| | - Cho R Hong
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
| | - Kevin O Hicks
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
| | - Stephen M F Jamieson
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
- Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland 1023, New Zealand
| | - Michael P Hay
- Auckland Cancer Society Research Centre, The University of Auckland, Auckland 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
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15
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Jandick NA, Kirner N, Miller CL. Mammalian orthoreovirus infection in human epidermal growth factor receptor 2 positive (HER2+) breast cancer cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.10.540250. [PMID: 37214868 PMCID: PMC10197616 DOI: 10.1101/2023.05.10.540250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Mammalian orthoreovirus (MRV) is a clinically benign oncolytic virus which has been investigated for use in multiple cancer types, including breast cancer (BC). In human clinical trials, MRV has been shown to be safe, and multiple BC patients have shown partial responses to intratumoral and intravenous virus delivery. Combination therapies inclusive of MRV and current FDA approved BC chemotherapies are being investigated to target metastatic, early BC, and triple negative BC. Though MRV is being tested clinically, we still do not fully understand the highly variable patient responses to MRV therapy. One of the most aggressive BC subtypes is HER2+ BC, in which human epidermal growth factor receptor 2 (HER2) is dysregulated, resulting in increased growth, survival, and metastasis of cancer cells. FDA approved therapies, trastuzumab and pertuzumab, target HER2 to prevent signaling of the phosphoinositide 3-kinase (PI3K) pathway. However, recent findings show that accumulation of hypoxia inducible factor-1 alpha (HIF-1α) in HER2+ BC cells contributes to trastuzumab resistance. In this work, we provide evidence that MRV infects, replicates in, and kills HER2 overexpressing cells. MRV infection is also found to have variable effects on signaling pathways that activate or are activated by HER2 expression. Finally, we show that MRV reduces HIF-1α accumulation in all the cell lines tested, including a HER2+ BC cell line. These studies provide further evidence that MRV holds promise for use in conjunction with trastuzumab to treat HER2+ BC patients.
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16
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Lacerda Q, Falatah H, Liu JB, Wessner CE, Oeffinger B, Rochani A, Leeper DB, Forsberg F, Curry JM, Kaushal G, Keith SW, O'Kane P, Wheatley MA, Eisenbrey JR. Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer. Pharmaceutics 2023; 15:pharmaceutics15041302. [PMID: 37111787 PMCID: PMC10145368 DOI: 10.3390/pharmaceutics15041302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/10/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O2 and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O2 and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation.
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Affiliation(s)
- Quezia Lacerda
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
- School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA 19104, USA
| | - Hebah Falatah
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
- School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA 19104, USA
- College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 22384, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah 22384, Saudi Arabia
| | - Ji-Bin Liu
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Corinne E Wessner
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
- School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA 19104, USA
| | - Brian Oeffinger
- School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA 19104, USA
| | - Ankit Rochani
- Department of Pharmaceutical Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Pharmaceutical Sciences, Wegmans School of Pharmacy, St. John Fisher University, Rochester, NY 14618, USA
| | - Dennis B Leeper
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Flemming Forsberg
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Joseph M Curry
- Department of Otolaryngology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Gagan Kaushal
- Department of Pharmaceutical Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Scott W Keith
- Division of Biostatistics, Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Patrick O'Kane
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Margaret A Wheatley
- School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA 19104, USA
| | - John R Eisenbrey
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
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17
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Toledo RA, Jimenez C, Armaiz-Pena G, Arenillas C, Capdevila J, Dahia PLM. Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia. Endocr Rev 2023; 44:312-322. [PMID: 36301191 DOI: 10.1210/endrev/bnac025] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 09/01/2022] [Indexed: 11/19/2022]
Abstract
Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel-Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.
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Affiliation(s)
- Rodrigo A Toledo
- Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
| | - Camilo Jimenez
- Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gustavo Armaiz-Pena
- Department of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Carlota Arenillas
- Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
| | - Jaume Capdevila
- Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Medical Oncology Department, Gastrointestinal and Endocrine Tumor Unit, Vall d'Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), IOB Quiron-Teknon, 08035 Barcelona, Spain
| | - Patricia L M Dahia
- Department of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
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Inada M, Nishimura Y, Hanaoka K, Nakamatsu K, Doi H, Uehara T, Komanishi M, Ishii K, Kaida H, Hosono M. Visualization of tumor hypoxia and re-oxygenation after stereotactic body radiation therapy in early peripheral lung cancer: A prospective study. Radiother Oncol 2023; 180:109491. [PMID: 36706956 DOI: 10.1016/j.radonc.2023.109491] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/11/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND PURPOSE In this study, fluoromisonidazole positron emission tomography (F-MISO PET/CT) was used to evaluate tumor hypoxia and re-oxygenation in patients with lung tumors treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS Patients with T1-2 N0 lung cancer were included in this study. The prescribed dose was 48-52 Gy in four fractions. F-MISO PET/CT was performed twice, before SBRT and 1-3 days after the first irradiation. The maximum standardized uptake value (SUVmax) and tumor/muscle ratio (TMR) were evaluated as indicators of hypoxia. The threshold for hypoxia was defined as a TMR of 1.30 or more. RESULTS Between 2016 and 2021, 15 patients were included. Pre-treatment tumor hypoxia was observed in nine tumors (60 %). TMR in all six tumors without pre-treatment hypoxia rose after single high-dose irradiation. In contrast, TMR in six of nine tumors with pre-treatment hypoxia dropped after irradiation, suggesting re-oxygenation. Although no local recurrence was noted, regional and/or distant relapses were seen in four patients (27 %). Of these, three had tumors with abnormal F-MISO uptake. The remaining patient had a tumor without signs of hypoxia on pre-treatment PET/CT. The 2-year progression free survival of patients with tumors with and without pre-treatment hypoxia were 30 % and 63 %, respectively (p = 0.319). CONCLUSION Tumor hypoxia reduced after single high-dose irradiation. Tumor with F-MISO uptake seems to be an unfavorable prognostic factor in lung SBRT.
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Affiliation(s)
- Masahiro Inada
- Departments of Radiation Oncology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan.
| | - Yasumasa Nishimura
- Departments of Radiation Oncology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Kohei Hanaoka
- Division of Positron Emission Tomography, Institute of Advanced Clinical Medicine, Kindai University, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Kiyoshi Nakamatsu
- Departments of Radiation Oncology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Hiroshi Doi
- Departments of Radiation Oncology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Takuya Uehara
- Departments of Radiation Oncology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Mikihito Komanishi
- Division of Positron Emission Tomography, Institute of Advanced Clinical Medicine, Kindai University, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Kazunari Ishii
- Departments of Radiology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Hayato Kaida
- Departments of Radiology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
| | - Makoto Hosono
- Departments of Radiation Oncology, Kindai University Faculty of Medicine, 377-2, Onohigashi, Osakasayama-city, Osaka, Japan
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Tomita N, Ishiyama H, Makita C, Ohshima Y, Nagai A, Baba F, Kuno M, Otsuka S, Kondo T, Sugie C, Kawai T, Takaoka T, Okazaki D, Torii A, Niwa M, Kita N, Takano S, Kawakami S, Matsuo M, Kumano T, Ito M, Adachi S, Abe S, Murao T, Hiwatashi A. Daily irradiation versus irradiation at two- to three-day intervals in stereotactic radiotherapy for patients with 1-5 brain metastases: study protocol for a multicenter open-label randomized phase II trial. BMC Cancer 2022; 22:1259. [PMID: 36471274 PMCID: PMC9720969 DOI: 10.1186/s12885-022-10371-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Radiobiological daily changes within tumors are considered to be quite different between stereotactic radiotherapy (SRT) (e.g., 50 Gy in 4 fractions) and conventional radiotherapy (e.g., 60 Gy in 30 fractions). We aim to assess the optimal interval of irradiation in SRT and compare outcomes of daily irradiation with irradiation at two- to three-day intervals in SRT for patients with one to five brain metastases (BM). METHODS This study is conducted as a multicenter open-label randomized phase II trial. Patients aged 20 or older with one to five BM, less than 3.0 cm diameter, and Karnofsky Performance Status ≥70 are eligible. A total of 70 eligible patients will be enrolled. After stratifying by the number of BMs (1, 2 vs. 3-5) and diameter of the largest tumor (< 2 cm vs. ≥ 2 cm), we randomly assigned patients (1:1) to receive daily irradiation (Arm 1), or irradiation at two- to three-day intervals (Arm 2). Both arms are performed with total dose of 27-30 Gy in 3 fractions. The primary endpoint is an intracranial local control rate, defined as intracranial local control at initially treated sites. We use a randomized phase II screening design with a two-sided α of 0∙20. The phase II trial is positive with p < 0.20. All analyses are intention to treat. This study is registered with the UMIN-clinical trials registry, number UMIN000048728. DISCUSSION This study will provide an assessment of the impact of SRT interval on local control, survival, and toxicity for patients with 1-5 BM. The trial is ongoing and is recruiting now. TRIAL REGISTRATION UMIN000048728. Date of registration: August 23, 2022. https://center6.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000055515 .
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Affiliation(s)
- Natsuo Tomita
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Hiromichi Ishiyama
- grid.410786.c0000 0000 9206 2938Department of Radiation Oncology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0329 Japan
| | - Chiyoko Makita
- grid.411704.7Department of Radiation Oncology, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Yukihiko Ohshima
- grid.411234.10000 0001 0727 1557Department of Radiology, Aichi Medical University, 1-1 Yazako-Karimata, Nagakute, Aichi 480-1195 Japan
| | - Aiko Nagai
- grid.260433.00000 0001 0728 1069Department of Radiation Oncology, Nagoya City University East Medical Center, 1-2-23 Wakamizu, Chikusa-ku, Nagoya, Aichi 464-8547 Japan
| | - Fumiya Baba
- grid.260433.00000 0001 0728 1069Department of Radiation Oncology, Nagoya City University West Medical Center, 1-1-1 Hirate-cho, Kita-ku, Nagoya, Aichi 462-8508 Japan
| | - Mayu Kuno
- Department of Radiation Oncology, Ichinomiya Municipal Hospital, 2-2-22 Bunkyo, Ichinomiya, Aichi 491-8558 Japan
| | - Shinya Otsuka
- grid.413724.70000 0004 0378 6598Department of Radiation Oncology, Okazaki City Hospital, 3-1 Goshoai, Koryuji-cho, Okazaki, Aichi 444-8553 Japan
| | - Takuhito Kondo
- grid.416417.10000 0004 0569 6780Department of Radiation Oncology, Nagoya Ekisaikai Hospital, 4-66 Syonen-cho, Nakagawa-ku, Nagoya, Aichi 454-8502 Japan
| | - Chikao Sugie
- Department of Radiation Oncology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi 466-8650 Japan
| | - Tatsuya Kawai
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Taiki Takaoka
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Dai Okazaki
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Akira Torii
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Masanari Niwa
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Nozomi Kita
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Seiya Takano
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
| | - Shogo Kawakami
- grid.410786.c0000 0000 9206 2938Department of Radiation Oncology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0329 Japan
| | - Masayuki Matsuo
- grid.411704.7Department of Radiation Oncology, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Tomoyasu Kumano
- grid.411704.7Department of Radiation Oncology, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Makoto Ito
- grid.411234.10000 0001 0727 1557Department of Radiology, Aichi Medical University, 1-1 Yazako-Karimata, Nagakute, Aichi 480-1195 Japan
| | - Sou Adachi
- grid.411234.10000 0001 0727 1557Department of Radiology, Aichi Medical University, 1-1 Yazako-Karimata, Nagakute, Aichi 480-1195 Japan
| | - Souichiro Abe
- grid.411234.10000 0001 0727 1557Department of Radiology, Aichi Medical University, 1-1 Yazako-Karimata, Nagakute, Aichi 480-1195 Japan
| | - Takayuki Murao
- Department of Radiation Oncology, Ichinomiya Municipal Hospital, 2-2-22 Bunkyo, Ichinomiya, Aichi 491-8558 Japan
| | - Akio Hiwatashi
- grid.411885.10000 0004 0469 6607Department of Radiation Oncology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 Japan
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Yu Y, Zhao W, Yuan X, Li R. Progress and prospects of nanozymes for enhanced antitumor therapy. Front Chem 2022; 10:1090795. [PMID: 36531332 PMCID: PMC9755492 DOI: 10.3389/fchem.2022.1090795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 11/21/2022] [Indexed: 09/06/2023] Open
Abstract
Nanozymes are nanomaterials with mimicked enzymatic activity, whose catalytic activity can be designed by changing their physical parameters and chemical composition. With the development of biomedical and material science, artificially created nanozymes have high biocompatibility and can catalyze specific biochemical reactions under biological conditions, thus playing a vital role in regulating physiological activities. Under pathological conditions, natural enzymes are limited in their catalytic capacity by the varying reaction conditions. In contrast, compared to natural enzymes, nanozymes have advantages such as high stability, simplicity of modification, targeting ability, and versatility. As a result, the novel role of nanozymes in medicine, especially in tumor therapy, is gaining increasing attention. In this review, function and application of various nanozymes in the treatment of cancer are summarized. Future exploration paths of nanozymes in cancer therapies based on new insights arising from recent research are outlined.
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Affiliation(s)
| | | | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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21
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Combination of light and Ru(II) polypyridyl complexes: Recent advances in the development of new anticancer drugs. Coord Chem Rev 2022. [DOI: 10.1016/j.ccr.2022.214656] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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22
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López-Cortés A, Prathap L, Ortiz-Prado E, Kyriakidis NC, León Cáceres Á, Armendáriz-Castillo I, Vera-Guapi A, Yumiceba V, Simbaña-Rivera K, Echeverría-Garcés G, García-Cárdenas JM, Pérez-Villa A, Guevara-Ramírez P, Abad-Sojos A, Bautista J, Puig San Andrés L, Varela N, Guerrero S. The close interaction between hypoxia-related proteins and metastasis in pancarcinomas. Sci Rep 2022; 12:11100. [PMID: 35773405 PMCID: PMC9246854 DOI: 10.1038/s41598-022-15246-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/21/2022] [Indexed: 11/25/2022] Open
Abstract
Many primary-tumor subregions exhibit low levels of molecular oxygen and restricted access to nutrients due to poor vascularization in the tissue, phenomenon known as hypoxia. Hypoxic tumors are able to regulate the expression of certain genes and signaling molecules in the microenvironment that shift it towards a more aggressive phenotype. The transcriptional landscape of the tumor favors malignant transformation of neighboring cells and their migration to distant sites. Herein, we focused on identifying key proteins that participate in the signaling crossroads between hypoxic environment and metastasis progression that remain poorly defined. To shed light on these mechanisms, we performed an integrated multi-omics analysis encompassing genomic/transcriptomic alterations of hypoxia-related genes and Buffa hypoxia scores across 17 pancarcinomas taken from the PanCancer Atlas project from The Cancer Genome Atlas consortium, protein-protein interactome network, shortest paths from hypoxia-related proteins to metastatic and angiogenic phenotypes, and drugs involved in current clinical trials to treat the metastatic disease. As results, we identified 30 hypoxia-related proteins highly involved in metastasis and angiogenesis. This set of proteins, validated with the MSK-MET Project, could represent key targets for developing therapies. The upregulation of mRNA was the most prevalent alteration in all cancer types. The highest frequencies of genomic/transcriptomic alterations and hypoxia score belonged to tumor stage 4 and positive metastatic status in all pancarcinomas. The most significantly associated signaling pathways were HIF-1, PI3K-Akt, thyroid hormone, ErbB, FoxO, mTOR, insulin, MAPK, Ras, AMPK, and VEGF. The interactome network revealed high-confidence interactions among hypoxic and metastatic proteins. The analysis of shortest paths revealed several ways to spread metastasis and angiogenesis from hypoxic proteins. Lastly, we identified 23 drugs enrolled in clinical trials focused on metastatic disease treatment. Six of them were involved in advanced-stage clinical trials: aflibercept, bevacizumab, cetuximab, erlotinib, ipatasertib, and panitumumab.
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Affiliation(s)
- Andrés López-Cortés
- Programa de Investigación en Salud Global, Facultad de Ciencias de la Salud, Universidad Internacional SEK, 170302, Quito, Ecuador.
- Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de Las Américas, 170124, Quito, Ecuador.
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain.
| | - Lavanya Prathap
- Department of Anatomy, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, 600077, Chennai, India
| | - Esteban Ortiz-Prado
- One Health Research Group, Universidad de Las Américas, 170124, Quito, Ecuador
| | | | - Ángela León Cáceres
- Heidelberg Institute of Global Health, Faculty of Medicine, University of Heidelberg, 69117, Heidelberg, Germany
| | - Isaac Armendáriz-Castillo
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain
- Instituto Nacional de Investigación en Salud Pública, 170136, Quito, Ecuador
- Facultad de Ingenierías y Ciencias Aplicadas, Universidad Internacional SEK, 170302, Quito, Ecuador
| | - Antonella Vera-Guapi
- Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747, Jena, Germany
| | - Verónica Yumiceba
- Institut Für Humangenetik Lübeck, Universität Zu Lübeck, 23562, Lübeck, Germany
| | - Katherine Simbaña-Rivera
- One Health Research Group, Universidad de Las Américas, 170124, Quito, Ecuador
- Latin American Network for Cancer Research (LAN-CANCER), Lima, Peru
| | - Gabriela Echeverría-Garcés
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain
| | - Jennyfer M García-Cárdenas
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain
- Laboratorio de Ciencia de Datos Biomédicos, Escuela de Medicina, Facultad de Ciencias Médicas de la Salud y de la Vida, Universidad Internacional del Ecuador, 170113, Quito, Ecuador
| | - Andy Pérez-Villa
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain
| | - Patricia Guevara-Ramírez
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain
| | | | | | | | - Nelson Varela
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology, Faculty of Medicine, University of Chile, 8320000, Santiago, Chile
| | - Santiago Guerrero
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28015, Madrid, Spain.
- Laboratorio de Ciencia de Datos Biomédicos, Escuela de Medicina, Facultad de Ciencias Médicas de la Salud y de la Vida, Universidad Internacional del Ecuador, 170113, Quito, Ecuador.
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Wadsworth BJ, Lee CM, Bennewith KL. Transiently hypoxic tumour cell turnover and radiation sensitivity in human tumour xenografts. Br J Cancer 2022; 126:1616-1626. [PMID: 35031765 PMCID: PMC9130130 DOI: 10.1038/s41416-021-01691-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/24/2021] [Accepted: 12/23/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Solid tumour perfusion can be unstable, creating transiently hypoxic cells that can contribute to radiation resistance. We investigated the in vivo lifetime of transiently hypoxic tumour cells and chronically hypoxic tumour cells during tumour growth and following irradiation. METHODS Hypoxic cells in SiHa and WiDr human tumour xenografts were labelled using pimonidazole and EF5, and turnover was quantified as the loss of labelled cells over time. The perfusion-modifying drug pentoxifylline was used to reoxygenate transiently hypoxic cells prior to hypoxia marker administration or irradiation. RESULTS Chronically hypoxic cells constantly turnover in SiHa and WiDr tumours, with half-lives ranging from 42-82 h and significant numbers surviving >96 h. Transiently hypoxic cells constitute 26% of the total hypoxic cells in WiDr tumours. These transiently hypoxic cells survive at least 24 h, but then rapidly turnover with a half-life of 34 h and are undetectable 72 h after labelling. Transiently hypoxic cells are radiation-resistant, although vascular dysfunction induced by 10 Gy of ionising radiation preferentially kills transiently hypoxic cells. CONCLUSIONS Transiently hypoxic tumour cells survive up to 72 h in WiDr tumours and are radiation-resistant, although transiently hypoxic cells are sensitive to vascular dysfunction induced by high doses of ionising radiation.
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Affiliation(s)
- Brennan J. Wadsworth
- Integrative Oncology, BC Cancer, Vancouver, BC Canada ,grid.17091.3e0000 0001 2288 9830Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Che-Min Lee
- Integrative Oncology, BC Cancer, Vancouver, BC Canada ,grid.17091.3e0000 0001 2288 9830Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC Canada
| | - Kevin L. Bennewith
- Integrative Oncology, BC Cancer, Vancouver, BC Canada ,grid.17091.3e0000 0001 2288 9830Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada ,grid.17091.3e0000 0001 2288 9830Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC Canada
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Zhao J, Yi Q, Li K, Chen L, Dai L, Feng J, Li Y, Zhou M, Sun J. A multi-omics deep learning model for hypoxia phenotype to predict tumor aggressiveness and prognosis in uveal melanoma for rationalized hypoxia-targeted therapy. Comput Struct Biotechnol J 2022; 20:3182-3194. [PMID: 35782742 PMCID: PMC9232399 DOI: 10.1016/j.csbj.2022.06.034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/13/2022] [Accepted: 06/13/2022] [Indexed: 11/21/2022] Open
Abstract
Uveal melanoma (UM) represents the most common primary intraocular malignancy in adults and is characterized by aggressive behaviors and a lack of targeted therapies. Hypoxia-targeted therapy has become a promising new therapeutic strategy in tumors. Therefore, a better understanding of the tumor hypoxia microenvironment is critical to improve the treatment efficacy of UM. In this study, we conducted an extensive multi-omics analysis to explore the heterogeneity and prognostic significance of the hypoxia microenvironment. We found that UM revealed the most significant degree of intertumoral heterogeneity in hypoxia by quantifying tumor hypoxia compared with other solid tumor types. Then we systematically correlated the hypoxia phenotypes with clinicopathological features and found that hypoxic UM tumors were associated with an increased risk of metastasis, more aggressive phenotypes, and unfavorable clinical outcomes. Integrative multi-omics analyses identified multidimensional molecular alterations related to hypoxia phenotypes, including elevated genome instability, co-occurring of 8q arm gains and loss of chromosome 3, and BAP1 mutations. Furthermore, hypoxic UM tumors could be characterized by increased CD8+ T cell infiltration and decreased naïve B cell and dysregulated metabolic pathways. Finally, we introduced DNN2HM, an interpretable deep neural network model to decode hypoxia phenotypes from multi-omics data. We showed that the DNN2HM improves hypoxia phenotype prediction and robustly predicts tumor aggressiveness and prognosis in different multi-center datasets. In conclusion, our study provides novel insight into UM tumor microenvironment, which may have clinical implications for future rationalized hypoxia-targeted therapy.
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The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma. Life Sci 2022; 288:120163. [PMID: 34822797 DOI: 10.1016/j.lfs.2021.120163] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/10/2021] [Accepted: 11/16/2021] [Indexed: 12/30/2022]
Abstract
AIMS To investigate the role of tumor acidification in cell behavior, migration, and treatment resistance of oral squamous cell carcinoma (OSCC). MAIN METHODS The SCC4 and SCC25 cell lines were exposed to acidified (pH 6.8) cell culture medium for 7 days. Alternatively, a long-term acidosis was induced for 21 days. In addition, to mimic dynamic pH fluctuation of the tumor microenvironment, cells were reconditioned to neutral pH after experimental acidosis. This study assessed cell proliferation and viability by sulforhodamine B and flow cytometry. Individual and collective cell migration was analyzed by wound healing, time lapse, and transwell assays. Modifications of cell phenotype, EMT induction and stemness potential were investigated by qRT-PCR, western blot, and immunofluorescence. Finally, resistance to chemo- and radiotherapy of OSCC when exposed to acidified environmental conditions (pH 6.8) was determined. KEY FINDINGS The exposure to an acidic microenvironment caused an initial reduction of OSCC cells viability, followed by an adaptation process. Acidic adapted cells acquired a mesenchymal-like phenotype along with increased migration and motility indexes. Moreover, tumoral extracellular acidity was capable to induce cellular stemness and to increase chemo- and radioresistance of oral cancer cells. SIGNIFICANCE In summary, the results showed that the acidic microenvironment leads to a more aggressive and treatment resistant OSCC cell population.
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Bouleftour W, Rowinski E, Louati S, Sotton S, Wozny AS, Moreno-Acosta P, Mery B, Rodriguez-Lafrasse C, Magne N. A Review of the Role of Hypoxia in Radioresistance in Cancer Therapy. Med Sci Monit 2021; 27:e934116. [PMID: 34728593 PMCID: PMC8573967 DOI: 10.12659/msm.934116] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hypoxia involves neoplastic cells. Unlike normal tissue, solid tumors are composed of aberrant vasculature, leading to a hypoxic microenvironment. Hypoxia is also known to be involved in both metastasis initiation and therapy resistance. Radiotherapy is the appropriate treatment in about half of all cancers, but loco-regional control failure and a disease recurrence often occur due to clinical radioresistance. Hypoxia induces radioresistance through a number of molecular pathways, and numerous strategies have been developed to overcome this. Nevertheless, these strategies have resulted in disappointing results, including adverse effects and limited efficacy. Additional clinical studies are needed to achieve a better understanding of the complex hypoxia pathways. This review presents an update on the mechanisms of hypoxia in radioresistance in solid tumors and the potential therapeutic solutions.
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Affiliation(s)
- Wafa Bouleftour
- Radiotherapy Department, Lucien Neuwirth Cancerology Institute, Saint Priest en Jarez, France
| | - Elise Rowinski
- Radiotherapy Department, Lucien Neuwirth Cancerology Institute, Saint Priest en Jarez, France
| | - Safa Louati
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, CNRS UMR 5822, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, France.,Hospices Civils de Lyon, Lyon, France
| | - Sandrine Sotton
- Radiotherapy Department, Lucien Neuwirth Cancerology Institute, Saint Priest en Jarez, France
| | - Anne-Sophie Wozny
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, CNRS UMR 5822, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, France.,Hospices Civils de Lyon, Lyon, France
| | - Pablo Moreno-Acosta
- Research Group in Cancer Biology, National Cancer Institute, Bogotá, Colombia
| | - Benoite Mery
- Radiotherapy Department, Lucien Neuwirth Cancerology Institute, Saint Priest en Jarez, France
| | - Claire Rodriguez-Lafrasse
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, CNRS UMR 5822, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, France.,Hospices Civils de Lyon, Lyon, France
| | - Nicolas Magne
- Radiotherapy Department, Lucien Neuwirth Cancerology Institute, Saint Priest en Jarez, France.,Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, CNRS UMR 5822, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, France.,Hospices Civils de Lyon, Lyon, France
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Zakeri K, Dunn L, Lee N. HPV-associated oropharyngeal cancer de-escalation strategies and trials: Past failures and future promise. J Surg Oncol 2021; 124:962-966. [PMID: 34595766 DOI: 10.1002/jso.26696] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 09/18/2021] [Indexed: 11/09/2022]
Abstract
HPV-associated oropharynx squamous cell carcinomas are radiosensitive and chemosensitive, thus, portending a favorable prognosis. Treatment de-intensification strategies aim to reduce toxicity while maintaining efficacy. Although approaches that have substituted cisplatin with cetuximab or omitted chemotherapy have not been successful, Transoral Robotic Surgery with de-intensified adjuvant therapy has been promising. Additionally, personalized approaches are taking advantage of tumor biology and utilizing tumor reduction or hypoxia on imaging as a predictive marker to successfully de-escalate radiotherapy and chemotherapy.
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Affiliation(s)
- Kaveh Zakeri
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Lara Dunn
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Nancy Lee
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Schaner PE, Williams BB, Chen EY, Pettus JR, Schreiber WA, Kmiec MM, Jarvis LA, Pastel DA, Zuurbier RA, DiFlorio-Alexander RM, Paydarfar JA, Gosselin BJ, Barth RJ, Rosenkranz KM, Petryakov SV, Hou H, Tse D, Pletnev A, Flood AB, Wood VA, Hebert KA, Mosher RE, Demidenko E, Swartz HM, Kuppusamy P. First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip. Front Oncol 2021; 11:743256. [PMID: 34660306 PMCID: PMC8517507 DOI: 10.3389/fonc.2021.743256] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 09/07/2021] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVE The overall objective of this clinical study was to validate an implantable oxygen sensor, called the 'OxyChip', as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing. METHODS Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry. RESULTS Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4-128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6-73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5-144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation. CONCLUSIONS Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes.
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Affiliation(s)
- Philip E. Schaner
- Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Benjamin B. Williams
- Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Eunice Y. Chen
- Department of Surgery, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Jason R. Pettus
- Department of Pathology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Wilson A. Schreiber
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Maciej M. Kmiec
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Lesley A. Jarvis
- Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - David A. Pastel
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Rebecca A. Zuurbier
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Roberta M. DiFlorio-Alexander
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Joseph A. Paydarfar
- Department of Surgery, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Benoit J. Gosselin
- Department of Surgery, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Richard J. Barth
- Department of Surgery, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Kari M. Rosenkranz
- Department of Surgery, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Sergey V. Petryakov
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Huagang Hou
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Dan Tse
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Alexandre Pletnev
- Department of Chemistry, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Ann Barry Flood
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Victoria A. Wood
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Kendra A. Hebert
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Robyn E. Mosher
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Eugene Demidenko
- Department of Biomedical Data Science, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Harold M. Swartz
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
| | - Periannan Kuppusamy
- Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
- Department of Radiology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
- Department of Chemistry, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, and Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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Prognostic significance of hypoxia-inducible factor-1α expression in advanced pharyngeal cancer without human papillomavirus infection. The Journal of Laryngology & Otology 2021; 135:625-633. [PMID: 34108057 DOI: 10.1017/s0022215121001468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE This study aimed to clarify the association between both hypoxia-inducible factor-1α and glucose transporter type-1 expression and survival outcome in advanced pharyngeal cancer without human papillomavirus infection. METHOD Twenty-five oropharyngeal and 55 hypopharyngeal cancer patients without human papillomavirus infection were enrolled. All patients had stage III-IV lesions and underwent concurrent chemoradiotherapy or surgery. Hypoxia-inducible factor-1α and glucose transporter type-1 expression were investigated in primary lesions by immunohistochemistry. RESULTS There were 41 and 39 cases with low and high hypoxia-inducible factor-1α expression, and 28 and 52 cases with low and high glucose transporter type-1 expression, respectively. There was no significant correlation between hypoxia-inducible factor-1α and glucose transporter type-1 expression. In univariate analysis, nodal metastasis, clinical stage and high hypoxia-inducible factor-1α expression, but not glucose transporter type-1 expression, predicted significantly worse prognosis. In multivariate analysis, hypoxia-inducible factor-1α overexpression was significantly correlated with poor overall survival, disease-specific survival and recurrence-free survival. CONCLUSION High hypoxia-inducible factor-1α expression was an independent risk factor for poor prognosis for advanced human papillomavirus-unrelated pharyngeal cancer.
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Iqbal MS, O'Hara J, Thorstad W, Kovarik J, Patil R, Kelly C, O'Hara J, Thorstad W. In Regard to Amdur et al. Pract Radiat Oncol 2021; 11:230-231. [PMID: 33941349 DOI: 10.1016/j.prro.2020.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 12/16/2020] [Indexed: 10/21/2022]
Affiliation(s)
- Muhammad Shahid Iqbal
- Department of Clinical Oncology, Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
| | - James O'Hara
- Department of Head and Neck Surgery, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Wade Thorstad
- Department of Radiation Oncology, Washington University, St. Louis, Missouri
| | - Josef Kovarik
- Department of Clinical Oncology, Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Rahul Patil
- Department of Clinical Oncology, Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Charles Kelly
- Department of Clinical Oncology, Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
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Modulating the Heat Stress Response to Improve Hyperthermia-Based Anticancer Treatments. Cancers (Basel) 2021; 13:cancers13061243. [PMID: 33808973 PMCID: PMC8001574 DOI: 10.3390/cancers13061243] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/02/2021] [Accepted: 03/09/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Hyperthermia is a method to expose a tumor to elevated temperatures. Heating of the tumor promotes the effects of various treatment regimens that are based on chemo and radiotherapy. Several aspects, however, limit the efficacy of hyperthermia-based treatments. This review provides an overview of the effects and limitations of hyperthermia and discusses how current drawbacks of the therapy can potentially be counteracted by inhibiting the heat stress response—a mechanism that cells activate to defend themselves against hyperthermia. Abstract Cancer treatments based on mild hyperthermia (39–43 °C, HT) are applied to a widening range of cancer types, but several factors limit their efficacy and slow down more widespread adoption. These factors include difficulties in adequate heat delivery, a short therapeutic window and the acquisition of thermotolerance by cancer cells. Here, we explore the biological effects of HT, the cellular responses to these effects and their clinically-relevant consequences. We then identify the heat stress response—the cellular defense mechanism that detects and counteracts the effects of heat—as one of the major forces limiting the efficacy of HT-based therapies and propose targeting this mechanism as a potentially universal strategy for improving their efficacy.
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O’Brien RM, Cannon A, Reynolds JV, Lysaght J, Lynam-Lennon N. Complement in Tumourigenesis and the Response to Cancer Therapy. Cancers (Basel) 2021; 13:1209. [PMID: 33802004 PMCID: PMC7998562 DOI: 10.3390/cancers13061209] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/16/2022] Open
Abstract
In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour microenvironment. These novel discoveries have advanced our understanding of the immunosuppressive mechanisms supporting tumour growth and uncovered potential therapeutic targets. This review discusses the current understanding of complement in cancer, outlining both direct and immune cell-mediated roles. The role of complement in response to therapies such as chemotherapy, radiation and immunotherapy is also presented. While complement activities are largely context and cancer type-dependent, it is evident that promising therapeutic avenues have been identified, in particular in combination therapies.
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Affiliation(s)
- Rebecca M. O’Brien
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
- Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland
| | - Aoife Cannon
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
| | - John V. Reynolds
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
| | - Joanne Lysaght
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
- Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
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Kho VM, Mekers VE, Span PN, Bussink J, Adema GJ. Radiotherapy and cGAS/STING signaling: Impact on MDSCs in the tumor microenvironment. Cell Immunol 2021; 362:104298. [PMID: 33592541 DOI: 10.1016/j.cellimm.2021.104298] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/14/2021] [Accepted: 01/17/2021] [Indexed: 12/20/2022]
Abstract
Myeloid derived suppressor cells (MDSCs) are a highly heterogeneous population of immature immune cells with immunosuppressive functions that are recruited to the tumor microenvironment (TME). MDSCs promote tumor growth and progression by inhibiting immune effector cell proliferation and function. MDSCs are affected by both novel anti-cancer therapies targeting the immune system to promote anti-tumor immunity, as well as by conventional treatments such as radiotherapy. Following radiotherapy, cytoplasmic double stranded DNA stimulates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, resulting in type I interferon production. Effectiveness of radiotherapy and cGAS/STING signaling are closely intertwined: activation of cGAS and STING is key to generate systemic anti-tumor immunity after irradiation. This review focuses on how radiotherapy and cGAS/STING signaling in MDSCs and/or tumor cells impact MDSC recruitment, expansion and function. The influence of conventional and ablative radiotherapy treatment schedules, inflammatory response following radiotherapy, and hypoxia are discussed as MDSC modulators.
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Affiliation(s)
- Vera M Kho
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Vera E Mekers
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Paul N Span
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Johan Bussink
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Gosse J Adema
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands.
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Abdlaty R, Doerwald-Munoz L, Farrell TJ, Hayward JE, Fang Q. Hyperspectral imaging assessment for radiotherapy induced skin-erythema: Pilot study. Photodiagnosis Photodyn Ther 2021; 33:102195. [PMID: 33515761 DOI: 10.1016/j.pdpdt.2021.102195] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/06/2021] [Accepted: 01/20/2021] [Indexed: 10/22/2022]
Abstract
Skin cancer (SC) is a widely spread disease in the USA, Canada, and Australia. Skin cancer patients may be treated by many different techniques including radiation therapy. However, radiation therapy has side effects, which may range from skin erythema to skin necrosis. As erythema is the early evidence of exposure to radiation, monitoring erythema is important to prevent more severe reactions. Visual assessment (VA) is the gold standard for evaluating erythema. Nevertheless, VA is not ideal, since it depends on the observer's experience and skills. Digital photography and hyperspectral imaging (HSI) are optical techniques that provide an opportunity for objective assessment of erythema. Erythema indices were computed from the spectral data using Dawson's technique. The Dawson relative erythema index proved to be highly correlated (97.1 %) with clinical visual assessment scores. In addition, on the 7th session of radiation therapy, the relative erythema index differentiates with 99 % significance between irradiated and non-radiated skin regions. In this study, HSI is compared to digital photography for skin erythema statistical classification.
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Affiliation(s)
- Ramy Abdlaty
- Department of Biomedical Engineering, Military Technical College, Cairo, Egypt; School of Biomedical Engineering, McMaster University, Ontario, Canada.
| | | | - Thomas J Farrell
- Juravinski Cancer Centre, Hamilton Health Sciences, Ontario, Canada; School of Interdisciplinary Science, McMaster University, Ontario, Canada
| | - Joseph E Hayward
- Juravinski Cancer Centre, Hamilton Health Sciences, Ontario, Canada; School of Interdisciplinary Science, McMaster University, Ontario, Canada
| | - Qiyin Fang
- School of Biomedical Engineering, McMaster University, Ontario, Canada; Department of Engineering Physics, McMaster University, Ontario, Canada
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Dadgar S, Troncoso JR, Siegel ER, Curry NM, Griffin RJ, Dings RPM, Rajaram N. Spectroscopic investigation of radiation-induced reoxygenation in radiation-resistant tumors. Neoplasia 2021; 23:49-57. [PMID: 33220616 PMCID: PMC7683290 DOI: 10.1016/j.neo.2020.11.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/29/2020] [Accepted: 11/03/2020] [Indexed: 12/12/2022]
Abstract
Fractionated radiation therapy is believed to reoxygenate and subsequently radiosensitize surviving hypoxic cancer cells. Measuring tumor reoxygenation between radiation fractions could conceivably provide an early biomarker of treatment response. However, the relationship between tumor reoxygenation and local control is not well understood. We used noninvasive optical fiber-based diffuse reflectance spectroscopy to monitor radiation-induced changes in hemoglobin oxygen saturation (sO2) in tumor xenografts grown from two head and neck squamous cell carcinoma cell lines - UM-SCC-22B and UM-SCC-47. Tumors were treated with 4 doses of 2 Gy over 2 consecutive weeks and diffuse reflectance spectra were acquired every day during the 2-week period. There was a statistically significant increase in sO2 in the treatment-responsive UM-SCC-22B tumors immediately following radiation. This reoxygenation trend was due to an increase in oxygenated hemoglobin (HbO2) and disappeared over the next 48 h as sO2 returned to preradiation baseline values. Conversely, sO2 in the relatively radiation-resistant UM-SCC-47 tumors increased after every dose of radiation and was driven by a significant decrease in deoxygenated hemoglobin (dHb). Immunohistochemical analysis revealed significantly elevated expression of hypoxia-inducible factor (HIF-1) in the UM-SCC-47 tumors prior to radiation and up to 48 h postradiation compared with the UM-SCC-22B tumors. Our observation of a decrease in dHb, a corresponding increase in sO2, as well as greater HIF-1α expression only in UM-SCC-47 tumors strongly suggests that the reoxygenation within these tumors is due to a decrease in oxygen consumption in the cancer cells, which could potentially play a role in promoting radiation resistance.
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Affiliation(s)
- Sina Dadgar
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | | | - Eric R Siegel
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Natalie M Curry
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Robert J Griffin
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Ruud P M Dings
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Narasimhan Rajaram
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
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Pogue BW, Zhang R, Cao X, Jia JM, Petusseau A, Bruza P, Vinogradov SA. Review of in vivo optical molecular imaging and sensing from x-ray excitation. JOURNAL OF BIOMEDICAL OPTICS 2021; 26:JBO-200308VR. [PMID: 33386709 PMCID: PMC7778455 DOI: 10.1117/1.jbo.26.1.010902] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/24/2020] [Indexed: 05/05/2023]
Abstract
SIGNIFICANCE Deep-tissue penetration by x-rays to induce optical responses of specific molecular reporters is a new way to sense and image features of tissue function in vivo. Advances in this field are emerging, as biocompatible probes are invented along with innovations in how to optimally utilize x-ray sources. AIM A comprehensive review is provided of the many tools and techniques developed for x-ray-induced optical molecular sensing, covering topics ranging from foundations of x-ray fluorescence imaging and x-ray tomography to the adaptation of these methods for sensing and imaging in vivo. APPROACH The ways in which x-rays can interact with molecules and lead to their optical luminescence are reviewed, including temporal methods based on gated acquisition and multipoint scanning for improved lateral or axial resolution. RESULTS While some known probes can generate light upon x-ray scintillation, there has been an emergent recognition that excitation of molecular probes by x-ray-induced Cherenkov light is also possible. Emission of Cherenkov radiation requires a threshold energy of x-rays in the high kV or MV range, but has the advantage of being able to excite a broad range of optical molecular probes. In comparison, most scintillating agents are more readily activated by lower keV x-ray energies but are composed of crystalline inorganic constituents, although some organic biocompatible agents have been designed as well. Methods to create high-resolution structured x-ray-optical images are now available, based upon unique scanning approaches and/or a priori knowledge of the scanned x-ray beam geometry. Further improvements in spatial resolution can be achieved by careful system design and algorithm optimization. Current applications of these hybrid x-ray-optical approaches include imaging of tissue oxygenation and pH as well as of certain fluorescent proteins. CONCLUSIONS Discovery of x-ray-excited reporters combined with optimized x-ray scan sequences can improve imaging resolution and sensitivity.
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Affiliation(s)
- Brian W. Pogue
- Thayer School of Engineering at Dartmouth, Hanover, New Hampshire, United States
- Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States
| | - Rongxiao Zhang
- Thayer School of Engineering at Dartmouth, Hanover, New Hampshire, United States
- Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States
| | - Xu Cao
- Thayer School of Engineering at Dartmouth, Hanover, New Hampshire, United States
| | - Jeremy Mengyu Jia
- Stanford University School of Medicine, Department of Radiation Oncology, Palo Alto, California, United States
| | - Arthur Petusseau
- Thayer School of Engineering at Dartmouth, Hanover, New Hampshire, United States
| | - Petr Bruza
- Thayer School of Engineering at Dartmouth, Hanover, New Hampshire, United States
| | - Sergei A. Vinogradov
- University of Pennsylvania, Perelman School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, Pennsylvania, United States
- University of Pennsylvania, School of Arts of Sciences, Department of Chemistry, Philadelphia, Pennsylvania, United States
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Lee TW, Lai A, Harms JK, Singleton DC, Dickson BD, Macann AMJ, Hay MP, Jamieson SMF. Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment in Head and Neck Cancer. Cancers (Basel) 2020; 12:E3743. [PMID: 33322840 PMCID: PMC7763264 DOI: 10.3390/cancers12123743] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/10/2020] [Accepted: 12/10/2020] [Indexed: 12/24/2022] Open
Abstract
Patient survival from head and neck squamous cell carcinoma (HNSCC), the seventh most common cause of cancer, has not markedly improved in recent years despite the approval of targeted therapies and immunotherapy agents. Precision medicine approaches that seek to individualise therapy through the use of predictive biomarkers and stratification strategies offer opportunities to improve therapeutic success in HNSCC. To enable precision medicine of HNSCC, an understanding of the microenvironment that influences tumour growth and response to therapy is required alongside research tools that recapitulate the features of human tumours. In this review, we highlight the importance of the tumour microenvironment in HNSCC, with a focus on tumour hypoxia, and discuss the fidelity of patient-derived xenograft and organoids for modelling human HNSCC and response to therapy. We describe the benefits of patient-derived models over alternative preclinical models and their limitations in clinical relevance and how these impact their utility in precision medicine in HNSCC for the discovery of new therapeutic agents, as well as predictive biomarkers to identify patients' most likely to respond to therapy.
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Affiliation(s)
- Tet Woo Lee
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; (T.W.L.); (A.L.); (J.K.H.); (D.C.S.); (B.D.D.); (M.P.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
| | - Amy Lai
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; (T.W.L.); (A.L.); (J.K.H.); (D.C.S.); (B.D.D.); (M.P.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland 1023, New Zealand
| | - Julia K. Harms
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; (T.W.L.); (A.L.); (J.K.H.); (D.C.S.); (B.D.D.); (M.P.H.)
| | - Dean C. Singleton
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; (T.W.L.); (A.L.); (J.K.H.); (D.C.S.); (B.D.D.); (M.P.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
| | - Benjamin D. Dickson
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; (T.W.L.); (A.L.); (J.K.H.); (D.C.S.); (B.D.D.); (M.P.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
| | - Andrew M. J. Macann
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
- Department of Radiation Oncology, Auckland City Hospital, Auckland 1023, New Zealand
| | - Michael P. Hay
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; (T.W.L.); (A.L.); (J.K.H.); (D.C.S.); (B.D.D.); (M.P.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
| | - Stephen M. F. Jamieson
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; (T.W.L.); (A.L.); (J.K.H.); (D.C.S.); (B.D.D.); (M.P.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland 1023, New Zealand
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Expression analysis based diagnostic potential of hypoxia-responsive genes in gastric tumorigenesis. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Nezhadi S, Saadat E, Handali S, Dorkoosh F. Nanomedicine and chemotherapeutics drug delivery: challenges and opportunities. J Drug Target 2020; 29:185-198. [PMID: 32772739 DOI: 10.1080/1061186x.2020.1808000] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer is considered as one of the biggest threats to humans worldwide. Researchers suggest that tumour is not just a single mass, it comprises cancerous cells surrounded by noncancerous cells such as immune cells, adipocytes and cancer stem cells (CSCs) in the extracellular matrix (ECM) containing distinct components such as proteins, glycoproteins and enzymes; thus tumour microenvironment (TME) is partially complex. Multiple interactions happen in the dynamic microenvironment (ME) lead to an acidic, hypoxic and stiff ME that is considered as one of the major contributors to cancer progression and metastasis. Furthermore, TME involves in drug resistance mechanisms and affects enhanced permeability and retention (EPR) in tumours. In such a scenario, the first step to accomplish satisfying results is the identification and recognition of this ME. Then designing proper drug delivery systems can perform selectively towards cancerous cells. In this way, several targeting and stimuli/enzyme responsive drug delivery systems have been designed. More importantly, it is necessary to design a drug delivery system that can penetrate deeper into the tumours, efficiently and selectively. Various drug delivery systems such as exosomes and size-switchable nanocarriers (NCs) could decrease side effects and increase tumour treatment results by selective accumulation in tumours. In this review, TME features, current drug delivery approaches, challenges and promising strategies towards cancer treatment are discussed.
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Affiliation(s)
- Sepideh Nezhadi
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Ir an
| | | | - Somayeh Handali
- Medical Biomaterial Research Center (MBRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Farid Dorkoosh
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Ir an.,Medical Biomaterial Research Center (MBRC), Tehran University of Medical Sciences, Tehran, Iran
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Quantitative ultrasound delta-radiomics during radiotherapy for monitoring treatment responses in head and neck malignancies. Future Sci OA 2020; 6:FSO624. [PMID: 33235811 PMCID: PMC7668124 DOI: 10.2144/fsoa-2020-0073] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aim: We investigated quantitative ultrasound (QUS) in patients with node-positive head and neck malignancies for monitoring responses to radical radiotherapy (RT). Materials & methods: QUS spectral and texture parameters were acquired from metastatic lymph nodes 24 h, 1 and 4 weeks after starting RT. K-nearest neighbor and naive-Bayes machine-learning classifiers were used to build prediction models for each time point. Response was detected after 3 months of RT, and patients were classified into complete and partial responders. Results: Single-feature naive-Bayes classification performed best with a prediction accuracy of 80, 86 and 85% at 24 h, week 1 and 4, respectively. Conclusion: QUS-radiomics can predict RT response at 3 months as early as 24 h with reasonable accuracy, which further improves into 1 week of treatment. Patients with head and neck cancer are often treated with radiation, which usually spans over 6–7 weeks. The response is usually measured 3 months after treatment completion. In this study, we had performed ultrasound scans from the patient’s neck node during radiation treatment (after 24 h, 1 and 4 weeks). Artificial intelligence was used to interpret the ultrasound imaging and predict the response to radiation at the end of 3 months. The scans obtained after the first week were able to predict the treatment response with reasonable accuracy (86%).
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Ratnayake R, Gunasekera SP, Ma JJ, Dang LH, Carney TJ, Paul VJ, Luesch H. Dolastatin 15 from a Marine Cyanobacterium Suppresses HIF-1α Mediated Cancer Cell Viability and Vascularization. Chembiochem 2020; 21:2356-2366. [PMID: 32237262 PMCID: PMC7438311 DOI: 10.1002/cbic.202000180] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 03/31/2020] [Indexed: 01/08/2023]
Abstract
Chemical investigation of a benthic marine cyanobacterium yielded the anticancer agent dolastatin 15, originally isolated from a mollusk. Dolastatin 15 is a microtubule-destabilizing agent with analogues undergoing clinical evaluation. Profiling against a panel of isogenic HCT116 colorectal cancer cells showed remarkable differential cytotoxicity against the parental cells over isogenic cells lacking HIF or other key players in the pathway, including oncogenic KRAS and VEGF. Dolastatin 15 displayed an antivascularization effect in human endothelial cells and in zebrafish vhl mutants with activated Hif, thus signifying its clinical potential as a treatment for solid tumors with an angiogenic component. Global transcriptome analysis with RNA sequencing suggested that dolastatin 15 could affect other major cancer pathways that might not directly involve tubulin or HIF. The identification of the true producer of a clinically relevant agent is important for sustainable supply, as is understanding the biosynthesis, and future genetic manipulation of the biosynthetic gene cluster for analogue production.
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Affiliation(s)
- Ranjala Ratnayake
- Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA
| | | | - Jia Jia Ma
- Institute of Molecular and Cell Biology (IMCB), A*STAR, Proteos, Singapore, 138673, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
| | - Long H Dang
- Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA
- Department of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Thomas J Carney
- Institute of Molecular and Cell Biology (IMCB), A*STAR, Proteos, Singapore, 138673, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
| | - Valerie J Paul
- Smithsonian Marine Station, 701 Seaway Drive, Fort Pierce, FL, 34949, USA
| | - Hendrik Luesch
- Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA
- Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore
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Wang P, Jiang S, Li Y, Luo Q, Lin J, Hu L, Xu C, Zhu J, Fan L. Fabrication of hypoxia-responsive and uperconversion nanoparticles-modified RBC micro-vehicles for oxygen delivery and chemotherapy enhancement. Biomater Sci 2020; 8:4595-4602. [PMID: 32700684 DOI: 10.1039/d0bm00678e] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Solid tumor cells in hypoxic regions resist chemotherapy treatment with conventional antitumor drugs (such as paclitaxel, PTX) because the inadequate O2 attenuates the intracellular generation of reactive oxygen species (ROS) and upregulates multidrug resistance protein expression. Hyperbaric O2 therapy concentrates on improving O2 delivery to the hypoxic tumor area, thereby enhancing the sensitivity of cancer cells to chemotherapy drugs. However, the implementation of this therapy often elicits immune response or potentiates toxicity of the drugs toward normal cells. In this work, we successfully fabricated RBC-based micro-vehicles for precise hypoxia-activated O2 delivery under the 980 nm laser irradiation. Interestingly, the subsequent chemotherapy of PTX for ovarian tumors was significantly enhanced owing to the alleviation of hypoxia tumor microenvironment. Meanwhile, the RBC-based micro-vehicles have low side tissue effects, superior biocompatibility, and ultra-low immune response. Overall, the RBC-based drug delivery system holds a fascinating perspective towards O2 delivery for chemotherapy enhancement in other clinical solid malignancies.
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Affiliation(s)
- Peiyuan Wang
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China.
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Enver N, Şahin A, Sönmez S, Demokan S. Most Cited Articles in Head and Neck Oncology. EAR, NOSE & THROAT JOURNAL 2020; 100:1061S-1072S. [PMID: 32579405 DOI: 10.1177/0145561320934920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES The number of citations an article receives is an important indication of its impact. The main objectives of this investigation provide readers with a practical guide in evaluating head and neck oncology literature and determine the characteristics of trends in ORL. METHODS This was a retrospective bibliometric analysis that did not involve human participant. The Thomson Reuters Web of Science was searched to determine the citations of all published HNO articles. Most cited 300 article analyzed and a total of 100 articles were included in our investigation under the topic search "Head AND NECK AND (cancer OR carcinoma OR oncology)." Articles include malignancies other than head and neck are excluded. The top 100 cited articles were selected and analyzed by 2 independent investigators. Country, Institution, First Author, Journal name, study design, cites per year information gathered and analyzed. RESULTS The journal with the highest number of top 100 cited articles was New England Journal Of Medicine with 19 paper, followed by The Journal of Clinical Oncology(17) and Cancer Research (12). The top article on the list (Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck-NEJM) has 2243 citations. A statistically significant association was found between the journal impact factor and the number of top 100 cited articles (P < .05). The United States had the highest number of articles (63). John Hopkins is differed from other institutions with 15 contributing articles. CONCLUSION Our analysis provides an insight into the citation frequency of top cited articles published in HNO to help recognize the quality of the works, discoveries and the trends steering the study of HNO. This is also a modern reading list for young HNO scientist.
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Affiliation(s)
- Necati Enver
- Department of Otorhinolaryngology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
| | - Akın Şahin
- Department of Otorhinolaryngology, Marmara University School of Medicine, Istanbul, Turkey
| | - Said Sönmez
- Department of Otorhinolaryngology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Semra Demokan
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
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Fu Q, Yu Z. Phosphoglycerate kinase 1 (PGK1) in cancer: A promising target for diagnosis and therapy. Life Sci 2020; 256:117863. [PMID: 32479953 DOI: 10.1016/j.lfs.2020.117863] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 12/22/2022]
Abstract
Phosphoglycerate kinase 1 (PGK1) is the first critical enzyme to produce ATP in the glycolytic pathway. PGK1 is not only a metabolic enzyme but also a protein kinase, which mediates the tumor growth, migration and invasion through phosphorylation some important substrates. Moreover, PGK1 is associated with poor treatment and prognosis of cancers. This manuscript reviews the structure, functions, post-translational modifications (PTMs) of PGK1 and its relationship with tumors, which demonstrates that PGK1 has indispensable value in the tumor progression. The current review highlights the important role of PGK1 in anticancer treatments.
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Affiliation(s)
- Qi Fu
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, PR China.; College of Bioscience and Technology, Weifang Medical University, Weifang, Shandong Province, PR China
| | - Zhenhai Yu
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, PR China..
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Radiation Damage to Tumor Vasculature Initiates a Program That Promotes Tumor Recurrences. Int J Radiat Oncol Biol Phys 2020; 108:734-744. [PMID: 32473180 DOI: 10.1016/j.ijrobp.2020.05.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/07/2020] [Accepted: 05/18/2020] [Indexed: 01/03/2023]
Abstract
This review, mostly of preclinical data, summarizes the evidence that radiation at doses relevant to radiation therapy initiates a pathway that promotes the reconstitution of the tumor vasculature leading to tumor recurrence. The pathway is not specific to tumors; it promotes repair of damaged and ischemic normal tissues by attracting proangiogenic cells from the bone marrow. For irradiated tumors the pathway comprises: (1) loss of endothelial cells and reduced tumor blood perfusion leading to increased tumor hypoxia and increased levels of hypoxia inducible factor-1 (HIF-1). Alternatively, increased HIF-1 levels may arise by reactive oxygen species (ROS) production caused by tumor reoxygenation. (2) Increased HIF-1 levels lead to increased levels in the tumor of the chemokine stromal cell-derived factor-1 (SDF-1, CXCL12), which captures monocytes/macrophages expressing the CXCR4 receptor of CXCL12. (3) The increased levels of tumor-associated macrophages (TAMs) become highly proangiogenic (M2 polarized) and restore the tumor vasculature, thereby promoting tumor recurrence. The relevance of this pathway for radiation therapy is that it can be blocked in a number of different ways including by inhibitors of monocytes/macrophages, of HIF-1, of CXCL12, of CXCR4, and of CSF-1R, the latter of which is responsible for the M2 polarization of the TAMs. All of these inhibitors produce a robust enhancement of the radiation response of a wide variety of preclinical tumor models. Further, the same inhibitors actually provide protection against radiation damage of several normal tissues. Some of these pathway inhibitors are available clinically, and a first-in-human trial of the CXCR4 inhibitor, plerixafor, with radiation therapy of glioblastoma has yielded promising results, including an impressive increase in local tumor control. Further clinical trials are warranted.
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Xiong Q, Liu B, Ding M, Zhou J, Yang C, Chen Y. Hypoxia and cancer related pathology. Cancer Lett 2020; 486:1-7. [PMID: 32439418 DOI: 10.1016/j.canlet.2020.05.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/18/2020] [Accepted: 05/05/2020] [Indexed: 12/15/2022]
Abstract
Hypoxic environments occur normally at high altitude, or in underground burrows and in deep sea habitats. They also occur pathologically in human ischemia and in hypoxic solid tumors. Hypoxia in various cancer types and its related molecular mechanisms are associated with a poor clinical outcome. This review will discuss how hypoxia can influence two aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic effects, as well as the indirect effects on tumor progression mediated by an altered tumor microenvironment. We will also discuss recent progress in identifying the functional roles of hypoxia-related factors (HIFs), along with their regulators and downstream target genes, in cancer stem cells and therapy. Importantly, we propose, using convergent evolution schemes to identify novel biomarkers for both hypoxia adaptation and hypoxic solid tumors as an important strategy in the future.
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Affiliation(s)
- Qiuxia Xiong
- Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China; Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China
| | - Baiyang Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Mingxia Ding
- Deparment of Urology, the Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China
| | - Jumin Zhou
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China
| | - Cuiping Yang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
| | - Yongbin Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
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Cheng Y, Weng S, Yu L, Zhu N, Yang M, Yuan Y. The Role of Hyperthermia in the Multidisciplinary Treatment of Malignant Tumors. Integr Cancer Ther 2020; 18:1534735419876345. [PMID: 31522574 PMCID: PMC7242805 DOI: 10.1177/1534735419876345] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hyperthermia is often used in combination with chemotherapy and radiotherapy for
cancer treatment. Recently, immunotherapy has become a popular research area,
breaking exciting new ground with concurrent immunotherapy and hyperthermia.
Much evidence has demonstrated the effectiveness of multidisciplinary
synergistic therapy, and the underlying mechanism has been gradually explored.
In this review, we focus on the mechanism of various cancer treatments in the
current literature and recent advances in hyperthermia. Additionally, we review
clinical studies of hyperthermia combined with other therapies in the previous
10 years and propose future prospects for hyperthermia in multidisciplinary
synergistic therapy.
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Affiliation(s)
- Yi Cheng
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Shanshan Weng
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Linzhen Yu
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Ning Zhu
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Mengyuan Yang
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Ying Yuan
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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Lazzari G, Silvano G. From Anemia to Erythropoietin Resistance in Head and Neck Squamous Cell Carcinoma Treatment: A Carousel Driven by Hypoxia. Onco Targets Ther 2020; 13:841-851. [PMID: 32099388 PMCID: PMC6996291 DOI: 10.2147/ott.s242263] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 01/16/2020] [Indexed: 01/05/2023] Open
Abstract
Anemia has been identified as a significant negative prognosticator in head and neck squamous cell carcinoma (HNSCC) concurrent chemoradiotherapy (CCRT). Irrespective of the causes, anemia in HNSCC is believed to contribute to intratumoral hypoxia, which reduces the effectiveness of radiotherapy and oxygen-dependent chemotherapy. Correction of anemia with recombinant human erythropoietin (rHu-EPO) has been performed as a surrogate for hypoxia compensation to improve tumor control and survival outcomes. However, the results of the most important EPO clinical trials have been disappointing. Following the recent finding that EPO and its receptor (EPOR) are both expressed in HNSCC specimens, a new hypothesis has been advanced. This postulates that hypoxic signaling might activate EPOR through the hypoxia-inducible factor (HIF) signaling pathway and its downstream effectors, including carbonic anhydrase 9 (CA-9), glucose transporter 1 (GLUT-1), and vascular endothelial growth factor (VEGF), leading to the failure of rHu-EPO treatment, as assessed from the results of the best-known EPO trials. This review addresses the relationship among anemia, hypoxia, and tumoral EPO/EPOR expression in HNSCC treatment in an attempt to elucidate the main mechanisms involved in the resistance to rHu-EPO therapy, as in a carousel.
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Affiliation(s)
- Grazia Lazzari
- Radiation Oncology Unit, Saint Giuseppe Moscati Hospital, Taranto 74100, Italy
| | - Giovanni Silvano
- Radiation Oncology Unit, Saint Giuseppe Moscati Hospital, Taranto 74100, Italy
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Predictive quantitative ultrasound radiomic markers associated with treatment response in head and neck cancer. Future Sci OA 2019; 6:FSO433. [PMID: 31915534 PMCID: PMC6920736 DOI: 10.2144/fsoa-2019-0048] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Aim: We aimed to identify quantitative ultrasound (QUS)-radiomic markers to predict radiotherapy response in metastatic lymph nodes of head and neck cancer. Materials & methods: Node-positive head and neck cancer patients underwent pretreatment QUS imaging of their metastatic lymph nodes. Imaging features were extracted using the QUS spectral form, and second-order texture parameters. Machine-learning classifiers were used for predictive modeling, which included a logistic regression, naive Bayes, and k-nearest neighbor classifiers. Results: There was a statistically significant difference in the pretreatment QUS-radiomic parameters between radiological complete responders versus partial responders (p < 0.05). The univariable model that demonstrated the greatest classification accuracy included: spectral intercept (SI)-contrast (area under the curve = 0.741). Multivariable models were also computed and showed that the SI-contrast + SI-homogeneity demonstrated an area under the curve = 0.870. The three-feature model demonstrated that the spectral slope-correlation + SI-contrast + SI-homogeneity-predicted response with accuracy of 87.5%. Conclusion: Multivariable QUS-radiomic features of metastatic lymph nodes can predict treatment response a priori. In this study, quantitative ultrasound (QUS) and machine-learning classification was used to predict treatment outcomes in head and neck cancer patients. Metastatic lymph nodes in the neck were scanned using conventional frequency ultrasound (US). Quantitative data were collected from the US-radiofrequency signal a priori. Machine-learning classification models were computed using QUS features; these included the linear fit parameters of the power spectrum, and second-order texture parameters of the QUS parametric images. Treatment outcomes were measured based on radiological response. Patients were classified into binary groups: radiologic complete response (CR) or radiological partial response (PR), which was assessed 3 months following treatment. Initial results demonstrate high accuracy (%Acc = 87.5%) for predicting radiological response. The results of this study suggest that QUS can be used to predict head and neck cancer response to radiotherapy a priori.
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