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Li K, Zeng X, Liu P, Zeng X, Lv J, Qiu S, Zhang P. The Role of Inflammation-Associated Factors in Head and Neck Squamous Cell Carcinoma. J Inflamm Res 2023; 16:4301-4315. [PMID: 37791117 PMCID: PMC10544098 DOI: 10.2147/jir.s428358] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/16/2023] [Indexed: 10/05/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC), which originates in the head or neck tissues, is characterized by high rates of recurrence and metastasis. Inflammation is important in HNSCC prognosis. Inflammatory cells and their secreted factors contribute to the various stages of HNSCC development through multiple mechanisms. In this review, the mechanisms through which inflammatory factors, signaling pathways, and cells contribute to the initiation and progression of HNSCC have been discussed in detail. Furthermore, the diagnostic and therapeutic potential of targeting inflammation in HNSCC has been discussed to gain new insights into improving patient prognosis.
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Affiliation(s)
- Kang Li
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Xianhai Zeng
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Peng Liu
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Xiaoxia Zeng
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Jie Lv
- School of Computer Science and Engineering, Yulin Normal University, Yulin, Guangxi, People’s Republic of China
| | - Shuqi Qiu
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
| | - Peng Zhang
- Department of Graduate and Scientific Research, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, People’s Republic of China
- Department of Otorhinolaryngology, Longgang Otorhinolaryngology Hospital & Shenzhen Key Laboratory of Otorhinolaryngology, Shenzhen Institute of Otorhinolaryngology, Shenzhen, Guangdong, People’s Republic of China
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Tsuchiya H, Matoba M, Nishino Y, Ota K, Doai M, Nagata H, Tuji H. Clinical utility of combined assessments of 4D volumetric perfusion CT, diffusion-weighted MRI and 18F-FDG PET-CT for the prediction of outcomes of head and neck squamous cell carcinoma treated with chemoradiotherapy. Radiat Oncol 2023; 18:24. [PMID: 36747228 PMCID: PMC9901150 DOI: 10.1186/s13014-023-02202-x] [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: 03/27/2022] [Accepted: 01/07/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Multiparametric imaging has been seen as a route to improved prediction of chemoradiotherapy treatment outcomes. Four-dimensional volumetric perfusion CT (4D PCT) is useful for whole-organ perfusion measurement, as it reflects the heterogeneity of the tumor and its perfusion parameters. However, there has been no study using multiparametric imaging including 4D PCT for the prognostic prediction of chemoradiotherapy. The purpose of this study was to determine whether combining assessments of 4D PCT with diffusion-weighted MRI (DWI) and 18F-fluorodeoxyglucose PET-CT could enhance prognostic accuracy in head and neck squamous cell carcinoma (HNSCC) patients treated with chemoradiotherapy. METHODS We examined 53 patients with HNSCC who underwent 4D PCT, DWI and PET-CT before chemoradiotherapy. The imaging and clinical parameters were assessed the relations to locoregional control (LRC) and progression-free survival (PFS) by logistic regression analyses. A receiver operating characteristic (ROC) analysis was performed to assess the accuracy of the significant parameters identified by the multivariate analysis for the prediction of LRC and PFS. We additionally assessed using the scoring system whether these independent parameters could have a complementary role for the prognostic prediction. RESULTS The median follow-up was 30 months. In multivariate analysis, blood flow (BF; p = 0.02) and blood volume (BV; p = 0.04) were significant prognostic factors for LRC, and BF (p = 0.03) and skewness of the ADC histogram (p = 0.02) were significant prognostic factors for PFS. A significant positive correlation was found between BF and BV (ρ = 0.6, p < 0.001) and between BF and skewness (ρ = 0.46, p < 0.01). The ROC analysis showed that prognostic accuracy for LRC of BF, BV, and combination of BF and BV were 77.8%, 70%, and 92.9%, and that for PFS of BF, skewness, and combination of BF and skewness were 55.6%, 63.2%, and 77.5%, respectively. The scoring system demonstrated that the combination of higher BF and higher BV was significantly associated with better LRC (p = 0.04), and the combination of lower BF and lower skewness was significantly associated with worse PFS (p = 0.004). CONCLUSION A combination of parameters derived from 4DPCT and ADC histograms may enhance prognostic accuracy in HNSCC patients treated with chemoradiotherapy.
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Affiliation(s)
- Hirokazu Tsuchiya
- grid.411998.c0000 0001 0265 5359Department of Radiology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku, Ishikawa 920-0293 Japan
| | - Munetaka Matoba
- Department of Radiology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
| | - Yuka Nishino
- grid.411998.c0000 0001 0265 5359Department of Radiology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku, Ishikawa 920-0293 Japan
| | - Kiyotaka Ota
- grid.411998.c0000 0001 0265 5359Department of Radiology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku, Ishikawa 920-0293 Japan
| | - Mariko Doai
- grid.411998.c0000 0001 0265 5359Department of Radiology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku, Ishikawa 920-0293 Japan
| | - Hiroji Nagata
- grid.411998.c0000 0001 0265 5359Section of Radiological Technology, Department of Medical Technology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku, Ishikawa 920-0293 Japan
| | - Hiroyuki Tuji
- grid.411998.c0000 0001 0265 5359Department of Head and Neck Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku, Ishikawa 920-0293 Japan
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The value of plasma hypoxia markers for predicting imaging-based hypoxia in patients with head-and-neck cancers undergoing definitive chemoradiation. Clin Transl Radiat Oncol 2022; 33:120-127. [PMID: 35243023 PMCID: PMC8881198 DOI: 10.1016/j.ctro.2022.02.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 11/22/2022] Open
Abstract
Higher osteopontin plasma levels correlate with more hypoxic tumors at baseline. Increased baseline osteopontin levels are associated with residual tumor hypoxia. Absent early hypoxia response is linked with higher VEGF and CTGF levels in week 5. Plasma hypoxic markers may serve as biomarkers favoring radiotherapy personalization. Background Methods Results Conclusion
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Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, McCole M, Derham JL, Chu KY, Teoh E, Chauhan J, O'Reilly D, Harris BHL, Macklin PS, Bull JA, Green M, Rodriguez-Berriguete G, Prevo R, Folkes LK, Campo L, Ferencz P, Croal PL, Flight H, Qi C, Holmes J, O'Connor JPB, Gleeson FV, McKenna WG, Harris AL, Bulte D, Buffa FM, Macpherson RE, Higgins GS. Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer. Clin Cancer Res 2021; 27:2459-2469. [PMID: 33597271 PMCID: PMC7611473 DOI: 10.1158/1078-0432.ccr-20-4128] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/17/2021] [Accepted: 02/11/2021] [Indexed: 01/11/2023]
Abstract
PURPOSE Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. RESULTS Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. CONCLUSIONS This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.
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Affiliation(s)
- Michael Skwarski
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
- Department of Oncology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Daniel R McGowan
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
- Radiation Physics and Protection, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Elizabeth Belcher
- Department of Cardiothoracic Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Francesco Di Chiara
- Department of Cardiothoracic Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Dionisios Stavroulias
- Department of Cardiothoracic Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Mark McCole
- Department of Cellular Pathology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Jennifer L Derham
- Department of Oncology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Kwun-Ye Chu
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
- Department of Oncology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Eugene Teoh
- Department of Oncology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Jagat Chauhan
- Ludwig Institute for Cancer Research Oxford, University of Oxford, Oxford, England, United Kingdom
| | - Dawn O'Reilly
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Benjamin H L Harris
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Philip S Macklin
- Nuffield Department of Medicine, University of Oxford, Oxford, England, United Kingdom
| | - Joshua A Bull
- Wolfson Centre for Mathematical Biology, University of Oxford, Oxford, England, United Kingdom
| | - Marcus Green
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | | | - Remko Prevo
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Lisa K Folkes
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Leticia Campo
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Petra Ferencz
- Institute of Biomedical Engineering, University of Oxford, Oxford, England, United Kingdom
| | - Paula L Croal
- Institute of Biomedical Engineering, University of Oxford, Oxford, England, United Kingdom
| | - Helen Flight
- Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Cathy Qi
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, England, United Kingdom
| | - Jane Holmes
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, England, United Kingdom
| | - James P B O'Connor
- Division of Cancer Sciences, University of Manchester, Manchester, England, United Kingdom
| | - Fergus V Gleeson
- Department of Radiology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - W Gillies McKenna
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Adrian L Harris
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Daniel Bulte
- Institute of Biomedical Engineering, University of Oxford, Oxford, England, United Kingdom
| | - Francesca M Buffa
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom
| | - Ruth E Macpherson
- Department of Radiology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
| | - Geoff S Higgins
- Department of Oncology, University of Oxford, Oxford, England, United Kingdom.
- Department of Oncology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, England, United Kingdom
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Exosomes secreted under hypoxia enhance stemness in Ewing's sarcoma through miR-210 delivery. Oncotarget 2020; 11:3633-3645. [PMID: 33088424 PMCID: PMC7546758 DOI: 10.18632/oncotarget.27702] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022] Open
Abstract
Intercellular communication between tumor cells within the hypoxic microenvironment promote aggressiveness and poor patient prognoses for reasons that remain unclear. Here we show that hypoxic Ewing’s sarcoma (EWS) cells release exosomes that promote sphere formation, a stem-like phenotype, in EWS cells by enhancing survival. Analysis of the hypoxic exosomal miRNA cargo identified a HIF-1α regulated miRNA, miR-210, as a potential mediator of sphere formation in cells exposed to hypoxic exosomes. Knockdown of HIF-1α in hypoxic EWS cells led to decreased exosomal miR-210 levels and reduced the capacity of hypoxic exosomes to form spheres. Inhibition of miR-210 in hypoxic spheres attenuated sphere formation and overexpression of miR-210 in normoxic spheres significantly enhanced the number of EWS spheres. Our results indicate that hypoxic exosomal miR-210 targets the proapoptotic protein CASP8AP2 in recipient cells. Moreover, the suppression of CASP8AP2 led to a reduction in apoptotic cells and increased sphere formation. Together, the findings in this study suggest that hypoxic exosomes promote stemness in EWS cells by delivering enriched miR-210 that is capable of down-regulating apoptotic pathways, resulting in the survival of cells with increased sphere formation. Future studies will further investigate the effects of EWS derived exosomal miRNAs on target genes and the role these interactions play in driving aggressiveness in hypoxic EWS tumors.
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van Schaik JE, Hanemaaijer SH, Halmos GB, Witjes MJH, van der Laan BFAM, van der Vegt B, Plaat BEC. Glycoprotein Nonmetastatic Melanoma Protein B as Potential Imaging Marker in Posttherapeutic Metastatic Head and Neck Cancer. Otolaryngol Head Neck Surg 2020; 163:1202-1208. [PMID: 32600105 PMCID: PMC7708663 DOI: 10.1177/0194599820932869] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Objective To evaluate expression of potential molecular imaging targets epidermal growth factor receptor (EGFR), glycoprotein nonmetastatic melanoma protein B (GPNMB), and vascular endothelial growth factor (VEGF) in lymph nodes (LNs) with or without head and neck squamous cell carcinoma (HNSCC) metastases after (chemo)radiation. Study Design Retrospective study comparing receptor expression in paired lymph nodes after initial treatment. Setting A tertiary referral hospital. Subjects and Methods Salvage neck dissection specimens of 40 patients treated with (chemo)radiation were selected. LNs that contained viable tumor, reactive changes after initial treatment, and normal LNs were analyzed using immunohistochemically determined H-scores and by calculating sensitivity and specificity rates and positive/negative predictive values (PPVs/NPVs). Results EGFR expression was found in 86% and GPNMB expression in 100% of the LNs with viable tumor. VEGF expression was present in all lymph node types. For EGFR, the sensitivity rate was 86%, and specificity rate was 81%. For GPNMB, these were 100% and 75%, respectively. PPV of EGFR was 61.8% and NPV was 98.2%. These were 56.4% and 100% for GPNMB, respectively. Conclusion In residual or recurrent HNSCC lymph node metastases, both EGFR and GPNMB show tumor-specific expression in immunohistochemistry, which may prove useful in future molecular imaging in salvage neck dissections. Immunohistochemically detected VEGF expression indicates that this target is not feasible for imaging purposes in salvage surgery. Therefore, GPNMB could be a new potential imaging target showing comparable results to EGFR in immunohistochemistry.
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Affiliation(s)
- Jeroen E van Schaik
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Saskia H Hanemaaijer
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - György B Halmos
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Max J H Witjes
- Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bernard F A M van der Laan
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bert van der Vegt
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Boudewijn E C Plaat
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Kang HS, Shin AY, Yeo CD, Park CK, Kim JS, Kim JW, Kim SJ, Lee SH, Kim SK. Clinical significance of anemia as a prognostic factor in non-small cell lung cancer carcinoma with activating epidermal growth factor receptor mutations. J Thorac Dis 2020; 12:1895-1902. [PMID: 32642093 PMCID: PMC7330305 DOI: 10.21037/jtd-19-3932] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Anemia is a frequent finding in cancer patients. Pre-treatment anemia is known to be associated with poor survival after surgery or stereotactic body radiation therapy of non-small cell lung cancer (NSCLC). However, little study was conducted in NSCLC with activating epidermal growth factor receptor (EGFR) mutations. Methods This was a multicenter retrospective study conducted in seven university teaching hospitals in the Republic of Korea from January 2009 to February 2016. A total of 290 patients were diagnosed with NSCLC harboring sensitizing EGFR mutations and treated with EGFR-tyrosine kinase inhibitor (TKI) as 1st line. Of these patients, 104 met the exclusion criteria. Pre-treatment anemia was defined according to World Health Organization criteria (Hb concentration <13 g/dL for men and <12 g/dL for women). Results A total of 186 patients were finally included for analysis. Of these patients, 86 (46.2%) and 100 (53.8%) patients were classified into anemia and non-anemia groups, respectively. The anemia group had shorter median overall survival (OS) than the non-anemia group [24.83 (95% CI, 17.49–32.17) months vs. 42.10 (95% CI, 31.87–52.34) months, P=0.031]. In multivariate analysis, anemia (aHR, 2.573; 95% CI, 1.122–5.901; P=0.026) was only independent factors for poor OS. Conclusions Our study suggests that pre-treatment anemia is a significant poor prognostic factor for OS of NSCLC patients with EGFR mutations treated with EGFR-TKI.
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Affiliation(s)
- Hye Seon Kang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ah Young Shin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chang Dong Yeo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chan Kwon Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ju Sang Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Woo Kim
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Joon Kim
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Haak Lee
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Kyoung Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Berahovich R, Liu X, Zhou H, Tsadik E, Xu S, Golubovskaya V, Wu L. Hypoxia Selectively Impairs CAR-T Cells In Vitro. Cancers (Basel) 2019; 11:cancers11050602. [PMID: 31052261 PMCID: PMC6562712 DOI: 10.3390/cancers11050602] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/18/2019] [Accepted: 04/26/2019] [Indexed: 01/01/2023] Open
Abstract
Hypoxia is a major characteristic of the solid tumor microenvironment. To understand how chimeric antigen receptor-T cells (CAR-T cells) function in hypoxic conditions, we characterized CD19-specific and BCMA-specific human CAR-T cells generated in atmospheric (18% oxygen) and hypoxic (1% oxygen) culture for expansion, differentiation status, and CD4:CD8 ratio. CAR-T cells expanded to a much lower extent in 1% oxygen than in 18% oxygen. Hypoxic CAR-T cells also had a less differentiated phenotype and a higher CD4:CD8 ratio than atmospheric CAR-T cells. CAR-T cells were then added to antigen-positive and antigen-negative tumor cell lines at the same or lower oxygen level and characterized for cytotoxicity, cytokine and granzyme B secretion, and PD-1 upregulation. Atmospheric and hypoxic CAR-T cells exhibited comparable cytolytic activity and PD-1 upregulation; however, cytokine production and granzyme B release were greatly decreased in 1% oxygen, even when the CAR-T cells were generated in atmospheric culture. Together, these data show that at solid tumor oxygen levels, CAR-T cells are impaired in expansion, differentiation and cytokine production. These effects may contribute to the inability of CAR-T cells to eradicate solid tumors seen in many patients.
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Affiliation(s)
- Robert Berahovich
- ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA.
| | - Xianghong Liu
- ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA.
| | - Hua Zhou
- ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA.
| | - Elias Tsadik
- ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA.
| | - Shirley Xu
- ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA.
| | - Vita Golubovskaya
- ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA.
- Department of Medicine, University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Lijun Wu
- ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA.
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Yanazume S, Karakida N, Higashi R, Fukuda M, Togami S, Kamio M, Ota S, Kobayashi H. Tumor bleeding requiring intervention and the correlation with anemia in uterine cervical cancer for definitive radiotherapy. Jpn J Clin Oncol 2018; 48:892-899. [PMID: 30165631 DOI: 10.1093/jjco/hyy113] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Accepted: 07/17/2018] [Indexed: 01/31/2023] Open
Abstract
Background The prognostic impact of tumor bleeding requiring intervention and the correlation with anemia on the survival outcome of cervical cancer radiotherapy is unclear. Methods One hundred and ninety-six patients requiring hemostatic intervention between January 2006 and March 2014 were retrospectively investigated. The correlation between anemia and bleeding during radiotherapy, the prognostic impact of genital bleeding during radiotherapy and the influence of blood transfusion were estimated. Results None of the patients had incomplete or prolonged treatment exceeding 1 week due to bleeding. All tumor bleeding could be controlled by gauze packing, and no patients suffered from fatal genital bleeding. Bleeding significantly correlated with progression-free survival (P = 0.015) and overall survival (P = 0.048). Regarding the risk factors of anemia: age (P = 0.043), FIGO stage (P < 0.001), tumor diameter (P < 0.001), and bleeding (P = 0.002) were significant. Multivariate analysis revealed FIGO stage (Odds Ratio: 2.360; 95% CI = 1.202-4.633; P = 0.013), tumor diameter (Odds Ratio: 2.089; 95% CI = 1.048-4.162; P = 0.036) and Bleeding (Odds Ratio: 2.226; 95% CI = 1.052-4.709; P = 0.036) were independent to anemia. Anemia (Hazard Ratio = 1.894; 95% CI = 1.082-3.318; P = 0.025) was only independently correlated with progression free survival, while bleeding (Hazard Ratio = 1.156; 95% CI = 0.556-2.406; P = 0.698) had no independent correlation. Blood transfusion did not improve progression-free survival in patients with anemia or genital bleeding (P = 0.742). Conclusion We have proved that genital bleeding requiring intervention during cervical cancer radiotherapy is a negligible prognostic factor and is the independent factor for causing anemia. Easily bleeding tumors are potential prognostic markers, which are not effectively treated using existing radiotherapy.
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Affiliation(s)
- Shintaro Yanazume
- Department of Obstetrics & Gynecology, Faculty of Medicine, Kagoshima University
| | - Noriko Karakida
- Department of Gynecology, National Hospital Organization Kagoshima Medical Center
| | - Ryutaro Higashi
- Department of Radiology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | - Mika Fukuda
- Department of Obstetrics & Gynecology, Faculty of Medicine, Kagoshima University
| | - Shinichi Togami
- Department of Obstetrics & Gynecology, Faculty of Medicine, Kagoshima University
| | - Masaki Kamio
- Department of Obstetrics & Gynecology, Faculty of Medicine, Kagoshima University
| | - Shunichiro Ota
- Department of Gynecology, National Hospital Organization Kagoshima Medical Center
| | - Hiroaki Kobayashi
- Department of Obstetrics & Gynecology, Faculty of Medicine, Kagoshima University
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10
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Sintuyanon N, Phoolcharoen W, Pavasant P, Sooampon S. Resveratrol Demonstrated Higher Antiproliferative and Antiangiogenic Efficacy Compared with Oxyresveratrol on Head and Neck Squamous Cell Carcinoma Cell Lines. Nat Prod Commun 2017. [DOI: 10.1177/1934578x1701201134] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Resveratrol and its derivative, oxyresveratrol, have various pharmacological effects. Several studies demonstrated the anticancer activity of resveratrol. However, little is known about the anticancer activity of oxyresveratrol. In this study, we compared the antiproliferative and antiangiogenic effects of oxyresveratrol and resveratrol. Three head and neck squamous cell carcinoma cell lines (HSC-3, HN-8, and HN-30) were treated with a range of concentrations of either resveratrol or oxyresveratrol. MTT assays demonstrated that resveratrol and oxyresveratrol significantly inhibited cell survival in a dose-dependent manner. Although ELISA and Real-time PCR revealed that oxyresveratrol inhibited vascular endothelial growth factor (VEGF) expression at both the mRNA and protein level, the reduction was lower than that of resveratrol. Altogether, these findings indicate that oxyresveratrol possesses anticancer properties by inhibiting cancer cell proliferation and VEGF expression. However, its efficacy is lower compared with that of resveratrol.
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Affiliation(s)
- Napaporn Sintuyanon
- Interdepartmental Program of Pharmacology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
| | - Waranyoo Phoolcharoen
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Prasit Pavasant
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Sireerat Sooampon
- Department of Pharmacology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
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11
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Szubert S, Moszynski R, Michalak S, Nowicki M, Sajdak S, Szpurek D. The associations between serum VEGF, bFGF and endoglin levels with microvessel density and expression of proangiogenic factors in malignant and benign ovarian tumors. Microvasc Res 2016; 107:91-6. [PMID: 27312585 DOI: 10.1016/j.mvr.2016.06.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 05/27/2016] [Accepted: 06/12/2016] [Indexed: 11/19/2022]
Abstract
AIM OF THE STUDY To investigate whether serum levels of VEGF, bFGF and endoglin correlate with tumor VEGF and bFGF expression or microvessel density (MVD) in ovarian cancer. PATIENTS AND METHODS Forty five patients with epithelial ovarian cancers (EOCs) and 38 patients with benign ovarian tumors (BOTs) were included into the study. Serum levels of VEGF, bFGF and endoglin were assessed using ELISA. The expression of VEGF and bFGF in tumor samples were evaluated using ELISA of supernatants obtained from tumor homogenization. MVD was analyzed using immunohistochemistry with antibodies against CD31, CD34 and CD105. RESULTS Serum VEGF levels were significantly higher in EOCs than in BOTs (436.6pg/ml [19.67-2860] vs 295.5pg/ml [123-539], P=0.025). Serum endoglin levels were lowered in the group EOCs when compared to BOTs (33,720g/ml [12,220-73,940] vs 42,390pg/ml [19,380-56,910], P=0.015). There were no differences in bFGF levels between studied groups. EOCs have significantly higher CD105 MVD (25 vessels/mm2 [0-57] vs 6 vessels/mm2 [0-70], P<0.001) and tumor VEGF (405.9pg/mg protein [0-3000] vs 2.225 [0-634.7], P<0.001) expression than BOTs, while, bFGF expression was higher in BOTs than in EOCs (2076pg/mg protein [668.1-8718] vs 847.3pg/mg protein [188.9-8333], P=0.003). In patients with EOCs we have observed negative correlation between serum VEGF concentration and its tissue expression (r Spearman=-0.571, P=0.0261), and serum VEGF concentration correlated positively with CD34-MVD (r Spearman=0.545, P=0.0289). In a multiple regression analysis we have observed only the negative correlation between serum VEGF and CD105-MVD (r=-0.5288, P=0.0427). CONCLUSIONS Serum VEGF is a useful marker for prediction of ovarian cancer MVD and tumor VEGF expression.
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Affiliation(s)
- Sebastian Szubert
- Division of Gynecological Surgery, Poznan University of Medical Sciences, Poland.
| | - Rafal Moszynski
- Division of Gynecological Surgery, Poznan University of Medical Sciences, Poland
| | - Slawomir Michalak
- Department of Neurochemistry and Neuropathology, Poznan University of Medical Sciences, Poland; Neuroimmunological Unit Polish Academy of Sciences, Poland
| | - Michal Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poland
| | - Stefan Sajdak
- Division of Gynecological Surgery, Poznan University of Medical Sciences, Poland
| | - Dariusz Szpurek
- Division of Gynecological Surgery, Poznan University of Medical Sciences, Poland; Department of Obstetrics and Gynecology, Leszno Regional Hospital, Leszno, Poland
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12
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Daruwalla J, Greish K, Malcontenti-Wilson C, Muralidharan V, Maeda H, Christophi C. Styrene maleic acid copolymer-pirarubicin induces tumor-selective oxidative stress and decreases tumor hypoxia as possible treatment of colorectal cancer liver metastases. Surgery 2015; 158:236-47. [PMID: 25999256 DOI: 10.1016/j.surg.2015.03.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 03/08/2015] [Accepted: 03/11/2015] [Indexed: 11/28/2022]
Abstract
BACKGROUND Pirarubicin, a derivative of doxorubicin, induces tumor destruction via the production of reactive oxygen species (ROS) but is associated with cardiotoxicity. As a macromolecule (conjugated to styrene-maleic acid [SMA]), SMA-pirarubicin is selective to tumors resulting in improved survival with decreased systemic toxicity. Tumor destruction is, however incomplete, and resistant cells at the periphery of the tumor contribute to recurrence. Tumor hypoxia is a major factor in tumor resistance. Understanding the effect of oxidative stress induced by SMA-pirarubicin on the tumor microenvironment may be key to overcoming resistance. This study investigated the pattern of ROS production and tumor hypoxia after treatment with SMA-pirarubicin in a murine model of colorectal liver metastases. METHODS Liver metastases were induced in male, CBA mice using a murine-derived colon cancer cell line. SMA-pirarubicin (maximum tolerated dose, 100 mg/kg) or pirarubicin, (maximum tolerated dose, 10 mg/kg) were administered intravenously 14 days after tumor induction. Systemic oxidative stress in serum, liver, and cardiac tissue was quantified using the thiobarbituric acid reactive substances assay. Flow cytometry and fluorescence microscopy were used to assess ROS production for 48 hours after treatment. Tumor hypoxia was quantified using immunohistochemistry for pimonidazole adducts. RESULTS SMA-pirarubicin (100 mg/kg) induced ROS exclusively in tumors with minimal levels in serum and cardiac tissue. ROS levels were induced in a time-dependent and dose-dependent manner optimal between 4 and 24 hours after drug administration. Although tumor hypoxia was decreased overall, residual tumor cells adjacent to patent vessels were hypoxic. CONCLUSION This study provides insight into the tumor microenvironment after chemotherapy. SMA-pirarubicin inhibits the growth of colorectal liver metastases by inducing ROS, which seems to be largely tumor selective. The temporal pattern of ROS production can be used to improve future dosing regimens. Furthermore, the observation that residual tumor cells are hypoxic clarifies the need for a multimodal approach with agents that can alter the hypoxic state to effect complete tumor destruction.
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Affiliation(s)
- Jurstine Daruwalla
- Department of Surgery, University of Melbourne, Austin Health, Victoria, Australia.
| | - Khaled Greish
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; Department of Oncology, Suez Canal University, Ismaïlia, Egypt
| | | | | | - Hiroshi Maeda
- Institute of Drug Delivery Science, Sojo University, Kumamoto, Japan
| | - Chris Christophi
- Department of Surgery, University of Melbourne, Austin Health, Victoria, Australia
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Ostheimer C, Bache M, Güttler A, Kotzsch M, Vordermark D. A pilot study on potential plasma hypoxia markers in the radiotherapy of non-small cell lung cancer. Osteopontin, carbonic anhydrase IX and vascular endothelial growth factor. Strahlenther Onkol 2013; 190:276-82. [PMID: 24322994 DOI: 10.1007/s00066-013-0484-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 10/16/2013] [Indexed: 11/29/2022]
Abstract
BACKGROUND Hypoxic radioresistance plays a critical role in the radiotherapy of cancer and adversely impacts prognosis and treatment response. This prospective study investigated the interrelationship and the prognostic significance of several hypoxia-related proteins in non-small cell lung cancer (NSCLC) patients treated by radiotherapy ± chemotherapy. MATERIAL AND METHODS Pretreatment osteopontin (OPN), vascular endothelial growth factor (VEGF) and carbonic anhydrase IX (CA IX) plasma levels were determined by ELISA in 55 NSCLC (M0) patients receiving 66 Gy curative-intent radiotherapy or chemoradiation. Marker correlation, association with clinicopathological parameters and the prognostic value of a biomarker combination was evaluated. RESULTS All biomarkers were linearly correlated and linked to different clinical parameters including lung function, weight loss (OPN), gross tumor volume (VEGF) and T stage (CA IX). High OPN (p = 0.03), VEGF (p = 0.02) and CA IX (p = 0.04) values were significantly associated with poor survival. Double marker combination additively increased the risk of death by a factor of 2 and high plasma levels of the triple combination OPN/VEGF/CA IX yielded a 5.9-fold risk of death (p = 0.009). The combined assessment of OPN/VEGF/CA IX correlated independently with prognosis (p = 0.03) in a multivariate Cox regression model including N stage, T stage and GTV. CONCLUSION This pilot study suggests that a co-detection augments the prognostic value of single markers and that the integration of OPN, VEGF and CA IX into a hypoxic biomarker profile for the identification of patients with largely hypoxic and radioresistant tumors should be further evaluated.
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Affiliation(s)
- C Ostheimer
- Department of Radiation Oncology, Martin-Luther-University Halle-Wittenberg, Dryanderstr. 4, 06110, Halle (Saale), Germany,
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14
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Khademi B, Soleimanpour M, Ghaderi A, Mohammadianpanah M. Prognostic and predictive value of serum vascular endothelial growth factor (VEGF) in squamous cell carcinoma of the head and neck. Oral Maxillofac Surg 2013; 18:187-96. [PMID: 23456015 DOI: 10.1007/s10006-013-0402-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 02/18/2013] [Indexed: 12/20/2022]
Abstract
INTRODUCTION This study aimed to investigate the prognostic and predictive value of serum vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinoma (HNSCC). METHOD Preoperative and 6-month postoperative serum VEGF levels were measured using a quantitative sandwich enzyme immunoassay technique in 55 consecutive patients with HNSCC and two control groups. The first control group included normal, healthy, age- and sex-matched individuals (n = 20), while the second control group included the patients who had history of HNSCC and were free of disease for at least 5 years (n = 25). RESULTS The mean baseline serum VEGF concentrations of the 55 patients with HNSCC and the first and the second control groups were 437.86, 42.56, and 48.03 pg/ml, respectively (P < 0.001). After a median follow-up of 75 months, 15 patients of the study group developed recurrent disease and 40 patients remained free of disease. The mean preoperative and 6-month postoperative serum VEGF levels for the 40 patients who did not have recurrent disease were respectively 327.69 and 153.50 pg/ml compared to 731.72 and 692.96 pg/ml for the 15 patients with recurrent disease (P < 0.001). High (≥540 pg/ml) serum VEGF level was associated with poor overall survival (P < 0.001). Moreover, multivariate analysis showed node stage (P < 0.001) and preoperative serum VEGF level (P = 0.020) as significant, independent prognostic factors for overall survival. CONCLUSION Preoperative or postoperative elevated serum levels of VEGF are highly predictive for disease recurrence and are associated with poor disease-free and overall survival of patients with HNSCC.
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Affiliation(s)
- Bijan Khademi
- Department of Otolaryngology, and Head and Neck Surgery, Khalili Hospital, Shiraz University of Medical Sciences, Shiraz, 71936-13511, Iran
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15
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Li JZ, Gao W, Chan JYW, Ho WK, Wong TS. Hypoxia in head and neck squamous cell carcinoma. ISRN OTOLARYNGOLOGY 2012; 2012:708974. [PMID: 23762617 PMCID: PMC3671689 DOI: 10.5402/2012/708974] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 09/23/2012] [Indexed: 11/23/2022]
Abstract
Hypoxia is a common feature in most of the solid tumors including head and neck squamous cell carcinoma (HNSCC). Hypoxia reflects the imbalance between oxygen consumption by the rapidly proliferating cancer cells and the insufficient oxygen delivery due to poor vascularization and blood supply. The hypoxic microenvironment in the HNSCC contributes to the development of aggressive carcinoma phenotype with high metastatic rate, resistance to therapeutic agents, and higher tumor recurrence rates, leading to low therapeutic efficiency and poor outcome. To overcome the therapeutic resistance due to hypoxia and improving the prognosis of the HNSCC patients, many approaches have been examined in laboratory studies and clinical trials. In this short paper, we discuss the mechanisms involved in the resistance of radiotherapy and chemotherapy in hypoxic condition. We also exploit the molecular mechanisms employed by the HNSCC cells to adapt the hypoxic condition and their tumorigenic role in head and neck, as well as the strategies to overcome hypoxia-induced therapeutic resistance.
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Affiliation(s)
- John Zenghong Li
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pok Fu Lam, Hong Kong
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16
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Christopoulos A, Ahn SM, Klein JD, Kim S. Biology of vascular endothelial growth factor and its receptors in head and neck cancer: beyond angiogenesis. Head Neck 2010; 33:1220-9. [PMID: 21755565 DOI: 10.1002/hed.21588] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2009] [Revised: 07/06/2010] [Accepted: 07/23/2010] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis is a necessary process for tumor progression and is driven through molecular interactions between cancer cells and neighboring vascular endothelial cells. The primary mediators of angiogenesis are the vascular endothelial growth factors and their respective receptors on endothelial cells. There are several U.S. Food and Drug Administration-approved anti-angiogenic agents in clinical use. In head and neck cancer there are clinical trials assessing the efficacy of anti-angiogenic agents in combination with chemoradiation therapy. Although the aforementioned growth factors and receptors have been traditionally viewed as anti-angiogenic targets, there are concomitant efforts to understand the role these molecules play within the tumor cells. In this review, we first discuss the biology of angiogenic proteins and the targeting of angiogenic molecules for cancer treatment. We summarize the current clinical trials of anti-angiogenic therapies in head and neck squamous cell carcinoma. Finally, the additional role these molecules play in tumor progression independent of angiogenesis is discussed.
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Affiliation(s)
- Apostolos Christopoulos
- Division of Oto-rhino-laryngology, Department of Surgery, Université de Montréal, Montreal, Quebec, Canada
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17
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Latham AM, Molina-París C, Homer-Vanniasinkam S, Ponnambalam S. An integrative model for vascular endothelial growth factor A as a tumour biomarker. Integr Biol (Camb) 2010; 2:397-407. [DOI: 10.1039/c0ib00008f] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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18
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Abrantes AM, Serra ME, Murtinho D, Gonsalves AR, Botelho MF. An insight into tumoral hypoxia: the radiomarkers and clinical applications. Oncol Rev 2009. [DOI: 10.1007/s12156-009-0001-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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Abstract
Tumor hypoxia or a reduction of the tissue oxygen tension is a key microenvironmental factor for tumor progression and treatment resistance in solid tumors. Because hypoxic tumor cells have been demonstrated to be more resistant to ionizing radiation, hypoxia has been a focus of laboratory and clinical research in radiation therapy for many decades. It is believed that proper detection of hypoxic regions would guide treatment options and ultimately improve tumor response. To date, most clinical efforts in targeting tumor hypoxia have yielded equivocal results due to the lack of appropriate patient selection. However, with improved understanding of the molecular pathways regulated by hypoxia and the discovery of novel hypoxia markers, the prospect of targeting hypoxia has become more tangible. This chapter will focus on the development of clinical biomarkers for hypoxia targeting.
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Affiliation(s)
- Quynh-Thu Le
- Department of Radiation Oncology, Stanford University, 875 Blake Wilbur Dr, MC 5847, Stanford, CA 94305-5847, USA.
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20
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Baghi M, Wagenblast J, Hambek M, Moertel S, Gstoettner W, Strebhardt K, Knecht R. Pre-treatment haemoglobin level predicts response and survival after TPF induction polychemotherapy in advanced head and neck cancer patients. Clin Otolaryngol 2008; 33:245-51. [PMID: 18559031 DOI: 10.1111/j.1749-4486.2008.01702.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To investigate the prognostic value of the pre-treatment haemoglobin level in patients with advanced squamous cell head and neck cancer treated with induction polychemotherapy. DESIGN Seventy-two patients with advanced squamous cell head and neck cancer received primary combination chemotherapy consisting of docetaxel 75 mg/m(2) on day 1, cisplatin 100 mg/m(2) on day 1, and 5-fluorouracil (5-FU) 1000 mg/m(2)/day on days 1-4 (total dose 4000 mg/m(2)), repeated on days 1, 22 and 43 followed by chemoradiation. The data collected included pre-treatment haemoglobin, response to treatment, disease-free and overall survival. RESULTS The pre-treatment haemoglobin level was found to be a significant predictor of response to induction chemotherapy (P = 0.01) and an independent predictor of overall survival [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.58-1.03, P = 0.0001] and disease free survival (HR 2.09, 95% CI 1.41-3.09, P = 0.0001). Furthermore N-stage was found to be a significant prognostic factor of overall survival (HR 9.24, 95% CI 6.90-21.34, P = 0.005). The Eastern Cooperative Oncology Group performance status scale was also found to be significant for disease free survival (HR 7.66, 95% CI 2.61-22.46, P = 0.003). CONCLUSION In patients with advanced squamous cell head and neck cancer, the haemoglobin level prior to induction chemotherapy is significantly related to outcome including response and survival.
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Affiliation(s)
- M Baghi
- Department of Otorhinolaryngology, School of Medicine, J. W. Goethe University, Frankfurt am Main, Germany
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21
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Lee NY, Le QT. New developments in radiation therapy for head and neck cancer: intensity-modulated radiation therapy and hypoxia targeting. Semin Oncol 2008. [PMID: 18544439 DOI: 10.1053/j.seminoncol.2008.03.00332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Intensity-modulated radiation therapy (IMRT) has revolutionized radiation treatment for head and neck cancers (HNCs). When compared to the traditional techniques, IMRT has the unique ability to minimize the dose delivered to normal tissues without compromising tumor coverage. As a result, side effects from high-dose radiation have decreased and patient quality of life has improved. In addition to toxicity reduction, excellent clinical outcomes have been reported for IMRT. The first part of this review will focus on clinical results of IMRT for HNC. Tumor hypoxia, or the condition of low oxygen, is a key factor for tumor progression and treatment resistance. Hypoxia develops in solid tumors due to aberrant blood vessel formation, fluctuation in blood flow, and increasing oxygen demands for tumor growth. Because hypoxic tumor cells are more resistant to ionizing radiation, hypoxia has been a focus of clinical research in radiation therapy for half a decade. Interest for targeting tumor hypoxia has waxed and waned as promising treatments emerged from the laboratory, only to fail in the clinics. However, with the development of new technologies, the prospect of targeting tumor hypoxia is more tangible. The second half of the review will focus on approaches for assessing tumor hypoxia and on the strategies for targeting this important microenvironmental factor in HNC.
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Affiliation(s)
- Nancy Y Lee
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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22
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Lee NY, Le QT. New developments in radiation therapy for head and neck cancer: intensity-modulated radiation therapy and hypoxia targeting. Semin Oncol 2008; 35:236-50. [PMID: 18544439 PMCID: PMC2494523 DOI: 10.1053/j.seminoncol.2008.03.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Intensity-modulated radiation therapy (IMRT) has revolutionized radiation treatment for head and neck cancers (HNCs). When compared to the traditional techniques, IMRT has the unique ability to minimize the dose delivered to normal tissues without compromising tumor coverage. As a result, side effects from high-dose radiation have decreased and patient quality of life has improved. In addition to toxicity reduction, excellent clinical outcomes have been reported for IMRT. The first part of this review will focus on clinical results of IMRT for HNC. Tumor hypoxia, or the condition of low oxygen, is a key factor for tumor progression and treatment resistance. Hypoxia develops in solid tumors due to aberrant blood vessel formation, fluctuation in blood flow, and increasing oxygen demands for tumor growth. Because hypoxic tumor cells are more resistant to ionizing radiation, hypoxia has been a focus of clinical research in radiation therapy for half a decade. Interest for targeting tumor hypoxia has waxed and waned as promising treatments emerged from the laboratory, only to fail in the clinics. However, with the development of new technologies, the prospect of targeting tumor hypoxia is more tangible. The second half of the review will focus on approaches for assessing tumor hypoxia and on the strategies for targeting this important microenvironmental factor in HNC.
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Affiliation(s)
- Nancy Y. Lee
- Assistant Attending Physician, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center
| | - Quynh-Thu Le
- Professor, Department of Radiation Oncology, Stanford University
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23
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Abstract
One unique feature of tumors is the presence of hypoxic regions, which occur predominantly at the tumor center. Hypoxia has a major impact on various aspects of tumor cell function and proliferation. Hypoxic tumor cells are relatively insensitive to conventional therapy owing to cellular adaptations effected by the hypoxic microenvironment. Recent efforts have aimed to alter the hypoxic state and to reverse these adaptations to improve treatment outcome. One way to increase tumor oxygen tensions is by hyperbaric oxygen (HBO) therapy. HBO therapy can influence the tumor microenvironment at several levels. It can alter tumor hypoxia, a potent stimulus that drives angiogenesis. Hyperoxia as a result of HBO also produces reactive oxygen species, which can damage tumors by inducing excessive oxidative stress. This review outlines the importance of oxygen to tumors and the mechanisms by which tumors survive under hypoxic conditions. It also presents data from both experimental and clinical studies for the effect of HBO on malignancy.
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Affiliation(s)
- Jurstine Daruwalla
- Department of Surgery, University of Melbourne, Austin Hospital, Level 8 Lance Townsend Building, Austin Health, Studley Road, Heidelberg, Victoria, 3084 Australia.
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Gisterek I, Sedlaczek P, Kornafel J, Harłoziñska-Szmyrka A, Lacko A. Serum vascular endothelial growth factor in patients with pharyngeal and laryngeal squamous cell carcinoma treated with radiotherapy. Am J Otolaryngol 2007; 28:73-7. [PMID: 17362809 DOI: 10.1016/j.amjoto.2006.06.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2006] [Indexed: 11/22/2022]
Abstract
The aim of this study was to assess the impact of radiotherapy on serum vascular endothelial growth factor (VEGF) levels in patients with pharyngeal and laryngeal cancer. Serum VEGF concentrations were determined in 37 patients before, during, and after radiotherapy by using a quantitative sandwich enzyme immunoassay technique. Most (25 patients [68%]) of the studied population were found to have high pretreatment VEGF concentration (of >700 pg/mL; median, 796.3 pg/mL). During radiotherapy, after receiving the total dose of 40 Gy, the median level of serum VEGF remained unchanged (795.2 pg/mL). Regardless of the treatment results, 2 months after completing irradiation the median VEGF level decreased to 448.9 pg/mL, and the difference between pre- and posttreatment medians was statistically significant (P < .05). No association between pretreatment serum VEGF concentrations and the size of tumor, lymph node status, and patients' age was found. The findings that radiotherapy produces serum VEGF decline in primary pharyngeal and laryngeal carcinomas (P = .065) may be related to the blocking effect of radiation on local angiogenesis.
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Affiliation(s)
- Iwona Gisterek
- Department of Oncology Medical, Academy of Wrocław, Wrocław, Poland.
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25
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Martin SG, Orridge C, Mukherjee A, Morgan DAL. Vascular Endothelial Growth Factor Expression Predicts Outcome after Primary Radiotherapy for Head and Neck Squamous Cell Cancer. Clin Oncol (R Coll Radiol) 2007; 19:71-6. [PMID: 17305257 DOI: 10.1016/j.clon.2006.10.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIMS To establish whether the expression of vascular endothelial growth factors (VEGFs) predicts prognosis in patients treated with primary radiotherapy for cancers of the upper aerodigestive tract. MATERIALS AND METHODS A retrospective analysis was undertaken of VEGF and VEGF-D expression in tumour tissue in pre-treatment biopsies from 27 patients who had been treated with primary radiotherapy for stage II-IV squamous head and neck carcinomas. Serial sections (4 microm) were cut from formalin-fixed, paraffin-embedded specimens and stained with monoclonal antibodies using standard immunoperoxidase methods. Two independent investigators assessed the staining intensity in a randomised, blind manner. Both negative and positive controls (placenta and/or tonsil) were included in the staining procedure. All patients were followed for a minimum of 5 years, or until death. Local control and overall survival were taken as end points for the comparative analysis between patients whose tumours expressed low levels and those that expressed high levels of the two growth factors. Comparisons were made using the Log-rank test with Kaplan-Meier actuarial survival analysis. RESULTS In patients with tumours expressing low levels of VEGF, 5-year local control was seen in 75% compared with 18% for those with high levels; overall survival was 75 and 23%, respectively. For those with low levels of VEGF-D, 5-year local control was 64% compared with 17% for those with high levels; overall survival was 58 and 20%, respectively. CONCLUSION Our results suggest that the expression of endothelial growth factors in squamous head and neck cancers may predict outcome after radiotherapy.
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Affiliation(s)
- S G Martin
- Department of Clinical Oncology, School of Molecular Medical Sciences, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK
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Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KSC, Chapman JD, Eckelman WC, Fyles AW, Giaccia AJ, Hill RP, Koch CJ, Krishna MC, Krohn KA, Lewis JS, Mason RP, Melillo G, Padhani AR, Powis G, Rajendran JG, Reba R, Robinson SP, Semenza GL, Swartz HM, Vaupel P, Yang D, Croft B, Hoffman J, Liu G, Stone H, Sullivan D. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 2007; 82:699-757. [PMID: 17118889 DOI: 10.1080/09553000601002324] [Citation(s) in RCA: 473] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
PURPOSE The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable. RESULTS Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. CONCLUSIONS This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.
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Affiliation(s)
- James L Tatum
- National Cancer Institute, Executive Plaza North, Room 6000, 6130 Executive Boulevard, Rockville, MD 20852-7440, USA.
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Chung CH, Wong S, Ang KK, Hammond EH, Dicker AP, Harari PM, Le QT. Strategic plans to promote head and neck cancer translational research within the radiation therapy oncology group: a report from the translational research program. Int J Radiat Oncol Biol Phys 2007; 69:S67-78. [PMID: 17848300 PMCID: PMC2064008 DOI: 10.1016/j.ijrobp.2007.04.090] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2007] [Revised: 03/28/2007] [Accepted: 04/05/2007] [Indexed: 11/28/2022]
Abstract
Head and neck cancer is the fifth most common cancer in the United States, with an overall survival rate of approximately 40-50%. In an effort to improve patient outcomes, research efforts designed to maximize benefit and reduce toxicities of therapy are in progress. Basic research in cancer biology has accelerated this endeavor and provided preclinical data and technology to support clinically relevant advances in early detection, prognostic and predictive biomarkers. Recent completion of the Human Genome Project has promoted the rapid development of novel "omics" technologies that allow more broad based study from a systems biology perspective. However, clinically relevant application of resultant gene signatures to clinical trials within cooperative groups has advanced slowly. In light of the large numbers of variables intrinsic to biomarker studies, validation of preliminary data for clinical implementation presents a significant challenge and may only be realized with large trials that involve significant patient numbers. The Radiation Therapy Oncology Group (RTOG) Head and Neck Cancer Translational Research Program recognizes this problem and brings together three unique features to facilitate this research: (1) availability of large numbers of clinical specimens from homogeneously treated patients through multi-institutional clinical trials; (2) a team of physicians, scientists, and staff focused on patient-oriented head-and-neck cancer research with the common goal of improving cancer care; and (3) a funding mechanism through the RTOG Seed Grant Program. In this position paper we outline strategic plans to further promote translational research within the framework of the RTOG.
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Affiliation(s)
- Christine H Chung
- Head and Neck Cancer Subcommittee, Translational Research Program, Radiation Therapy Oncology Group: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA.
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Stadler P, Putnik K, Kreimeyer T, Sprague LD, Koelbl O, Schäfer C. Split course hyperfractionated accelerated radio-chemotherapy (SCHARC) for patients with advanced head and neck cancer: influence of protocol deviations and hemoglobin on overall survival, a retrospective analysis. BMC Cancer 2006; 6:279. [PMID: 17150114 PMCID: PMC1702360 DOI: 10.1186/1471-2407-6-279] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Accepted: 12/07/2006] [Indexed: 11/17/2022] Open
Abstract
Background The advantage of hyperfractionated accelerated radiation therapy for advanced head and neck cancer has been reported. Furthermore, randomized trials and meta-analyses have confirmed the survival benefit of additional chemotherapy to radiotherapy. We retrospectively analyzed the efficiency and toxicity of the Regensburg standard therapy protocol "SCHARC" and the overall survival of our patients. Methods From 1997 to 2004, 64 patients suffering from advanced head and neck cancer (88 % stage IV, 12 % stage III) were assigned to receive the SCHARC protocol. Around half of the patients were diagnosed with oro-hypopharynx carcinoma (52 %), one third with tongue and floor of mouth tumors (29 %) and one fifth (19 %) suffered from H & N cancer at other sites. The schedule consisted of one therapy block with 30 Gy in 20 fractions over a two week period with concomitant chemotherapy (d 1–5: 20 mg/m2/d DDP + 750–1000 mg/m2/d 5FU (cont. infusion). This therapy block was repeated after a fortnight break up to a cumulative dose of 60 Gy and followed by a boost up to 70 Gy (69–70.5 Gy). All patients assigned to this scheme were included in the survival evaluation. Results Forty patients (63 %) received both radiation and chemotherapy according to the protocol. The mean follow up was 2.3 years (829 d) and the median follow up was 1.9 years (678 d), respectively. The analysis of survival revealed an estimated 3 year overall survival rate of 57 %. No patient died of complications, 52 patients (80 %) had acute grade 2–3 mucositis, and 33 patients (58 %) suffered from acute grade 3 skin toxicity. Leucopenia was no major problem (mean nadir 3.4 g/nl, no patient < 1.0 g/nl) and the mean hemoglobin value decreased from 13.2 to 10.5 g/dl. Univariate analysis of survival showed a better outcome for patients with a hemoglobin nadir >10.5 g/dl and for patients who completed the protocol. Conclusion The SCHARC protocol was effective in patients diagnosed with advanced head and neck cancer. It led to long-term disease control and survival in about 50 % of the patients with significant but acceptable toxicity. Most patients were not anemic at beginning of therapy. Therefore, we could assess the influence of pre-treatment hemoglobin on survival. However, a low hemoglobin nadir was associated with poor outcome. This result suggests an influence of anemia during therapy on prognosis.
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Affiliation(s)
- Peter Stadler
- Department of Radiotherapy and Radiation Oncology, University Hospital Regensburg, Germany
- Praxis Muehleninsel Landshut-Muehldorf-Dingolfing, Germany
| | - Kurt Putnik
- Department of Radiotherapy and Radiation Oncology, University Hospital Regensburg, Germany
| | - Thore Kreimeyer
- Department of Radiotherapy and Radiation Oncology, University Hospital Regensburg, Germany
| | - Lisa D Sprague
- Department of Radiotherapy and Radiation Oncology, University Hospital TU Munich, Germany
| | - Oliver Koelbl
- Department of Radiotherapy and Radiation Oncology, University Hospital Regensburg, Germany
| | - Christof Schäfer
- Department of Radiotherapy and Radiation Oncology, University Hospital Regensburg, Germany
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Goethals L, Debucquoy A, Perneel C, Geboes K, Ectors N, De Schutter H, Penninckx F, McBride WH, Begg AC, Haustermans KM. Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers. Int J Radiat Oncol Biol Phys 2006; 65:246-54. [PMID: 16618579 DOI: 10.1016/j.ijrobp.2006.01.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Revised: 01/03/2006] [Accepted: 01/03/2006] [Indexed: 11/26/2022]
Abstract
PURPOSE To detect and quantify hypoxia in colorectal adenocarcinomas by use of pimonidazole and iododeoxyuridine (IdUrd) as extrinsic markers and carbonic anhydrase IX (CA IX), microvessel density (MVD), epidermal growth-factor receptor (EGFR), and vascular endothelial growth factor (VEGF) as intrinsic markers of hypoxia. METHODS AND MATERIAL Twenty patients with an adenocarcinoma of the left colon and rectum treated by primary surgery were injected with pimonidazole and IdUrd. Serial sections of tumor biopsies were single stained for VEGF, EGFR, Ki67, and double stained for blood vessels in combination with either pimonidazole, IdUrd, or CA IX. Percentage of expression was scored as well as colocalization of pimonidazole with CA IX. RESULTS The median percentage of hypoxia, as judged by pimonidazole staining, was 16.7% (range, 0-52.4%). The expression of pimonidazole correlated inversely with the total MVD and endothelial cord MVD (R = -0.55, p = 0.01; R = -0.47, p = 0.04). Good colocalization was found between pimonidazole and CA IX in only 30% of tumors, with no correlation overall between pimonidazole and CA IX, VEGF, or EGFR or between the different intrinsic markers. Cells around some vessels (0.08-11%) were negative for IdUrd but positive for Ki 67, which indicated their lack of perfusion at the time of injection. CONCLUSION Chronic and acute hypoxic regions are present in colorectal tumors, as shown by pimonidazole and IdUrd staining. Only in a minority of tumors did an association exist between the areas stained by pimonidazole and those positive for CA IX. Pimonidazole also did not correlate with expression of other putative intrinsic hypoxia markers (VEGF, EGFR).
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Affiliation(s)
- Laurence Goethals
- Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium
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Wergin MC, Roos M, Inteeworn N, Laluhovà D, Allemann K, Kaser-Hotz B. The influence of fractionated radiation therapy on plasma vascular endothelial growth factor (VEGF) concentration in dogs with spontaneous tumors and its impact on outcome. Radiother Oncol 2006; 79:239-44. [PMID: 16677728 DOI: 10.1016/j.radonc.2006.03.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2004] [Revised: 01/19/2006] [Accepted: 03/28/2006] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND PURPOSE Vascular endothelial growth factor (VEGF), a specific pro-angiogenic factor is proposed to be involved in cancer progression and resistance to radiation therapy by promoting angiogenesis and by protecting endothelial cells from radiation induced apoptosis. The aim of this study, was first to assess the influence of ionizing radiation on plasma VEGF concentration in spontaneous canine tumors during fractionated radiation therapy with curative or palliative intent and second to analyze plasma VEGF concentration as predictor for treatment outcome. PATIENTS AND METHODS For plasma VEGF analysis a human VEGF enzyme linked immunosorbent assay was used. Sixty dogs with various tumor types were included in this study. Dogs were irradiated with either low dose per fx (3-3.5 Gy per fraction, total dose: 42-49 Gy, group A: curative intent) or high dose per fx (6-8 Gy per fraction, total dose: 24-30 Gy, group B: palliative intent). Blood samples were taken before and after dose application at certain time points during therapy. Follow-up evaluation was performed for analysis of time to treatment failure and survival. RESULTS Repeated measures analysis showed no increase of plasma VEGF in dogs treated with fractionated radiation therapy (group A and B). Dichotomizing baseline plasma VEGF into two groups with high and low plasma VEGF, resulted in shorter time to treatment failure in dogs with high plasma VEGF levels (TTF, group A: P=0.038, group B: P=0.041). CONCLUSIONS This study demonstrated that dogs with a plasma VEGF level higher than 5 pg/ml had a poorer outcome after radiation therapy. It is therefore, suggested, to use plasma VEGF as predictor for treatment outcome in radiation therapy.
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Affiliation(s)
- Melanie C Wergin
- Diagnostic Imaging and Radio-Oncology, Vetsuisse Faculty, University of Zurich, Switzerland.
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De Schutter H, Landuyt W, Verbeken E, Goethals L, Hermans R, Nuyts S. The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy +/- chemotherapy. BMC Cancer 2005; 5:42. [PMID: 15847702 PMCID: PMC1097720 DOI: 10.1186/1471-2407-5-42] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2004] [Accepted: 04/25/2005] [Indexed: 01/30/2023] Open
Abstract
Background Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC) treated by radiotherapy ± chemotherapy. Methods We used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67), immunohistochemistry for carbonic anhydrase IX (CA IX) and glucose transporter-1 (GLUT-1) was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34), enzyme linked immunosorbent assay (ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated. Results For CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02) and disease-free survival (p = 0.04) with a trend for regional control (p = 0.06). In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009), disease-free survival (p = 0.02) and overall survival (p = 0.005). Conclusion To our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be the most important parameter to judge radiotherapy responses. Furthermore, the combined assessment of CA IX and GLUT-1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers.
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Affiliation(s)
- Harlinde De Schutter
- Department of Radiation Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
| | - Willy Landuyt
- Department of Radiation Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
| | - Erik Verbeken
- Department of Pathology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
| | - Laurence Goethals
- Department of Radiation Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
| | - Robert Hermans
- Department of Radiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
| | - Sandra Nuyts
- Department of Radiation Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
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Ludovini V, Gregorc V, Pistola L, Mihaylova Z, Floriani I, Darwish S, Stracci F, Tofanetti FR, Ferraldeschi M, Di Carlo L, Ragusa M, Daddi G, Tonato M. Vascular endothelial growth factor, p53, Rb, Bcl-2 expression and response to chemotherapy in advanced non-small cell lung cancer. Lung Cancer 2005; 46:77-85. [PMID: 15364135 DOI: 10.1016/j.lungcan.2004.03.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2003] [Revised: 03/26/2004] [Accepted: 03/31/2004] [Indexed: 11/25/2022]
Abstract
Vascular endothelial growth factor (VEGF) increases microvascular permeability and stimulates endothelial cell growth. p53 Overexpression has been associated with resistance to cisplatin-based chemotherapy in patients (pts) with NSCLC. The aim of this study was to evaluate the predictive role of VEGF for chemotherapy response, its relationship with p53, Rb, Bcl-2 and hemoglobin levels and its impact on overall survival in pts with advanced NSCLC. Bronchial or fine-needle biopsy specimens from 85 pts with NSCLC obtained before chemotherapy were analyzed using an immunohistochemical method for VEGF, p53, Rb and Bcl-2. There were 73 males and 12 females with a median age of 62.6 years. The majority of pts (48%) had squamous cell histology. Ten pts had stage IIIA, 25 stage IIIB and 50 stage IV. Thirty six (43%) pts had positive immunostaining for VEGF, 37 (44%) had positive p53, 53 (62%) had negative Rb and 4 (5%) had positive Bcl-2. VEGF was negatively correlated with Rb (r(s) = 0.26; P = 0.015), positively with Bcl-2 (r(s) = 0.22; P = 0.42), whereas no statistically significant correlation with p53, age, stage and histological type was found. In a logistic regression model, adjusting for treatment, VEGF expression was not associated with chemotherapy response (odds ratio (OR) = 1.01; P = 0.085 ), unlike p53 positivity and Rb negativity ( OR = 4.0, P = 0.005; OR = 2.6, P = 0.016, respectively). A statistically significant higher VEGF expression was detected in the subgroups defined, using as cut-off value Hb median level (13.3g/dl) (chi-square = 5.00; ; one d.f.; P = 0.025). At a median follow-up time of 8.4 years, 2-year survival was 21%. After adjustment for stage and chemotherapy treatment, VEGF expression was not associated with a better overall survival (OR = 1.06; P = 0.80), unlike Bcl-2 positivity showed a statistically significant effect (OR = 0.28; p = 0.02). Our results suggest that VEGF is weakly correlated with regulators of apoptosis and has not been shown to be an independent predictive factor for resistance to cisplatin-based chemotherapy and prognostic for survival.
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Affiliation(s)
- Vienna Ludovini
- Division of Medical Oncology, Policlinico Monteluce Hospital, Via Brunamonti 51, 06122 Perugia, Italy.
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Gebbia V, Di Marco P, Citarrella P. Systemic chemotherapy in elderly patients with locally advanced and/or inoperable squamous cell carcinoma of the head and neck: impact of anemia and role of recombinant human erythropoietin. Crit Rev Oncol Hematol 2003; 48:S49-S55. [PMID: 14563521 DOI: 10.1016/j.critrevonc.2003.07.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
A review of the incidence and management of anemia in elderly patients with head and neck carcinoma treated with systemic chemotherapy. The role of recombinant human erythropoietin in preventing or correcting chemotherapy-related anemia has been focused. Data concerning the prospective use of recombinant human erythropoietin (rhEpo) in a series of unfit elderly patients (EPs) treated with carboplatin plus 5-fluorouracil. Patients were randomly assigned to receive subcutaneous rhEpo 10,000U three times per week (TIW) (23 elderly patients) or no treatment (22 control patients). Recombinant hEpo was able to prevent anemia and to reduce transfusional requirements in treated patients as compared to untreated controls with a statistically significant difference. rhEpo also caused a positive effect on quality of life (QoL) parameters.
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Affiliation(s)
- Vittorio Gebbia
- Medical Oncology Researcher, Chair of Hematology, University of Palermo, Via Alessandro Paternostro n. 48, 9013 Palermo, Italy.
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Dunst J, Kuhnt T, Strauss HG, Krause U, Pelz T, Koelbl H, Haensgen G. Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys 2003; 56:778-87. [PMID: 12788185 DOI: 10.1016/s0360-3016(03)00123-8] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE The prognostic impact of anemia in cervical cancers is well established. We have investigated the impact of anemia on prognosis and patterns of relapse in cervical cancers. Furthermore, we analyzed the relationship between anemia, tumor hypoxia, and angiogenesis. METHODS AND MATERIALS Eighty-seven patients (mean age 58 years) with squamous cell cancer of the cervix (Stage IIB: n = 19; Stage IIIB: n = 59; Stage IVA: n = 9) were prospectively enrolled in the study from 1995 through 1999. Patients underwent definitive radiotherapy with a combination of external beam radiotherapy (45-50.4 Gy) and high-dose-rate brachytherapy (5 x 7 Gy). Tumor oxygenation was measured with the Eppendorf pO(2)-histograph before radiotherapy and after 19.8 Gy. Angiogenesis was determined by measuring the microvessel density in pretreatment biopsies in 46 patients. The impact of tumor oxygenation (at 0 Gy and 19.8 Gy), hemoglobin (hb) level (at 0 Gy and 19.8 Gy), angiogenesis and clinical parameters on survival and relapse was investigated. RESULTS The 3-year overall survival rate (after a median follow-up of 42 months) was 57% for the whole group of patients, 72% for Stage IIB, 60% for Stage IIIB, and 22% for Stage IVA. The presence of pretreatment anemia had a significant impact on the relapse rate. However, the midtherapy hb level (at 19.8 Gy) had the strongest impact on local failure rate and survival: 3-year local failure rate was 6% in 20 patients with a hb > 13 g/dL at 19.8 Gy, 15% in 47 patients with an hb between 11 and 13 g/dL, and 67% in 20 patients with an hb < 11 g/dL, p = 0.0001. This was associated with a significant impact on the 3-year overall survival, 79% vs. 64% vs. 32%. Twenty-three tumors were poorly oxygenated at both measurements (oxygen pressure [median pO(2)] < 15 mm Hg before therapy and at 19.8 Gy). This group had a significantly lower 3-year overall survival as compared with patients with high pO(2) before and/or at 19.8 Gy (38% vs. 68%, p = 0.02), and these poorly oxygenated tumors had also a significantly increased microvessel density. In a multivariate model, the midtherapy hb level maintained an overwhelming impact on local failure rate and survival. CONCLUSION Hemoglobin level during radiotherapy was the strongest prognostic factor for local control and survival. We could further identify a poor prognostic subgroup with persisting hypoxia during radiotherapy, low hb levels, and increased angiogenesis. According to these findings, an association between anemia, poor tumor oxygenation, and angiogenesis is likely.
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Affiliation(s)
- Juergen Dunst
- Department of Radiotherapy, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
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Feldman L, Sytkowski AJ. Pleiotrophic actions of erythropoietin. Environ Health Prev Med 2003; 7:239-45. [PMID: 21432392 PMCID: PMC2723462 DOI: 10.1007/bf02908882] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2002] [Accepted: 08/15/2002] [Indexed: 11/29/2022] Open
Abstract
Erythropoietin is the prime regulator of red blood cell production. However, recent evidence suggests that the hormone has multiple effects outside the hematopoietic system. Functional receptors have been identified on a wide variety of normal and malignant cell types, and numerous biologic effects of the hormone on these cells have been observed both in vitro and in vivo. These findings are causing a reassessment of the understanding of erythropoietin physiology. Moreover, there are important implications for the use of recombinant erythropoietin in the clinical setting.
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Affiliation(s)
- Laurie Feldman
- Laboratory for Cell and Molecular Biology, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, 330 Brookline Ave., W/BL 548, 02215 Boston, Massachusetts USA
| | - Arthur J. Sytkowski
- Laboratory for Cell and Molecular Biology, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, 330 Brookline Ave., W/BL 548, 02215 Boston, Massachusetts USA
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Guo WJ, Li J, Ling WL, Bai YR, Zhang WZ, Cheng YF, Gu WH, Zhuang JY. Influence of hepatic arterial blockage on blood perfusion and VEGF, MMP-1 expression of implanted liver cancer in rats. World J Gastroenterol 2002; 8:476-9. [PMID: 12046073 PMCID: PMC4656424 DOI: 10.3748/wjg.v8.i3.476] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of hepatic arterial blockage on blood perfusion of transplanted cancer in rat liver and the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-1 (MMP-1), and to explore the mechanisms involved in transarterial embolization (TAE)-induced metastasis of liver cancer preliminarily.
METHODS: Walker 256 carcinosarcoma was transplanted into rat liver to establish the liver cancer model. Hepatic arterial ligation (HAL) was used to block the hepatic arterial blood supply and simulate TAE. Blood perfusion of tumor in control, laparotomy control, and HAL group was analyzed by Hoechst 33342 labeling assay, the serum VEGF level was assayed by ELISA, the expression of VEGF and MMP-1 mRNA was detected by in situ hybridization.
RESULTS: Two days after HAL, the number of Hoechst 33342 labeled cells which represent the blood perfusion of tumor directly and hypoxia of tumor indirectly in HAL group decreased significantly compared with that in control group (329 ± 29 vs 384 ± 19, P < 0.01). The serum VEGF level in the HAL group increased significantly as against that of the control group (93 ng·L-1± 44 ng·L-1vs 55 ng·L-1± 19 ng·L-1, P < 0.05). The expression of VEGF and MMP-1 mRNA in the tumor tissue of the HAL group increased significantly compared with that of the control and the laparotomy control groups (P < 0.05). The blood perfusion data of the tumor, represented by the number of Hoechst 33342 labeled cells, showed a good linear inverse correlation with the serum VEGF level (r = -0.606, P < 0.05) and the expression of VEGF mRNA in the tumor tissue (r = -0.338, P < 0.01).
CONCLUSION: Blockage of hepatic arterial blood supply results in decreased blood perfusion and increased expression of metastasis-associated genes VEGF and MMP-1 of transplanted liver cancer in rats. Decreased blood perfusion and hypoxia may be the major cause of up-regulated expression of VEGF.
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MESH Headings
- Animals
- Carcinoma 256, Walker/blood supply
- Carcinoma 256, Walker/genetics
- Carcinoma 256, Walker/secondary
- Embolization, Therapeutic/adverse effects
- Endothelial Growth Factors/blood
- Endothelial Growth Factors/genetics
- Gene Expression
- Hepatic Artery
- Ligation
- Liver Neoplasms, Experimental/blood supply
- Liver Neoplasms, Experimental/genetics
- Lymphokines/blood
- Lymphokines/genetics
- Male
- Matrix Metalloproteinase 1/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Rats
- Rats, Wistar
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factors
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Affiliation(s)
- Wei-Jian Guo
- Department of Oncology, Xinhua Hospital of Shanghai Second Medical University, 1665 Kongjiang Road, Shanghai 200092, China.
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