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Guerreiro A, Compañón I, Lazaris FS, Labão-Almeida C, Oroz P, Ghirardello M, Marques MC, Corzana F, Bernardes GJL. Non-Natural MUC1 Glycopeptide Homogeneous Cancer Vaccine with Enhanced Immunogenicity and Therapeutic Activity. Angew Chem Int Ed Engl 2024; 63:e202411009. [PMID: 39275921 DOI: 10.1002/anie.202411009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 09/16/2024]
Abstract
Glycopeptides derived from the glycoprotein mucin-1 (MUC1) have shown potential as tumor-associated antigens for cancer vaccine development. However, their low immunogenicity and non-selective conjugation to carriers present significant challenges for the clinical efficacy of MUC1-based vaccines. Here, we introduce a novel vaccine candidate based on a structure-guided design of an artificial antigen derived from MUC1 glycopeptide. This engineered antigen contains two non-natural amino acids and has an α-S-glycosidic bond, where sulfur replaces the conventional oxygen atom linking the peptide backbone to the sugar N-acetylgalactosamine. The glycopeptide is then specifically conjugated to the immunogenic protein carrier CRM197 (Cross-Reactive Material 197), a protein approved for human use. Conjugation involves selective reduction and re-bridging of a disulfide in CRM197, allowing the attachment of a single copy of MUC1. This strategy results in a chemically defined vaccine while maintaining both the structural integrity and immunogenicity of the protein carrier. The vaccine elicits a robust Th1-like immune response in mice and generates antibodies capable of recognizing human cancer cells expressing tumor-associated MUC1. When tested in mouse models of colon adenocarcinoma and pancreatic cancer, the vaccine is effective both as a prophylactic and therapeutic use, significantly delaying tumor growth. In therapeutic applications, improved outcomes were observed when the vaccine was combined with an anti-programmed cell death protein 1 (anti-PD-1) checkpoint inhibitor. Our strategy reduces batch-to-batch variability and enhances both immunogenicity and therapeutic potential. This site-specific approach disputes a prevailing dogma where glycoconjugate vaccines require multivalent display of antigens.
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Affiliation(s)
- Ana Guerreiro
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
- Basinnov Lifesciences, Av. José Malhoa 2, Escritório 3.7, 1070-325, Lisboa, Portugal
| | - Ismael Compañón
- Departamento de Química and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Madre de Dios, 53, 26006, Logroño, Spain
| | - Foivos S Lazaris
- Departamento de Química and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Madre de Dios, 53, 26006, Logroño, Spain
| | - Carlos Labão-Almeida
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
| | - Paula Oroz
- Departamento de Química and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Madre de Dios, 53, 26006, Logroño, Spain
| | - Mattia Ghirardello
- Departamento de Química and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Madre de Dios, 53, 26006, Logroño, Spain
| | - Marta C Marques
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
| | - Francisco Corzana
- Departamento de Química and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Madre de Dios, 53, 26006, Logroño, Spain
| | - Gonçalo J L Bernardes
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
- Basinnov Lifesciences, Av. José Malhoa 2, Escritório 3.7, 1070-325, Lisboa, Portugal
- Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK
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2
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Li L, Sun Y. Circulating tumor DNA methylation detection as biomarker and its application in tumor liquid biopsy: advances and challenges. MedComm (Beijing) 2024; 5:e766. [PMID: 39525954 PMCID: PMC11550092 DOI: 10.1002/mco2.766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 11/16/2024] Open
Abstract
Circulating tumor DNA (ctDNA) methylation, an innovative liquid biopsy biomarker, has emerged as a promising tool in early cancer diagnosis, monitoring, and prognosis prediction. As a noninvasive approach, liquid biopsy overcomes the limitations of traditional tissue biopsy. Among various biomarkers, ctDNA methylation has garnered significant attention due to its high specificity and early detection capability across diverse cancer types. Despite its immense potential, the clinical application of ctDNA methylation faces substantial challenges pertaining to sensitivity, specificity, and standardization. In this review, we begin by introducing the basic biology and common detection techniques of ctDNA methylation. We then explore recent advancements and the challenges faced in the clinical application of ctDNA methylation in liquid biopsies. This includes progress in early screening and diagnosis, identification of clinical molecular subtypes, monitoring of recurrence and minimal residual disease (MRD), prediction of treatment response and prognosis, assessment of tumor burden, and determination of tissue origin. Finally, we discuss the future perspectives and challenges of ctDNA methylation detection in clinical applications. This comprehensive overview underscores the vital role of ctDNA methylation in enhancing cancer diagnostic accuracy, personalizing treatments, and effectively monitoring disease progression, providing valuable insights for future research and clinical practice.
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Affiliation(s)
- Lingyu Li
- Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for CancersNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Yingli Sun
- Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for CancersNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
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3
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Magowan D, Abdulshafea M, Thompson D, Rajamoorthy SI, Owen R, Harris D, Prosser S. Blood-based biomarkers and novel technologies for the diagnosis of colorectal cancer and adenomas: a narrative review. Biomark Med 2024; 18:493-506. [PMID: 38900496 DOI: 10.1080/17520363.2024.2345583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 03/12/2024] [Indexed: 06/21/2024] Open
Abstract
Aim: Blood-based biomarkers have shown promise for diagnosing colorectal cancer (CRC) and adenomas (CRA). This review summarizes recent studies in this area. Methods: A literature search was undertaken for 01/01/2017-01/03/2023. Criteria included CRC, CRA, liquid-biopsy, blood-based tests and diagnosis. Results: 12,378 studies were reduced to 178 for data extraction. Sixty focused on proteomics, 53 on RNA species, 30 on cfDNA methylation, seven on antigens and autoantibodies and 28 on novel techniques. 169 case control and nine cohort studies. Number of participants ranged 100-54,297, mean age 58.26. CRC sensitivity and specificity ranged 9.10-100% and 20.40-100%, respectively. CRA sensitivity and specificity ranged 8.00-95.70% and 4.00-97.00%, respectively. Conclusion: Sensitive and specific blood-based tests exist for CRC and CRA. However, studies demonstrate heterogenous techniques and reporting quality. Further work should concentrate on validation and meta-analyzes.
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Affiliation(s)
- Drew Magowan
- Swansea University, Singleton Park, SA2 8PP, Swansea, UK
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Mansour Abdulshafea
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Dominic Thompson
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Shri-Ishvarya Rajamoorthy
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Rhiannon Owen
- Swansea University, Singleton Park, SA2 8PP, Swansea, UK
| | - Dean Harris
- Swansea University, Singleton Park, SA2 8PP, Swansea, UK
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
| | - Susan Prosser
- Swansea Bay University Health Board, Department of General Surgery, Morriston Hospital, SA6 6NL, Swansea, UK
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Shen Y, Chen J, Wu J, Li T, Yi C, Wang K, Wang P, Sun C, Ye H. Combination of an Autoantibody Panel and Alpha-Fetoprotein for Early Detection of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cancer Prev Res (Phila) 2024; 17:227-235. [PMID: 38489403 DOI: 10.1158/1940-6207.capr-23-0311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/04/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
The purpose of this study was to identify biomarkers associated with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and to develop a new combination with good diagnostic performance. This study was divided into four phases: discovery, verification, validation, and modeling. A total of four candidate tumor-associated autoantibodies (TAAb; anti-ZIC2, anti-PCNA, anti-CDC37L1, and anti-DUSP6) were identified by human proteome microarray (52 samples) and bioinformatics analysis. Subsequently, these candidate TAAbs were further confirmed by indirect ELISA with two testing cohorts (120 samples for verification and 663 samples for validation). The AUC for these four TAAbs to identify patients with HBV-HCC from chronic hepatitis B (CHB) patients ranged from 0.693 to 0.739. Finally, a diagnostic panel with three TAAbs (anti-ZIC2, anti-CDC37L1, and anti-DUSP6) was developed. This panel showed superior diagnostic efficiency in identifying early HBV-HCC compared with alpha-fetoprotein (AFP), with an AUC of 0.834 [95% confidence interval (CI), 0.772-0.897] for this panel and 0.727 (95% CI, 0.642-0.812) for AFP (P = 0.0359). In addition, the AUC for this panel to identify AFP-negative patients with HBV-HCC was 0.796 (95% CI, 0.734-0.858), with a sensitivity of 52.4% and a specificity of 89.0%. Importantly, the panel in combination with AFP significantly increased the positive rate for early HBV-HCC to 84.1% (P = 0.005) and for late HBV-HCC to 96.3% (P < 0.001). Our findings suggest that AFP and the autoantibody panel may be independent but complementary serologic biomarkers for HBV-HCC detection. PREVENTION RELEVANCE We developed a robust diagnostic panel for identifying patients with HBV-HCC from patients with CHB. This autoantibody panel provided superior diagnostic performance for HBV-HCC at an early stage and/or with negative AFP results. Our findings suggest that AFP and the autoantibody panel may be independent but complementary biomarkers for HBV-HCC detection.
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MESH Headings
- Adult
- Female
- Humans
- Male
- Middle Aged
- alpha-Fetoproteins/analysis
- alpha-Fetoproteins/immunology
- Autoantibodies/blood
- Autoantibodies/immunology
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/immunology
- Carcinoma, Hepatocellular/virology
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/blood
- Early Detection of Cancer/methods
- Enzyme-Linked Immunosorbent Assay
- Hepatitis B virus/immunology
- Hepatitis B virus/isolation & purification
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/virology
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/diagnosis
- Liver Neoplasms/virology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/immunology
- Liver Neoplasms/blood
- Aged
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Affiliation(s)
- Yajing Shen
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The State Key Laboratory of Esophageal Cancer Prevention & Treatment and The Key Laboratory of Tumor Epidemiology of Henan, Zhengzhou, Henan, China
| | - Jiajun Chen
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Jinyu Wu
- Xi'an Center for Disease Control and Prevention, Xi'an, Shaanxi, China
| | - Tiandong Li
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The State Key Laboratory of Esophageal Cancer Prevention & Treatment and The Key Laboratory of Tumor Epidemiology of Henan, Zhengzhou, Henan, China
| | - Chuncheng Yi
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The State Key Laboratory of Esophageal Cancer Prevention & Treatment and The Key Laboratory of Tumor Epidemiology of Henan, Zhengzhou, Henan, China
| | - Keyan Wang
- The State Key Laboratory of Esophageal Cancer Prevention & Treatment and The Key Laboratory of Tumor Epidemiology of Henan, Zhengzhou, Henan, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The State Key Laboratory of Esophageal Cancer Prevention & Treatment and The Key Laboratory of Tumor Epidemiology of Henan, Zhengzhou, Henan, China
| | - Changqing Sun
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- School of Nursing and Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The State Key Laboratory of Esophageal Cancer Prevention & Treatment and The Key Laboratory of Tumor Epidemiology of Henan, Zhengzhou, Henan, China
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5
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Cheng Y, Li Q, Sun G, Li T, Zou Y, Ye H, Wang K, Shi J, Wang P. Serum anti-CFL1, anti-EZR, and anti-CYPA autoantibody as diagnostic markers in ovarian cancer. Sci Rep 2024; 14:9757. [PMID: 38684875 PMCID: PMC11058243 DOI: 10.1038/s41598-024-60544-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/24/2024] [Indexed: 05/02/2024] Open
Abstract
The purpose of this study was to identify novel autoantibodies against tumor-associated antigens (TAAs) and explore a diagnostic panel for Ovarian cancer (OC). Enzyme-linked immunosorbent assay was used to detect the expression of five anti-TAA autoantibodies in the discovery (70 OC and 70 normal controls) and validation cohorts (128 OC and 128 normal controls). Machine learning methods were used to construct a diagnostic panel. Serum samples from 81 patients with benign ovarian disease were used to identify the specificity of anti-TAA autoantibodies for OC. In both the discovery and validation cohorts, the expression of anti-CFL1, anti-EZR, anti-CYPA, and anti-PFN1 was higher in patients with OC than that in normal controls. The area under the receiver operating characteristic curve, sensitivity, and specificity of the panel containing anti-CFL1, anti-EZR, and anti-CYPA were 0.762, 55.56%, and 81.31%. The panel identified 53.06%, 53.33%, and 51.11% of CA125 negative, HE4 negative and the Risk of Ovarian Malignancy Algorithm negative OC patients, respectively. The combination of the three anti-TAA autoantibodies can serve as a favorable diagnostic tool for OC and has the potential to be a complementary biomarker for CA125 and HE4 in the diagnosis of ovarian cancer.
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Affiliation(s)
- Yifan Cheng
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Qing Li
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Guiying Sun
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Tiandong Li
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Yuanlin Zou
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Keyan Wang
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China.
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China.
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6
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Li T, Wang P, Sun G, Zou Y, Cheng Y, Wang H, Lu Y, Shi J, Wang K, Zhang Q, Ye H. hccTAAb Atlas: An Integrated Knowledge Database for Tumor-Associated Autoantibodies in Hepatocellular Carcinoma. J Proteome Res 2024; 23:728-737. [PMID: 38156953 DOI: 10.1021/acs.jproteome.3c00579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
Tumor-associated autoantibodies (TAAbs) have demonstrated potential as biomarkers for cancer detection. However, the understanding of their role in hepatocellular carcinoma (HCC) remains limited. In this study, we aimed to systematically collect and standardize information about these TAAbs and establish a comprehensive database as a platform for in-depth research. A total of 170 TAAbs were identified from published papers retrieved from PubMed, Web of Science, and Embase. Following normative reannotation, these TAAbs were referred to as 162 official symbols. The hccTAAb (tumor-associated autoantibodies in hepatocellular carcinoma) atlas was developed using the R Shiny framework and incorporating literature-based and multiomics data sets. This comprehensive online resource provides key information such as sensitivity, specificity, and additional details such as official symbols, official full names, UniProt, NCBI, HPA, neXtProt, and aliases through hyperlinks. Additionally, hccTAAb offers six analytical modules for visualizing expression profiles, survival analysis, immune infiltration, similarity analysis, DNA methylation, and DNA mutation analysis. Overall, the hccTAAb Atlas provides valuable insights into the mechanisms underlying TAAb and has the potential to enhance the diagnosis and treatment of HCC using autoantibodies. The hccTAAb Atlas is freely accessible at https://nscc.v.zzu.edu.cn/hccTAAb/.
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Affiliation(s)
- Tiandong Li
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Guiying Sun
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Yuanlin Zou
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Yifan Cheng
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Han Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Yin Lu
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Keyan Wang
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qiang Zhang
- School of Nursing and Health, Zhengzhou University, Zhengzhou 450001, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Tumor Epidemiology & State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
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7
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Bermejo IA, Guerreiro A, Eguskiza A, Martínez-Sáez N, Lazaris FS, Asín A, Somovilla VJ, Compañón I, Raju TK, Tadic S, Garrido P, García-Sanmartín J, Mangini V, Grosso AS, Marcelo F, Avenoza A, Busto JH, García-Martín F, Hurtado-Guerrero R, Peregrina JM, Bernardes GJL, Martínez A, Fiammengo R, Corzana F. Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses. JACS AU 2024; 4:150-163. [PMID: 38274250 PMCID: PMC10807005 DOI: 10.1021/jacsau.3c00587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/08/2023] [Accepted: 11/09/2023] [Indexed: 01/27/2024]
Abstract
Mucin-1 (MUC1) glycopeptides are exceptional candidates for potential cancer vaccines. However, their autoantigenic nature often results in a weak immune response. To overcome this drawback, we carefully engineered synthetic antigens with precise chemical modifications. To be effective and stimulate an anti-MUC1 response, artificial antigens must mimic the conformational dynamics of natural antigens in solution and have an equivalent or higher binding affinity to anti-MUC1 antibodies than their natural counterparts. As a proof of concept, we have developed a glycopeptide that contains noncanonical amino acid (2S,3R)-3-hydroxynorvaline. The unnatural antigen fulfills these two properties and effectively mimics the threonine-derived antigen. On the one hand, conformational analysis in water shows that this surrogate explores a landscape similar to that of the natural variant. On the other hand, the presence of an additional methylene group in the side chain of this analog compared to the threonine residue enhances a CH/π interaction in the antigen/antibody complex. Despite an enthalpy-entropy balance, this synthetic glycopeptide has a binding affinity slightly higher than that of its natural counterpart. When conjugated with gold nanoparticles, the vaccine candidate stimulates the formation of specific anti-MUC1 IgG antibodies in mice and shows efficacy comparable to that of the natural derivative. The antibodies also exhibit cross-reactivity to selectively target, for example, human breast cancer cells. This investigation relied on numerous analytical (e.g., NMR spectroscopy and X-ray crystallography) and biophysical techniques and molecular dynamics simulations to characterize the antigen-antibody interactions. This workflow streamlines the synthetic process, saves time, and reduces the need for extensive, animal-intensive immunization procedures. These advances underscore the promise of structure-based rational design in the advance of cancer vaccine development.
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Affiliation(s)
- Iris A. Bermejo
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Ana Guerreiro
- Instituto
de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa 1649-028, Portugal
| | - Ander Eguskiza
- Department
of Biotechnology, University of Verona, Verona 37134, Italy
| | - Nuria Martínez-Sáez
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
- Departamento
de Tecnología y Química Farmacéuticas, Universidad de Navarra, Pamplona 31008, Spain
| | - Foivos S. Lazaris
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Alicia Asín
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Víctor J. Somovilla
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Ismael Compañón
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Tom K. Raju
- Angiogenesis
Group, Oncology Area, Center for Biomedical
Research of La Rioja (CIBIR), Logroño 26006, Spain
| | - Srdan Tadic
- Angiogenesis
Group, Oncology Area, Center for Biomedical
Research of La Rioja (CIBIR), Logroño 26006, Spain
| | - Pablo Garrido
- Angiogenesis
Group, Oncology Area, Center for Biomedical
Research of La Rioja (CIBIR), Logroño 26006, Spain
| | - Josune García-Sanmartín
- Angiogenesis
Group, Oncology Area, Center for Biomedical
Research of La Rioja (CIBIR), Logroño 26006, Spain
| | - Vincenzo Mangini
- Center
for
Biomolecular Nanotechnologies@UniLe, Istituto
Italiano di Tecnologia (IIT), Arnesano, Lecce 73010, Italy
| | - Ana S. Grosso
- Applied
Molecular Biosciences Unit UCIBIO, Department of Chemistry, NOVA School of Science and Technology, Caparica 2829-516, Portugal
- Associate
Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, Caparica 2829-516, Portugal
| | - Filipa Marcelo
- Applied
Molecular Biosciences Unit UCIBIO, Department of Chemistry, NOVA School of Science and Technology, Caparica 2829-516, Portugal
- Associate
Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, Caparica 2829-516, Portugal
| | - Alberto Avenoza
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Jesús H. Busto
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Fayna García-Martín
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Ramón Hurtado-Guerrero
- Institute
of Biocomputation and Physics of Complex Systems, University of Zaragoza, Zaragoza 50018, Spain
- Copenhagen
Center for Glycomics, Department of Cellular and Molecular Medicine,
Faculty of Health Sciences, University of
Copenhagen, Copenhagen 2200, Denmark
- Fundación
ARAID, Zaragoza 50018, Spain
| | - Jesús M. Peregrina
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
| | - Gonçalo J. L. Bernardes
- Instituto
de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa 1649-028, Portugal
- Yusuf
Hamied Department of Chemistry, University
of Cambridge, Cambridge CB2 1EW, U.K.
| | - Alfredo Martínez
- Angiogenesis
Group, Oncology Area, Center for Biomedical
Research of La Rioja (CIBIR), Logroño 26006, Spain
| | - Roberto Fiammengo
- Department
of Biotechnology, University of Verona, Verona 37134, Italy
- Center
for
Biomolecular Nanotechnologies@UniLe, Istituto
Italiano di Tecnologia (IIT), Arnesano, Lecce 73010, Italy
| | - Francisco Corzana
- Department
of Chemistry and Instituto de Investigación en Química
de la Universidad de La Rioja (IQUR), Universidad
de La Rioja, Logroño 26006, Spain
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8
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Zhang P, Wu Z, Zhou T, Yang D, Mu Q, Zhang W, Yu L, Zhang S, Hu Y, Mu J, Jia W. Autoantibody repertoire profiling in tissue and blood identifies colorectal cancer-specific biomarkers. Cancer Sci 2024; 115:83-93. [PMID: 37985391 PMCID: PMC10823280 DOI: 10.1111/cas.16011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 11/22/2023] Open
Abstract
Autoantibodies (AAbs) in the blood of colorectal cancer (CRC) patients have been evaluated for tumor detection. However, it remains uncertain whether these AAbs are specific to tumor-associated antigens. In this study, we explored the IgG and IgM autoantibody repertoires in both the in situ tissue microenvironment and peripheral blood as potential tumor-specific biomarkers. We applied high-density protein arrays to profile AAbs in the tumor-infiltrating lymphocyte supernatants and corresponding serum from four patients with CRC, as well as in the serum of three noncancer controls. Our findings revealed that there were more reactive IgM AAbs than IgG in both the cell supernatant and corresponding serum, with a difference of approximately 3-5 times. Immunoglobulin G was predominant in the serum, while IgM was more abundant in the cell supernatant. We identified a range of AAbs present in both the supernatant and the corresponding serum, numbering between 432 and 780, with an average of 53.3% shared. Only 4.7% (n = 23) and 0.2% (n = 2) of reactive antigens for IgG and IgM AAbs, respectively, were specific to CRC. Ultimately, we compiled a list of 19 IgG AAb targets as potential tumor-specific AAb candidates. Autoantibodies against one of the top candidates, p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A), were significantly elevated in 53 CRC patients compared to 119 controls (p < 0.0001). The project revealed that tissue-derived IgG AAbs, rather than IgM, are the primary source of tumor-specific AAbs in peripheral blood. It also identified potential tumor-specific AAbs that could be applied for noninvasive screening of CRC.
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Affiliation(s)
- Pei‐Fen Zhang
- Affiliated Tumor Hospital of Xinjiang Medical UniversityÜrümqiChina
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Ziyi Wu
- Department of Radiation OncologyFujian Medical University Cancer Hospital, Fujian Cancer HospitalFuzhouChina
| | - Ting Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Da‐Wei Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- School of Public HealthSun Yat‐sen UniversityGuangzhouChina
| | - Quan‐Kai Mu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Wen‐Bin Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Long Yu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Shao‐Dan Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Ye‐Zhu Hu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Jianbing Mu
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthRockvilleMarylandUSA
| | - Wei‐Hua Jia
- Affiliated Tumor Hospital of Xinjiang Medical UniversityÜrümqiChina
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
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9
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Sun G, Chen H, Xia J, Li T, Ye H, Li J, Zhang X, Cheng Y, Wang K, Shi J, Wang P. Diagnostic performance of anti-MAGEA family protein autoantibodies in esophageal squamous cell carcinoma. Int Immunopharmacol 2023; 125:111041. [PMID: 37866309 DOI: 10.1016/j.intimp.2023.111041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/27/2023] [Accepted: 10/08/2023] [Indexed: 10/24/2023]
Abstract
MAGEA family proteins are immunogenic and can produce corresponding autoantibodies, and we aim to evaluate the diagnostic value of anti-MAGEA family protein autoantibodies in esophageal squamous cell carcinoma (ESCC). Protein chip was used to detect the expression level of anti-MAGEA autoantibodies (IgG and IgM) in 20 mixed serum samples. Enzyme linked immunosorbent assay was adopted to determine the expression level of autoantibodies in 1019 serum samples (423 ESCC, 423 healthy control (HC), 173 benign esophageal disease (BED)), and stepwise logistic regression analysis was used for developing a diagnostic model. Eight anti-MAGEA autoantibodies were screened out based on the protein chip. The levels of 7 autoantibodies (MAGEA1-IgG, MAGEA3-IgG, MAGEA3-IgM, MAGEA4-IgG, MAGEA6-IgG, MAGEA10-IgG, MAGEA12-IgG) in ESCC were significantly higher than that in HC, and the levels of anti-MAGEA1 IgG, anti-MAGEA3-IgG, anti-MAGEA4-IgG, anti-MAGEA10-IgG and anti-MAGEA12-IgG autoantibodies in ESCC group were significantly higher than those in BED group. The area under curve (AUC), sensitivity and specificity of the logistic regression model (MAGEA1-IgG, MAGEA4-IgG, MAGEA6-IgG, MAGEA12-IgG) in the training set and the validation set were 0.725 and 0.698, 55.2% and 51.8%, 80.4% and 84.5%, respectively, in distinguishing ESCC and HC. The model also could distinguish between ESCC and BED, with the AUC of 0.743, sensitivity of 55.4% and specificity of 89.0%. The positive rate of the model combined with cytokeratin 19 fragment to diagnose ESCC reached 78.0%. The study identified anti-MAGEA autoantibodies with potential diagnostic value for ESCC, which may provide new promising for the detection of the disease.
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Affiliation(s)
- Guiying Sun
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Huili Chen
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Junfen Xia
- Office of Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Tiandong Li
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hua Ye
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Jiaxin Li
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Xiaoyue Zhang
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yifan Cheng
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Keyan Wang
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China; Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China; Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Peng Wang
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China; Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, Henan Province, China.
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10
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Li T, Xia J, Yun H, Sun G, Shen Y, Wang P, Shi J, Wang K, Yang H, Ye H. A novel autoantibody signatures for enhanced clinical diagnosis of pancreatic ductal adenocarcinoma. Cancer Cell Int 2023; 23:273. [PMID: 37974212 PMCID: PMC10655307 DOI: 10.1186/s12935-023-03107-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 10/25/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that requires precise diagnosis for effective treatment. However, the diagnostic value of carbohydrate antigen 19 - 9 (CA19-9) is limited. Therefore, this study aims to identify novel tumor-associated autoantibodies (TAAbs) for PDAC diagnosis. METHODS A three-phase strategy comprising discovery, test, and validation was implemented. HuProt™ Human Proteome Microarray v3.1 was used to screen potential TAAbs in 49 samples. Subsequently, the levels of potential TAAbs were evaluated in 477 samples via enzyme-linked immunosorbent assay (ELISA) in PDAC, benign pancreatic diseases (BPD), and normal control (NC), followed by the construction of a diagnostic model. RESULTS In the discovery phase, protein microarrays identified 167 candidate TAAbs. Based on bioinformatics analysis, fifteen tumor-associated antigens (TAAs) were selected for further validation using ELISA. Ten TAAbs exhibited differentially expressed in PDAC patients in the test phase (P < 0.05), with an area under the curve (AUC) ranging from 0.61 to 0.76. An immunodiagnostic model including three TAAbs (anti-HEXB, anti-TXLNA, anti-SLAMF6) was then developed, demonstrating AUCs of 0.81 (58.0% sensitivity, 86.0% specificity) and 0.78 (55.71% sensitivity, 87.14% specificity) for distinguishing PDAC from NC. Additionally, the model yielded AUCs of 0.80 (58.0% sensitivity, 86.25% specificity) and 0.83 (55.71% sensitivity, 100% specificity) for distinguishing PDAC from BPD in the test and validation phases, respectively. Notably, the combination of the immunodiagnostic model with CA19-9 resulted in an increased positive rate of PDAC to 92.91%. CONCLUSION The immunodiagnostic model may offer a novel serological detection method for PDAC diagnosis, providing valuable insights into the development of effective diagnostic biomarkers.
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Affiliation(s)
- Tiandong Li
- College of Public Health, Zhengzhou University, 450001, Zhengzhou, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Junfen Xia
- Office of Health Care, The Third Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Huan Yun
- Zhengzhou University, 450001, Zhengzhou, Henan Province, China
| | - Guiying Sun
- College of Public Health, Zhengzhou University, 450001, Zhengzhou, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Yajing Shen
- College of Public Health, Zhengzhou University, 450001, Zhengzhou, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, 450001, Zhengzhou, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Keyan Wang
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Hongwei Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan Province, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, 450001, Zhengzhou, Henan Province, China.
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 450052, Zhengzhou, Henan Province, China.
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11
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Liu RX, Wen C, Ye W, Li Y, Chen J, Zhang Q, Li W, Liang W, Wei L, Zhang J, Chan KW, Wang X, Yang X, Liu H. Altered B cell immunoglobulin signature exhibits potential diagnostic values in human colorectal cancer. iScience 2023; 26:106140. [PMID: 36879799 PMCID: PMC9984553 DOI: 10.1016/j.isci.2023.106140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 12/27/2022] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Antibody-secreting B cells have long been considered the central element of gut homeostasis; however, tumor-associated B cells in human colorectal cancer (CRC) have not been well characterized. Here, we show that the clonotype, phenotype, and immunoglobulin subclasses of tumor-infiltrating B cells have changed compared to adjacent normal tissue B cells. Remarkably, the tumor-associated B cell immunoglobulin signature alteration can also be detected in the plasma of patients with CRC, suggesting that a distinct B cell response was also evoked in CRC. We compared the altered plasma immunoglobulin signature with the existing method of CRC diagnosis. Our diagnostic model exhibits improved sensitivity compared to the traditional biomarkers, CEA and CA19-9. These findings disclose the altered B cell immunoglobulin signature in human CRC and highlight the potential of using the plasma immunoglobulin signature as a non-invasive method for the assessment of CRC.
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Affiliation(s)
- Rui-Xian Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.,Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chuangyu Wen
- Affiliated Dongguan Hospital, Southern Medical University, Dongguan, Guangdong 523059, China
| | - Weibiao Ye
- Affiliated Dongguan Hospital, Southern Medical University, Dongguan, Guangdong 523059, China
| | - Yewei Li
- Department of Statistical Science, School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Junxiong Chen
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Qian Zhang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Weiqian Li
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Wanfei Liang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Lili Wei
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jingdan Zhang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Ka-Wo Chan
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xueqin Wang
- International Institute of Finance, School of Management, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Xiangling Yang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Huanliang Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.,Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
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12
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Casagrande GMS, Silva MDO, Reis RM, Leal LF. Liquid Biopsy for Lung Cancer: Up-to-Date and Perspectives for Screening Programs. Int J Mol Sci 2023; 24:2505. [PMID: 36768828 PMCID: PMC9917347 DOI: 10.3390/ijms24032505] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 12/19/2022] [Indexed: 01/31/2023] Open
Abstract
Lung cancer is the deadliest cancer worldwide. Tissue biopsy is currently employed for the diagnosis and molecular stratification of lung cancer. Liquid biopsy is a minimally invasive approach to determine biomarkers from body fluids, such as blood, urine, sputum, and saliva. Tumor cells release cfDNA, ctDNA, exosomes, miRNAs, circRNAs, CTCs, and DNA methylated fragments, among others, which can be successfully used as biomarkers for diagnosis, prognosis, and prediction of treatment response. Predictive biomarkers are well-established for managing lung cancer, and liquid biopsy options have emerged in the last few years. Currently, detecting EGFR p.(Tyr790Met) mutation in plasma samples from lung cancer patients has been used for predicting response and monitoring tyrosine kinase inhibitors (TKi)-treated patients with lung cancer. In addition, many efforts continue to bring more sensitive technologies to improve the detection of clinically relevant biomarkers for lung cancer. Moreover, liquid biopsy can dramatically decrease the turnaround time for laboratory reports, accelerating the beginning of treatment and improving the overall survival of lung cancer patients. Herein, we summarized all available and emerging approaches of liquid biopsy-techniques, molecules, and sample type-for lung cancer.
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Affiliation(s)
| | - Marcela de Oliveira Silva
- Molecular Oncology Research Center, Barretos Cancer Hospital, 1331 Rua Antenor Duarte Vilela, Barretos 14784-400, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, 1331 Rua Antenor Duarte Vilela, Barretos 14784-400, Brazil
- Life and Health Sciences Research Institute (ICVS), School of Medicine, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Letícia Ferro Leal
- Molecular Oncology Research Center, Barretos Cancer Hospital, 1331 Rua Antenor Duarte Vilela, Barretos 14784-400, Brazil
- Barretos School of Medicine Dr. Paulo Prata—FACISB, Barretos 14785-002, Brazil
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13
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Cancer Is Associated with the Emergence of Placenta-Reactive Autoantibodies. Biomedicines 2023; 11:biomedicines11020316. [PMID: 36830854 PMCID: PMC9953527 DOI: 10.3390/biomedicines11020316] [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: 12/15/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/25/2023] Open
Abstract
Placenta-specific antigens are minimally expressed or unexpressed in normal adult tissues, while they are widely expressed in cancer. In the course of carcinogenesis, a vast array of autoantibodies (AAbs) is produced. Here, we used a quantitative approach to determine the reactivity of AAbs in the sera of patients with breast (BrC: N = 100, 100% female, median age: 51 years), gastric (GC: N = 30, 46.6% female, median age: 57 years), bladder (BC: N = 29, 34.4% female, median age: 57 years), and colorectal (CRC: N = 34, 41.1% female, median age: 51 years) cancers against first-trimester (FTP) and full-term placental proteome (TP) in comparison with age- and sex-matched non-cancer individuals. Human-on-human immunohistochemistry was used to determine reactive target cells in FTP. The effect of pregnancy on the emergence of placenta-reactive autoantibodies was tested using sera from pregnant women at different trimesters of pregnancy. Except for BC, patients with BrC (p < 0.0284), GC (p < 0.0002), and CRC (p < 0.0007) had significantly higher levels of placenta-reactive AAbs. BrC (p < 0.0001) and BC (p < 0.0409) in the early stages triggered higher autoantibody reactivity against FTP. The reactivities of BrC sera with FTP did not show an association with ER, PR, or HER2 expression. Pregnancy in the third trimester was associated with the induction of TP- and not FTP-reactive autoantibodies (=0.018). The reactivity of BrC sera with placental proteins was found to be independent of gravidity or abortion. BrC sera showed a very strong and specific pattern of reactivity with scattered cells beneath the syncytiotrophoblast layer. Our results reinforce the concept of the coevolution of placentation and cancer and shed light on the future clinical application of the placental proteome for the non-invasive early detection and treatment of cancer.
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14
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Shlyapnikov YM, Malakhova EA, Potoldykova NV, Svetocheva YA, Vinarov AZ, Zinchenko DV, Zernii EY, Zamyatnin AA, Shlyapnikova EA. Non-Invasive Diagnostics of Renal Cell Carcinoma Using Ultrasensitive Immunodetection of Cancer-Retina Antigens. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:658-666. [PMID: 36154884 DOI: 10.1134/s0006297922070070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/06/2022] [Accepted: 06/15/2022] [Indexed: 06/16/2023]
Abstract
Renal cell carcinoma (RCC) is the most common urological malignancy with a high mortality and low detection rate. One of the approaches to improving its diagnostics may be the search for new non-invasive biomarkers in liquid biopsy and development of more sensitive methods for their detection. Cancer-retina antigens, which are known to be aberrantly expressed in malignant tumors, are present in liquid biopsy at extremely low concentrations. Using the developed multiplex immunoassay with a detection limit of 0.1 pg/ml, urine and serum samples of 89 patients with RCC and 50 non-cancer patients were examined for the presence of cancer-retina antigens (arrestin, recoverin, rhodopsin kinase, and transducin); the difference between the RCC and control groups was evaluated with the χ2 test. The results showed high diagnostic efficiency of a combination of arrestin and recoverin: at a threshold of 0.1 pg/ml, the sensitivity was 96%, specificity 92%, and AUC = 0.96 (95% confidence interval, 0.93-0.99). Seven days after nephrectomy, the concentration of the antigens returned to the level characteristic of the control group. Therefore, arrestin in a combination with recoverin can serve as a diagnostic non-invasive urinary biomarker of RCC.
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Affiliation(s)
- Yuri M Shlyapnikov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
| | - Ekaterina A Malakhova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
| | - Natalia V Potoldykova
- Institute for Urology and Reproductive Health, Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
| | - Yana A Svetocheva
- Institute for Urology and Reproductive Health, Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
| | - Andrei Z Vinarov
- Institute for Urology and Reproductive Health, Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
| | - Dmitry V Zinchenko
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino, Moscow Region, 117997, Russia.
| | - Evgeni Yu Zernii
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
| | - Andrey A Zamyatnin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, 119991, Russia
- Department of Biotechnology, Sirius University of Science and Technology, Sochi, 354340, Russia
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK
| | - Elena A Shlyapnikova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
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15
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Zeneyedpour L, Stingl C, Kros JM, Sillevis Smitt PAE, Luider TM. Novel Antibody-Peptide Binding Assay Indicates Presence of Immunoglobulins against EGFR Phospho-Site S1166 in High-Grade Glioma. Int J Mol Sci 2022; 23:5061. [PMID: 35563452 PMCID: PMC9100080 DOI: 10.3390/ijms23095061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
We investigated the feasibility of detecting the presence of specific autoantibodies against potential tumor-associated peptide antigens by enriching these antibody-peptide complexes using Melon Gel resin and mass spectrometry. Our goal was to find tumor-associated phospho-sites that trigger immunoreactions and raise autoantibodies that are detectable in plasma of glioma patients. Such immunoglobulins can potentially be used as targets in immunotherapy. To that aim, we describe a method to detect the presence of antibodies in biological samples that are specific to selected clinically relevant peptides. The method is based on the formation of antibody-peptide complexes by mixing patient plasma with a glioblastoma multiforme (GBM) derived peptide library, enrichment of antibodies and antibody-peptide complexes, the separation of peptides after they are released from immunoglobulins by molecular weight filtration and finally mass spectrometric quantification of these peptides. As proof of concept, we successfully applied the method to dinitrophenyl (DNP)-labeled α-casein peptides mixed with anti-DNP. Further, we incubated human plasma with a phospho-peptide library and conducted targeted analysis on EGFR and GFAP phospho-peptides. As a result, immunoaffinity against phospho-peptide GSHQIS[+80]LDNPDYQQDFFPK (EGFR phospho-site S1166) was detected in high-grade glioma (HGG) patient plasma but not in healthy donor plasma. For the GFAP phospho-sites selected, such immunoaffinity was not observed.
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Affiliation(s)
- Lona Zeneyedpour
- Department of Neurology, Erasmus MC, 3015 GD Rotterdam, The Netherlands; (L.Z.); (C.S.); (P.A.E.S.S.)
| | - Christoph Stingl
- Department of Neurology, Erasmus MC, 3015 GD Rotterdam, The Netherlands; (L.Z.); (C.S.); (P.A.E.S.S.)
| | - Johan M. Kros
- Department of Pathology, Erasmus MC, 3015 GD Rotterdam, The Netherlands;
| | | | - Theo M. Luider
- Department of Neurology, Erasmus MC, 3015 GD Rotterdam, The Netherlands; (L.Z.); (C.S.); (P.A.E.S.S.)
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16
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Al-hadlaq SM, Balto HA, Hassan WM, Marraiki NA, El-Ansary AK. Biomarkers of non-communicable chronic disease: an update on contemporary methods. PeerJ 2022; 10:e12977. [PMID: 35233297 PMCID: PMC8882335 DOI: 10.7717/peerj.12977] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 01/31/2022] [Indexed: 01/11/2023] Open
Abstract
Chronic diseases constitute a major global burden with significant impact on health systems, economies, and quality of life. Chronic diseases include a broad range of diseases that can be communicable or non-communicable. Chronic diseases are often associated with modifications of normal physiological levels of various analytes that are routinely measured in serum and other body fluids, as well as pathological findings, such as chronic inflammation, oxidative stress, and mitochondrial dysfunction. Identification of at-risk populations, early diagnosis, and prediction of prognosis play a major role in preventing or reducing the burden of chronic diseases. Biomarkers are tools that are used by health professionals to aid in the identification and management of chronic diseases. Biomarkers can be diagnostic, predictive, or prognostic. Several individual or grouped biomarkers have been used successfully in the diagnosis and prediction of certain chronic diseases, however, it is generally accepted that a more sophisticated approach to link and interpret various biomarkers involved in chronic disease is necessary to improve our current procedures. In order to ensure a comprehensive and unbiased coverage of the literature, first a primary frame of the manuscript (title, headings and subheadings) was drafted by the authors working on this paper. Second, based on the components drafted in the preliminary skeleton a comprehensive search of the literature was performed using the PubMed and Google Scholar search engines. Multiple keywords related to the topic were used. Out of screened papers, only 190 papers, which are the most relevant, and recent articles were selected to cover the topic in relation to etiological mechanisms of different chronic diseases, the most recently used biomarkers of chronic diseases and finally the advances in the applications of multivariate biomarkers of chronic diseases as statistical and clinically applied tool for the early diagnosis of chronic diseases was discussed. Recently, multivariate biomarkers analysis approach has been employed with promising prospect. A brief discussion of the multivariate approach for the early diagnosis of the most common chronic diseases was highlighted in this review. The use of diagnostic algorithms might show the way for novel criteria and enhanced diagnostic effectiveness inpatients with one or numerous non-communicable chronic diseases. The search for new relevant biomarkers for the better diagnosis of patients with non-communicable chronic diseases according to the risk of progression, sickness, and fatality is ongoing. It is important to determine whether the newly identified biomarkers are purely associations or real biomarkers of underlying pathophysiological processes. Use of multivariate analysis could be of great importance in this regard.
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Affiliation(s)
- Solaiman M. Al-hadlaq
- Department of Restorative Dental Sciences, College of Dentistry, King Saud University, Riyadh, Saudi Arabia
| | - Hanan A. Balto
- Department of Restorative Dental Sciences, College of Dentistry, King Saud University, Riyadh, Saudi Arabia,Central Research Laboratory, Female Campus, King Saud University, Riyadh, Saudi Arabia
| | - Wail M. Hassan
- Department of Biomedical Sciences, University of Missouri-Kansas City School of Medicine, Kansas City, KS, United States of America
| | - Najat A. Marraiki
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Afaf K. El-Ansary
- Central Research Laboratory, Female Campus, King Saud University, Riyadh, Saudi Arabia
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17
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Perales S, Torres C, Jimenez-Luna C, Prados J, Martinez-Galan J, Sanchez-Manas JM, Caba O. Liquid biopsy approach to pancreatic cancer. World J Gastrointest Oncol 2021; 13:1263-1287. [PMID: 34721766 PMCID: PMC8529923 DOI: 10.4251/wjgo.v13.i10.1263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/18/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to pose a major clinical challenge. There has been little improvement in patient survival over the past few decades, and it is projected to become the second leading cause of cancer mortality by 2030. The dismal 5-year survival rate of less than 10% after the diagnosis is attributable to the lack of early symptoms, the absence of specific biomarkers for an early diagnosis, and the inadequacy of available chemotherapies. Most patients are diagnosed when the disease has already metastasized and cannot be treated. Cancer interception is vital, actively intervening in the malignization process before the development of a full-blown advanced tumor. An early diagnosis of PC has a dramatic impact on the survival of patients, and improved techniques are urgently needed to detect and evaluate this disease at an early stage. It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position; however, liquid biopsies are readily available and can provide useful information for the diagnosis, prognosis, stratification, and follow-up of patients with PC and for the design of individually tailored treatments. The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates, proteins, cell-free nucleic acids, circulating tumor cells, metabolome compounds, exosomes, and platelets in blood as potential biomarkers for PC, focusing on their clinical relevance and potential for improving patient outcomes.
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Affiliation(s)
- Sonia Perales
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Carolina Torres
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Joaquina Martinez-Galan
- Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, Granada 18011, Spain
| | | | - Octavio Caba
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
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18
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Niloofa R, De Zoysa MI, Seneviratne LS. Autoantibodies in the diagnosis, prognosis, and prediction of colorectal cancer. J Cancer Res Ther 2021; 17:819-833. [PMID: 34528528 DOI: 10.4103/jcrt.jcrt_64_19] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Colorectal cancer (CRC) is the second-most commonly diagnosed cancer worldwide. Early diagnosis improves prognosis and long-term outcomes. Several studies have found tumor-associated autoantibodies in CRC patients. We aimed to provide an overview on CRC-associated autoantibodies and their reported diagnostic, prognostic, and predictive performance when used singly or in combination. We systematically reviewed studies on CRC-related autoantibodies published till March 2018 and critically analyzed the role of these autoantibodies in CRC. In general, autoantibodies were of low sensitivity when tested individually and the diagnostic characteristics improved when tested in combination. Autoantibodies against CCD83, carcinoembryonic antigen, MAPKAPK3, RPH 3AL, SEC61b, and SPAG9 showed high sensitivity and specificity when tested alone. When tested in combination, autoantibodies against three antigens (PIM1, MAPKAPK3, and ACVR2B) showed high sensitivity and specificity. So far, most CRC-associated autoantibodies have been evaluated in single or in a small number of studies. In contrast, anti-p53 antibodies have been studied in a larger number of CRC studies, but, so far, none of them have high diagnostic characteristics. CRC-associated autoantibodies are detectable from the early stages of malignancy, pointing to their possible use in the early detection of CRC. Some studies suggest that CRC-associated autoantibodies may be a guide to prognosis in CRC.
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Affiliation(s)
- Roshan Niloofa
- Department of Zoology and Environmental Sciences, Faculty of Science, University of Colombo, Colombo, Sri Lanka
| | - M Ishan De Zoysa
- Department of Surgery, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - L Suranjith Seneviratne
- Department of Zoology and Environmental Sciences, Faculty of Science, University of Colombo, Colombo, Sri Lanka
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19
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Ahmadi H, Shogen K, Fujita K, Honjo T, Kakimi K, Futami J. Unusual aggregation property of recombinantly expressed cancer-testis antigens in mammalian cells. J Biochem 2021; 170:435-443. [PMID: 34247245 DOI: 10.1093/jb/mvab081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 07/02/2021] [Indexed: 11/13/2022] Open
Abstract
Transient expression of human intracellular proteins in human embryonic kidney (HEK) 293 cells is a reliable system for obtaining soluble proteins with biologically active conformations. Contrary to conventional concepts, we found that recombinantly expressed intracellular cancer-testis antigens (CTAs) showed frequent aggregation in HEK293 cells. Although experimental subcellular localization of recombinant CTAs displayed proper cytosolic or nuclear localization, some proteins showed aggregated particles in the cell. This aggregative property was not observed in recombinant housekeeping proteins. No significant correlation was found between the aggregative and biophysical properties, such as hydrophobicity, contents of intrinsically disordered regions, and expression levels, of CTAs. These results can be explained in terms of structural instability of CTAs, which are specifically expressed in the testis and aberrantly expressed in cancer cells and function as a hub in the protein-protein network using intrinsically disordered regions. Hence, we speculate that recombinantly expressed CTAs failed to form this protein complex. Thus, unfolded CTAs formed aggregated particles in the cell.
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Affiliation(s)
- Hannaneh Ahmadi
- Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan
| | - Kohei Shogen
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Kana Fujita
- Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
| | - Tomoko Honjo
- Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan
| | - Kazuhiro Kakimi
- Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
| | - Junichiro Futami
- Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.,Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530, Japan
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20
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Yang J, Gong C, Ke Q, Fang Z, Chen X, Ye M, Xu X. Insights Into the Function and Clinical Application of HDAC5 in Cancer Management. Front Oncol 2021; 11:661620. [PMID: 34178647 PMCID: PMC8222663 DOI: 10.3389/fonc.2021.661620] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/18/2021] [Indexed: 12/20/2022] Open
Abstract
Histone deacetylase 5 (HDAC5) is a class II HDAC. Aberrant expression of HDAC5 has been observed in multiple cancer types, and its functions in cell proliferation and invasion, the immune response, and maintenance of stemness have been widely studied. HDAC5 is considered as a reliable therapeutic target for anticancer drugs. In light of recent findings regarding the role of epigenetic reprogramming in tumorigenesis, in this review, we provide an overview of the expression, biological functions, regulatory mechanisms, and clinical significance of HDAC5 in cancer.
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Affiliation(s)
- Jun Yang
- Department of Orthopedic Surgery, Sanmen People's Hospital of Zhejiang Province, Sanmenwan Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Sanmen, China
| | - Chaoju Gong
- Central Laboratory, The Municipal Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Qinjian Ke
- Central Laboratory, Sanmen People's Hospital of Zhejiang Province, Sanmenwan Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Sanmen, China
| | - Zejun Fang
- Central Laboratory, Sanmen People's Hospital of Zhejiang Province, Sanmenwan Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Sanmen, China
| | - Xiaowen Chen
- Department of Pathophysiology, Zunyi Medical University, Zunyi, China
| | - Ming Ye
- Department of General Surgery, Sanmen People's Hospital of Zhejiang Province, Sanmenwan Branch of the First Affiliated Hospital, College of Medicine, Zhejiang University, Sanmen, China
| | - Xi Xu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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21
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Wang R, Zhao H, Liu Y, Kang B, Cai J. Antinuclear Antibodies With a Nucleolar Pattern Are Associated With a Significant Reduction in the Overall Survival of Patients With Leukemia: A Retrospective Cohort Study. Front Oncol 2021; 11:631038. [PMID: 33718211 PMCID: PMC7952743 DOI: 10.3389/fonc.2021.631038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 01/25/2021] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Antinuclear antibodies (ANAs) have been reported to be associated with cancers. However, the role of different ANA patterns in cancers is poorly understood, especially in leukemia. This study aimed to investigate the association between ANA patterns and the outcome of leukemia in a retrospective cohort. METHODS A total of 429 adult patients initially diagnosed with leukemia at Henan Provincial People's Hospital from January 2014 to December 2018 were included in this study, including information on patients without positive ANAs at the time of initial diagnosis, preexisting autoimmune diseases, infectious diseases, etc. The data were retrieved up to December 2020. The final sample included 196 adult patients. The risk of death outcome according to ANA patterns was estimated using multivariable Cox proportional hazards models and the overall survival for ANA patterns was analyzed using Kaplan-Meier curve. RESULTS ANAs with a nucleolar pattern versus negative ANA were associated with a two-fold increased risk of death outcome in leukemia, independent of sex, age, leukemia immunophenotype, cytogenetic abnormality, treatment, and blood transfusion. Further analysis revealed that the association was more significant in elder patients (≥60 years) and patients treated with tyrosine kinase inhibitor or chemotherapy (P for interaction = 0.042 and 0.010). Notably, the patients with a nucleolar pattern had shorter survival than the patients with a non-nucleolar pattern or without ANA (p < 0.001). CONCLUSION ANAs with a nucleolar pattern are a significant predictor of poor prognosis, providing clues for prognostic assessment in patients with leukemia.
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Affiliation(s)
- Rong Wang
- Department of Clinical Laboratory, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
| | - Huijuan Zhao
- Basic Medical College, Henan University of Science and Technology, Luoyang, China
| | - Yang Liu
- Department of Clinical Laboratory, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
| | - Bing Kang
- Institute of Medical Genetics, Henan Provincial People’s Hospital, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
| | - Jun Cai
- Department of Clinical Laboratory, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
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22
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Chen X, Sun J, Wang X, Yuan Y, Cai L, Xie Y, Fan Z, Liu K, Jiao X. A Meta-Analysis of Proteomic Blood Markers of Colorectal Cancer. Curr Med Chem 2021; 28:1176-1196. [PMID: 32338203 DOI: 10.2174/0929867327666200427094054] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/23/2020] [Accepted: 03/24/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Early diagnosis will significantly improve the survival rate of colorectal cancer (CRC); however, the existing methods for CRC screening were either invasive or inefficient. There is an emergency need for novel markers in CRC's early diagnosis. Serum proteomics has gained great potential in discovering novel markers, providing markers that reflect the early stage of cancer and prognosis prediction of CRC. In this paper, the results of proteomics of CRC studies were summarized through a meta-analysis in order to obtain the diagnostic efficiency of novel markers. METHODS A systematic search on bibliographic databases was performed to collect the studies that explore blood-based markers for CRC applying proteomics. The detection and validation methods, as well as the specificity and sensitivity of the biomarkers in these studies, were evaluated. Newcastle- Ottawa Scale (NOS) case-control studies version was used for quality assessment of included studies. RESULTS Thirty-four studies were selected from 751 studies, in which markers detected by proteomics were summarized. In total, fifty-nine proteins were classified according to their biological function. The sensitivity, specificity, or AUC varied among these markers. Among them, Mammalian STE20-like protein kinase 1/ Serine threonine kinase 4 (MST1/STK4), S100 calcium-binding protein A9 (S100A9), and Tissue inhibitor of metalloproteinases 1 (TIMP1) were suitable for effect sizes merging, and their diagnostic efficiencies were recalculated after merging. MST1/STK4 obtained a sensitivity of 68% and a specificity of 78%. S100A9 achieved a sensitivity of 72%, a specificity of 83%, and an AUC of 0.88. TIMP1 obtained a sensitivity of 42%, a specificity of 88%, and an AUC of 0.71. CONCLUSION MST1/STK4, S100A9, and TIMP1 showed excellent performance for CRC detection. Several other markers also presented optimized diagnostic efficacy for CRC early detection, but further verification is still needed before they are suitable for clinical use. The discovering of more efficient markers will benefit CRC treatment.
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Affiliation(s)
- Xiang Chen
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Jiayu Sun
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Xue Wang
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yumeng Yuan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Leshan Cai
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yanxuan Xie
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Zhiqiang Fan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Kaixi Liu
- Shantou Central Hospital, Shantou, Guangdong 515041, China
| | - Xiaoyang Jiao
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
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23
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Yang SH, Liu CT, Hong CQ, Huang ZY, Wang HZ, Wei LF, Lin YW, Guo HP, Peng YH, Xu YW. Autoantibodies against p53, MMP-7, and Hsp70 as Potential Biomarkers for Detection of Nonmelanoma Skin Cancers. DISEASE MARKERS 2021; 2021:5592693. [PMID: 34336006 PMCID: PMC8289574 DOI: 10.1155/2021/5592693] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/31/2021] [Indexed: 02/05/2023]
Abstract
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are two predominant histological types of nonmelanoma skin cancer (NMSC), lacking effective early diagnostic markers. In this study, we assessed the diagnostic value of autoantibodies against p53, MMP-7, and Hsp70 in skin SCC and BCC. ELISA was performed to detect levels of autoantibodies in sera from 101 NMSC patients and 102 normal controls, who were recruited from the Cancer Hospital of Shantou University Medical College. A receiver operator characteristic curve was used to evaluate the diagnostic value. The serum levels of autoantibodies against p53, MMP-7, and Hsp70 were higher in NMSCs than those in the normal controls (all P < 0.01). The AUC of the three-autoantibody panel was 0.841 (95% CI: 0.788-0.894) with the sensitivity and specificity of 60.40% and 91.20% when differentiating NMSCs from normal controls. Furthermore, measurement of this panel could differentiate early-stage skin cancer patients from normal controls (AUC: 0.851; 95% CI: 0.793-0.908). Data from Oncomine showed that the level of p53 mRNA was elevated in BCC (P < 0.05), and the Hsp70 mRNA was upregulated in SCC (P < 0.001). This serum three-autoantibody panel might function in assisting the early diagnosis of NMSC.
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Affiliation(s)
- Shi-Han Yang
- Department of Dermatology and Venereology, Affiliated Shantou Hospital of Sun Yat-sen University, 114 Waima Road, Shantou 515041, China
| | - Can-Tong Liu
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou 515041, China
- Precision Medicine Research Center, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China
| | - Chao-Qun Hong
- Department of Oncological Laboratory Research, The Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou 515041, China
| | - Ze-Yuan Huang
- Department of Dermatology and Venereology, Affiliated Shantou Hospital of Sun Yat-sen University, 114 Waima Road, Shantou 515041, China
| | - Huan-Zhu Wang
- Department of Dermatology and Venereology, Affiliated Shantou Hospital of Sun Yat-sen University, 114 Waima Road, Shantou 515041, China
| | - Lai-Feng Wei
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou 515041, China
- Precision Medicine Research Center, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China
| | - Yi-Wei Lin
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou 515041, China
- Precision Medicine Research Center, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China
| | - Hai-Peng Guo
- Department of Head and Neck Surgery, The Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou 515041, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou 515041, China
- Precision Medicine Research Center, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China
- Guangdong Esophageal Cancer Research Institute, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou 515041, China
- Precision Medicine Research Center, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China
- Guangdong Esophageal Cancer Research Institute, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China
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24
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Butt J, Blot WJ, Visvanathan K, Le Marchand L, Wilkens LR, Chen Y, Sesso HD, Teras L, Ryser MD, Hyslop T, Wassertheil-Smoller S, Tinker LF, Potter JD, Song M, Berndt SI, Waterboer T, Pawlita M, Epplein M. Auto-antibodies to p53 and the Subsequent Development of Colorectal Cancer in a U.S. Prospective Cohort Consortium. Cancer Epidemiol Biomarkers Prev 2020; 29:2729-2734. [PMID: 32972968 DOI: 10.1158/1055-9965.epi-20-0780] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/01/2020] [Accepted: 09/21/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Auto-antibodies to tumor suppressor p53 are found in a subset of patients with colorectal cancer. A recent prospective study in the United States has reported a significant 1.8-fold increased odds for colorectal cancer development with prediagnostic seropositivity to p53. In this study, we sought to examine this association in a U.S. colorectal cancer cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for colorectal cancer. METHODS Auto-antibodies to p53 were measured in prediagnostic blood samples of 3,702 incident colorectal cancer cases and 3,702 controls, matched by age, race, and sex, from 9 U.S. prospective cohorts. The association of seropositivity to p53 with colorectal cancer risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression. RESULTS Overall, 5% of controls and 7% of cases were seropositive to p53, resulting in a statistically significant 33% increased colorectal cancer risk [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.09-1.61]. By follow-up time, the association was only significant with colorectal cancer diagnoses within 4 years after blood draw (OR, 2.27; 95% CI, 1.62-3.19), but not thereafter (OR, 0.97; 95% CI, 0.76-1.24). CONCLUSIONS In this large consortium of prospective cohorts, we found that prediagnostic seropositivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing colorectal cancer within 4 years after blood draw. IMPACT Our finding suggests that p53 seropositivity may not be a useful predictor of long-term colorectal cancer risk; however, it might be considered as a marker to aid in the early diagnosis of colorectal cancer.
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Affiliation(s)
- Julia Butt
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Cancer Control and Population Sciences Program, Duke Cancer Institute, and Department of Population Health Sciences, Duke University, Durham, North Carolina
| | - William J Blot
- Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii
| | - Lynne R Wilkens
- Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii
| | - Yu Chen
- Department of Population Health, New York University School of Medicine, New York, New York
| | - Howard D Sesso
- Brigham and Women's Hospital, Boston, Massachusetts.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Lauren Teras
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Marc D Ryser
- Department of Population Health Sciences, and Department of Mathematics, Duke University, Durham, North Carolina
| | - Terry Hyslop
- Cancer Control and Population Sciences Program, Duke Cancer Institute, and Department of Population Health Sciences, Duke University, Durham, North Carolina.,Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | | | - Lesley F Tinker
- Cancer Prevention Program, Division of Public Health Sciences at Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - John D Potter
- Centre for Public Health Research, Massey University, Wellington, New Zealand.,Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Sonja I Berndt
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Pawlita
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Meira Epplein
- Cancer Control and Population Sciences Program, Duke Cancer Institute, and Department of Population Health Sciences, Duke University, Durham, North Carolina
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25
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Wang H, Zhang B, Li X, Zhou D, Li Y, Jia S, Qi S, Xu A, Zhao X, Wang J, Bai Z, Cao B, Li N, Dai M, Chen H, Huang J. Identification and Validation of Novel Serum Autoantibody Biomarkers for Early Detection of Colorectal Cancer and Advanced Adenoma. Front Oncol 2020; 10:1081. [PMID: 32793472 PMCID: PMC7387658 DOI: 10.3389/fonc.2020.01081] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/29/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Colorectal cancer (CRC) comprises a large proportion of malignant tumors, and early detection of CRC is critical for effective treatment and optimal prognosis. We aimed to discover and validate serum autoantibodies for early detection of CRC. Methods: Combined with CRC-associated autoantibodies discovered by serological proteome and multiplex analyses, 26 predefined autoantibodies were evaluated in 315 samples (130 CRCs, 75 advanced adenomas, and 110 healthy controls) by protein microarray analysis. Autoantibodies with potential detection value were verified by enzyme-linked immunosorbent assays (ELISAs). Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the accuracy of the biomarkers. Results: Four serum autoantibodies (ALDH1B1, UQCRC1, CTAG1, and CENPF) showed statistically different levels between patients with advanced neoplasm (CRC or advanced adenoma) and controls in microarray analysis, which were validated by ELISAs. Among the four biomarkers, the ALDH1B1 autoantibody showed the highest detection value with area under the curve (AUC) values of 0.70 and 0.74 to detect CRC and advanced adenoma with sensitivities of 75.68 and 62.31% and specificities of 63.06 and 73.87%, respectively. By combining the four biomarkers, the performance was improved with an AUC of 0.79 to detect CRC and advanced adenomas. Conclusion: The ALDH1B1 autoantibody has a good potential for early detection of CRC and advanced adenoma, and measuring serum autoantibodies against tumor-associated antigens may improve detection of early CRC.
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Affiliation(s)
- Hejing Wang
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bei Zhang
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojin Li
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Donghu Zhou
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yanmeng Li
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Siyu Jia
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Saiping Qi
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Anjian Xu
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaomu Zhao
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jin Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhigang Bai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bangwei Cao
- National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ni Li
- Office of Cancer Screening, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Dai
- Office of Cancer Screening, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongda Chen
- Office of Cancer Screening, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian Huang
- Experimental Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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26
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Bermejo IA, Navo CD, Castro-López J, Guerreiro A, Jiménez-Moreno E, Sánchez Fernández EM, García-Martín F, Hinou H, Nishimura SI, García Fernández JM, Mellet CO, Avenoza A, Busto JH, Bernardes GJL, Hurtado-Guerrero R, Peregrina JM, Corzana F. Synthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp 2-iminosugar fragment. Chem Sci 2020; 11:3996-4006. [PMID: 34122869 PMCID: PMC8152572 DOI: 10.1039/c9sc06334j] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The Tn antigen (GalNAc-α-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines. An anti-cancer vaccine based on an unnatural antigen with an sp2-iminosugar fragment.![]()
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Affiliation(s)
- Iris A Bermejo
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química E-26006 Logroño Spain
| | - Claudio D Navo
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química E-26006 Logroño Spain .,CIC BioGUNE, Bizkaia Technology Park Building 800 48170 Derio Spain
| | - Jorge Castro-López
- Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza Zaragoza Spain
| | - Ana Guerreiro
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa Avenida Professor Egas Moniz 1649-028 Lisboa Portugal
| | - Ester Jiménez-Moreno
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química E-26006 Logroño Spain
| | | | - Fayna García-Martín
- Graduate School and Faculty of Advanced Life Science, Laboratory of Advanced Chemical Biology, Hokkaido University N21 W11 Sapporo 001-0021 Japan
| | - Hiroshi Hinou
- Graduate School and Faculty of Advanced Life Science, Laboratory of Advanced Chemical Biology, Hokkaido University N21 W11 Sapporo 001-0021 Japan
| | - Shin-Ichiro Nishimura
- Graduate School and Faculty of Advanced Life Science, Laboratory of Advanced Chemical Biology, Hokkaido University N21 W11 Sapporo 001-0021 Japan
| | - José M García Fernández
- Instituto de Investigaciones Químicas (IIQ), CSIC-Universidad de Sevilla E-41092 Sevilla Spain
| | - Carmen Ortiz Mellet
- Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla E-41012 Sevilla Spain
| | - Alberto Avenoza
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química E-26006 Logroño Spain
| | - Jesús H Busto
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química E-26006 Logroño Spain
| | - Gonçalo J L Bernardes
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa Avenida Professor Egas Moniz 1649-028 Lisboa Portugal.,Department of Chemistry, University of Cambridge Lensfield Road CB2 1EW Cambridge UK
| | - Ramón Hurtado-Guerrero
- Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza Zaragoza Spain.,Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, University of Copenhagen Copenhagen Denmark.,Fundación ARAID Zaragoza Spain
| | - Jesús M Peregrina
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química E-26006 Logroño Spain
| | - Francisco Corzana
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química E-26006 Logroño Spain
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27
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Zhao F, Cao M, Jiang XH, Xie K, Ye SR, Yie SM. A specific autoantibody against a novel tumour-association antigen derived from human DNA-topoiomerase I is a potential biomarker for early diagnosis and favourable prognosis in patients with colorectal carcinoma. Biomarkers 2020; 25:149-156. [PMID: 31922440 DOI: 10.1080/1354750x.2020.1714734] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Context: We previously reported a novel tumour associated antigen (TTA) with molecular weight around 48 kDa and identified the novel TTA as a fragment derived from human DNA-topoiomerase I (TOP1). We termed the novel TAA as TOPO48 and termed autoantibody against the TAA as anti-TOPO48 autoantibody.Objective: To explore the clinical significance of anti-TOPO48 autoantibody in patients with colorectal carcinoma (CRC).Materials and methods: Serum levels of the autoantibody in patients with CRC or benign tumours and healthy volunteers were measured with a specific ELISA.Results: CRC patients at early stage had higher frequency of positive levels of the autoantibody and CRC patients with positive autoantibody levels had higher overall survival rate than those with negative autoantibody levels.Conclusion: The autoantibody is a potential biomarker for early diagnosis and favourable prognosis of CRC.
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Affiliation(s)
- Feng Zhao
- State Key Laboratory of Biotherapy and Cancer, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China
| | - Mei Cao
- Core Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospitals, Chengdu, PR China
| | - Xiao-Hui Jiang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, PR China
| | - Ke Xie
- Department of Oncology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospitals, Chengdu, PR China
| | - Shang-Rong Ye
- Chengdu Cancer Bioengineering Research Institute, Chengdu, PR China
| | - Shang-Mian Yie
- Chengdu Cancer Bioengineering Research Institute, Chengdu, PR China
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28
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Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol 2020; 20:294-307. [DOI: 10.1038/s41577-019-0257-x] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
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29
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Camacho-Encina M, Balboa-Barreiro V, Rego-Perez I, Picchi F, VanDuin J, Qiu J, Fuentes M, Oreiro N, LaBaer J, Ruiz-Romero C, Blanco FJ. Discovery of an autoantibody signature for the early diagnosis of knee osteoarthritis: data from the Osteoarthritis Initiative. Ann Rheum Dis 2019; 78:1699-1705. [PMID: 31471297 PMCID: PMC6900252 DOI: 10.1136/annrheumdis-2019-215325] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/23/2019] [Accepted: 08/22/2019] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To find autoantibodies (AAbs) in serum that could be useful to predict incidence of radiographic knee osteoarthritis (KOA). DESIGN A Nucleic-acid Programmable Protein Arrays (NAPPA) platform was used to screen AAbs against 2125 human proteins in sera at baseline from participants free of radiographic KOA belonging to the incidence and non-exposed subcohorts of the Osteoarthritis Initiative (OAI) who developed or not, radiographic KOA during a follow-up period of 96 months. NAPPA-ELISA were performed to analyse reactivity against methionine adenosyltransferase two beta (MAT2β) and verify the results in 327 participants from the same subcohorts. The association of MAT2β-AAb levels with KOA incidence was assessed by combining several robust biostatistics analysis (logistic regression, Receiver Operating Characteristic and Kaplan-Meier curves). The proposed prognostic model was replicated in samples from the progression subcohort of the OAI. RESULTS In the screening phase, six AAbs were found significantly different at baseline in samples from incident compared with non-incident participants. In the verification phase, high levels of MAT2β-AAb were significantly associated with the future incidence of KOA and with an earlier development of the disease. The incorporation of this AAb in a clinical model for the prognosis of incident radiographic KOA significantly improved the identification/classification of patients who will develop the disorder. The usefulness of the model to predict radiographic KOA was confirmed on a different OAI subcohort. CONCLUSIONS The measurement of AAbs against MAT2β in serum might be highly useful to improve the prediction of OA development, and also to estimate the time to incidence.
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Affiliation(s)
- María Camacho-Encina
- Grupo de Investigación de Reumatología, Unidad de Proteomica, INIBIC-Complejo Hospitalario Universitario A Coruña, SERGAS, Universidad de A Coruña, A Coruña, Spain
| | - Vanesa Balboa-Barreiro
- Grupo de Epidemiología Clínica y Bioestadística, INIBIC-Complejo Hospitalario Universitario A Coruña, SERGAS, Universidad de A Coruña, A Coruña, Spain
| | - Ignacio Rego-Perez
- Grupo de Investigacion de Reumatologia, Unidad de Genomica, INIBIC-Complexo Hospitalario Universitario de A Coruña, SERGAS, Universidad de A Coruña, A Coruña, Spain
| | - Florencia Picchi
- Grupo de Investigación de Reumatología, Unidad de Proteomica, INIBIC-Complejo Hospitalario Universitario A Coruña, SERGAS, Universidad de A Coruña, A Coruña, Spain
| | - Jennifer VanDuin
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute-Arizona State University, Tempe, Arizona, USA
| | - Ji Qiu
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute-Arizona State University, Tempe, Arizona, USA
| | - Manuel Fuentes
- Department of Medicine and General Cytometry Service-Nucleus. Proteomics Unit. CIBER-ONC, Cancer Research Center (IBMCC/CSIC/USAL/IBSAL), Salamanca, Spain
| | - Natividad Oreiro
- Grupo de Investigacion Reumatologia, Unidad de Investigacion Clinica, INIBIC-Complejo Hospitalario Universitario A Coruña, SERGAS, Universidad de A Coruña, A Coruña, Spain
| | - Joshua LaBaer
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute-Arizona State University, Tempe, Arizona, USA
| | - Cristina Ruiz-Romero
- Grupo de Investigación de Reumatología, Unidad de Proteomica, INIBIC-Complejo Hospitalario Universitario A Coruña, SERGAS, Universidad de A Coruña, A Coruña, Spain
| | - Francisco J Blanco
- Grupo de Investigacion de Reumatologia, INIBIC-Complejo Hospitalario Universitario A Coruña, SERGAS, Departamento de Medicina, Universidad de A Coruña, A Coruña, Spain
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30
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Liu S, Tan Q, Song Y, Shi Y, Han X. Anti‐p53 autoantibody in blood as a diagnostic biomarker for colorectal cancer: A meta‐analysis. Scand J Immunol 2019; 91:e12829. [DOI: 10.1111/sji.12829] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 09/15/2019] [Accepted: 09/15/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Shuxia Liu
- Department of Clinical Laboratory National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
- Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing China
| | - Qiaoyun Tan
- Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing China
| | - Yuanyuan Song
- Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing China
| | - Yuankai Shi
- Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing China
| | - Xiaohong Han
- Department of Clinical Laboratory National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
- Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing China
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31
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Zhou Y, Cui J, Du H. Autoantibody-targeted TAAs in pancreatic cancer: A comprehensive analysis. Pancreatology 2019; 19:760-768. [PMID: 31255446 DOI: 10.1016/j.pan.2019.06.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 05/23/2019] [Accepted: 06/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer is one of the leading causes of cancer mortality and lacks efficient biomarkers for early diagnosis. In the early stages of pancreatic cancer, humoral immunity can respond to a certain amount of tumor-associated antigens (TAAs) with the production of corresponding autoantibodies. Such autoantibody-targeted TAAs (autoTAAs) are highly likely to indicate early events during pancreatic carcinogenesis. Herein, we performed a comprehensive analysis of these autoTAAs to explore their physiological function and their involvement and prognostic value in pancreatic cancer. METHODS We first searched the literature to identify the autoTAAs. A PPI network of these autoTAAs was constructed, and core network modules were extracted by Cytoscape software. GO annotation and KEGG pathway analysis were performed to analyze the main physiological functions of these autoTAAs. The prognostic value of autoTAAs in pancreatic cancer was analyzed by using RNA-seq data generated by TCGA. RESULTS The PPI network including 98 autoTAAs was constructed, and 2 subgroups were extracted as core modules. GO and KEGG analysis revealed that key functions and pathways of these autoTAAs were significantly enriched in nucleotide repair, protein synthesis, and cancer-associated events. MSH2, EZR, PGK1, VCL and ANXA2 have prognostic value in pancreatic cancer, and high mRNA expression of these 5 proteins is associated with unfavorable prognosis in pancreatic cancer. CONCLUSIONS AutoTAAs may be associated with early events in the carcinogenesis of pancreatic cancer. MSH2, EZR, PGK1, VCL and ANXA2 predict poor prognosis in pancreatic cancer. Some autoTAAs also have prognostic value in other cancers.
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Affiliation(s)
- Yabin Zhou
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Jiawen Cui
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, China
| | - Hongwu Du
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, China.
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32
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Antony F, Deantonio C, Cotella D, Soluri MF, Tarasiuk O, Raspagliesi F, Adorni F, Piazza S, Ciani Y, Santoro C, Macor P, Mezzanzanica D, Sblattero D. High-throughput assessment of the antibody profile in ovarian cancer ascitic fluids. Oncoimmunology 2019; 8:e1614856. [PMID: 31428516 PMCID: PMC6685609 DOI: 10.1080/2162402x.2019.1614856] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 04/25/2019] [Accepted: 04/27/2019] [Indexed: 12/31/2022] Open
Abstract
The identification of effective biomarkers for early diagnosis, prognosis, and response to treatments remains a challenge in ovarian cancer (OC) research. Here, we present an unbiased high-throughput approach to profile ascitic fluid autoantibodies in order to obtain a tumor-specific antigen signature in OC. We first reported the reactivity of immunoglobulins (Igs) purified from OC patient ascites towards two different OC cell lines. Using a discovery set of Igs, we selected tumor-specific antigens from a phage display cDNA library. After biopanning, 700 proteins were expressed as fusion protein and used in protein array to enable large-scale immunoscreening with independent sets of cancer and noncancerous control. Finally, the selected antigens were validated by ELISA. The initial screening identified eight antigenic clones: CREB3, MRPL46, EXOSC10, BCOR, HMGN2, HIP1R, OLFM4, and KIAA1755. These antigens were all validated by ELISA in a study involving ascitic Igs from 153 patients (69 with OC, 34 with other cancers and 50 without cancer), with CREB3 showing the highest sensitivity (86.95%) and specificity (98%). Notably, we were able to identify an association between the tumor-associated (TA) antibody response and the response to a first-line tumor treatment (platinum-based chemotherapy). A stronger association was found by combining three antigens (BCOR, CREB3, and MRLP46) as a single antibody signature. Measurement of an ascitic fluid antibody response to multiple TA antigens may aid in the identification of new prognostic signatures in OC patients and shift attention to new potentially relevant targets.
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Affiliation(s)
- Frank Antony
- Department of Health Sciences, and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Cecilia Deantonio
- Department of Health Sciences, and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Diego Cotella
- Department of Health Sciences, and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Maria Felicia Soluri
- Department of Health Sciences, and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Olga Tarasiuk
- Department of Health Sciences, and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | | | - Fulvio Adorni
- Epidemiology Unit, Institute of Biomedical Technologies, National Research Council, Milan, Italy
| | - Silvano Piazza
- Bioinformatics and Functional Genomics Unit, Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), Area Science Park Trieste, Italy
| | - Yari Ciani
- Bioinformatics and Functional Genomics Unit, Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), Area Science Park Trieste, Italy
| | - Claudio Santoro
- Department of Health Sciences, and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Paolo Macor
- Department of Life Science, University of Trieste, Trieste, Italy
| | - Delia Mezzanzanica
- Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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33
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Chen T, Du D, Chen J, Zhou P, Weinstein JN, Yao L, Liu Y. ZC3H12A Expression in Different Stages of Colorectal Cancer. Oncoscience 2019; 6:301-311. [PMID: 31106233 PMCID: PMC6508193 DOI: 10.18632/oncoscience.480] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 02/01/2019] [Indexed: 12/17/2022] Open
Abstract
Identification of CRC patients with early-stage disease provides the opportunity for curative local resection. However, robust markers for stage I tumor prediction are yet to be developed. We analyzed RNA-sequencing data of 221 CRC samples using the TCGA dataset to identify novel biomarkers for stage I CRC. We next validated the TCGA finding in an independent GEO cohort of 290 CRC patients and in a third cohort of 110 CRC tumors and matched normal samples. We further performed correlative analysis of ZC3H12A gene expression with clinicopathologic features and disease-free survival. Expression correlation of ZC3H12A with the chemokine ligands was evaluated via Student’s t-test. In the TCGA cohort, stage I CRC patients had significantly higher ZC3H12A mRNA expression as compared with the other three stages combined and with the other individual stages in a pairwise manner (P<0.001 for all comparisons). The significant association of ZC3H12A gene expression with stages was further validated in the GEO cohort and in the additional third cohort. In support of these findings, we further found that patients with lower ZC3H12A expression had more aggressive tumor features and shorter disease-free survival. Biologically, ZC3H12A expression was significantly correlated with expression of three chemokine ligands (CXCL1, CXCL2 and CXCL3), suggesting that immune response dysregulation likely contributes to CRC development. Our results demonstrate ZC3H12A’s potential role in identification of CRC patients with early-stage disease.
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Affiliation(s)
- Tao Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Di Du
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jian Chen
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Pinghong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital of Fudan University, Shanghai, China
| | - John N Weinstein
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Liqing Yao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yuexin Liu
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Baldin AV, Grishina AN, Korolev DO, Kuznetsova EB, Golovastova MO, Kalpinskiy AS, Alekseev BY, Kaprin AD, Zinchenko DV, Savvateeva LV, Varshavsky VA, Zernii EY, Vinarov AZ, Bazhin AV, Philippov PP, Zamyatnin AA. Autoantibody against arrestin-1 as a potential biomarker of renal cell carcinoma. Biochimie 2018; 157:26-37. [PMID: 30389514 DOI: 10.1016/j.biochi.2018.10.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 10/25/2018] [Indexed: 12/28/2022]
Abstract
Renal cell carcinoma (RCC) is the second-most common uronephrological cancer. In the absence of specific symptoms, early diagnosis of RCC is challenging. Monitoring of the aberrant expression of tumour-associated antigens (TAAs) and related autoantibody response is considered as a novel approach of RCC diagnostics. The aim of this study was to examine the aberrant expression of arrestin-1 in renal tumours, to investigate the possible epigenetic mechanism underlying arrestin-1 expression, and to assess the frequency of anti-arrestin-1 autoantibody response. Immunohistochemistry was used to assess the presence of arrestin-1 in primary tumours and metastases of 39 patients with RCC and renal oncocytoma. Bisulfite sequencing was employed to analyse the methylation status of the promoter of the SAG gene encoding arrestin-1. Western blot analysis was performed to detect autoantibodies against arrestin-1 in serum samples of 36 RCC and oncocytoma patients. Arrestin-1 was found to be expressed in RCC (58.7% of cases) and renal oncocytoma (90% of cases) cells, while being absent in healthy kidney. The expression of arrestin-1 in RCC metastases was more prominent than in primary tumours. Hypomethylation of the SAG gene promoter is unlikely to be the mechanism for the aberrant expression of arrestin-1. Autoantibodies against arrestin-1 were detected in sera of 75% of RCC patients. Taken together, our findings suggest employment of autoantibody against arrestin-1 as biomarker of RCC.
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Affiliation(s)
- Alexey V Baldin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia.
| | - Alena N Grishina
- Anatomic Pathology Department, Sechenov First Moscow State Medical University, 119991, Moscow, Russia.
| | - Dmitry O Korolev
- Institute of Uronephrology and Human Reproductive Health, Sechenov First Moscow State Medical University, 119991, Moscow, Russia
| | - Ekaterina B Kuznetsova
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia; Research Centre for Medical Genetics, 115522, Moscow, Russia.
| | - Marina O Golovastova
- Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia
| | - Alexey S Kalpinskiy
- P.A. Hertzen Moscow Oncology Research Center, National Medical Research Center of Radiology, 125284, Moscow, Russia
| | - Boris Y Alekseev
- P.A. Hertzen Moscow Oncology Research Center, National Medical Research Center of Radiology, 125284, Moscow, Russia
| | - Andrey D Kaprin
- P.A. Hertzen Moscow Oncology Research Center, National Medical Research Center of Radiology, 125284, Moscow, Russia.
| | - Dmitry V Zinchenko
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Pushchino, Moscow Region, 142290 Russia.
| | - Lyudmila V Savvateeva
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia
| | - Vladimir A Varshavsky
- Anatomic Pathology Department, Sechenov First Moscow State Medical University, 119991, Moscow, Russia
| | - Evgeni Yu Zernii
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia; Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia.
| | - Andrey Z Vinarov
- Institute of Uronephrology and Human Reproductive Health, Sechenov First Moscow State Medical University, 119991, Moscow, Russia.
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
| | - Pavel P Philippov
- Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia
| | - Andrey A Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia; Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia.
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Jiang XH, Yao ZY, He X, Zhang JB, Xie K, Chen J, Cao M, Zhang J, Yie SM. Clinical significance of plasma anti-TOPO48 autoantibody and blood survivin-expressing circulating cancer cells in patients with early stage endometrial carcinoma. Arch Gynecol Obstet 2018; 299:229-237. [PMID: 30341503 DOI: 10.1007/s00404-018-4938-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 09/05/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE To examine the clinical significance of an autoantibody (AAb) against a novel tumor-associated antigen (TAA) derived from human DNA-topoisomerase I, termed as TOPO48 AAb, and peripheral blood survivin-expressing circulating cells (CCC) in patients with early stage endometrial cancer (EC). METHODS Blood samples were collected from 80 patients with early stage EC and 80 age-matched healthy subjects. Plasma levels of the TOPO48 AAb were measured with a specific antibody capture enzyme-linked immunosorbent assay (ELISA) and blood survivin-expressing CCC assessed with a reverse transcription-polymerase chain reaction products based on a hybridization-enzyme-linked immunosorbent assay (RT-PCR-ELISA). Sixty patients were followed up for 36 months after the initial assay test. RESULTS There were 75% and 60% samples with positive levels of the TOPO48 AAb and survivin-expressing CCC in the cancer patients, respectively. However, the cumulative positive rate of combination of the two markers was increased to 93.3% with 0.927 (95% CI 0.871-0.984) of area under the curve (AUC) in receiver operating characteristic (ROC) curve analysis. During the follow-up period, patients with positive TOPO48 AAb but negative surviving-expressing CCC had a higher survival rate and a longer survival time than those with negative AAb but positive CCC (P = 0.01). CONCLUSIONS The combination of TOPO48 AAb and survivin-expressing CCC may be used as a novel recipe to improve the efficiency of early diagnosis and provide more accurate prognostic prediction in patients with early stage EC.
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Affiliation(s)
- Xiao-Hui Jiang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Human Sperm Bank, West China Second University Hospital of Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Zou-Ying Yao
- Department of Traditional Chinese Medicine, Lishui Central Hospital, Lishui, 323000, Zhejiang, People's Republic of China
| | - Xu He
- Core Laboratory, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Jian-Bo Zhang
- Core Laboratory, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Ke Xie
- Department of Oncology, Sichuan Academy of Medical Sciences Sichuan Provincial People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Jie Chen
- Core Laboratory, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Mei Cao
- Core Laboratory, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Jian Zhang
- Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, Sichuan, People's Republic of China
| | - Shang-Mian Yie
- Chengdu Cancer Bioengineering Research Institute, 37 Twelve Bridge Road, Chengdu, 610048, Sichuan, People's Republic of China.
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Xiu Y, Sun B, Jiang Y, Wang A, Liu L, Liu Y, Sun S, Huangfu M. Diagnostic Value of the Survivin Autoantibody in Four Types of Malignancies. Genet Test Mol Biomarkers 2018; 22:384-389. [PMID: 29924656 DOI: 10.1089/gtmb.2017.0278] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Tumor-associated antigen overexpression, which has been reported in many types of cancers, may trigger autoantibody secretion. The present study was designed to test whether levels of circulating autoantibodies to survivin protein-derived antigens is altered in liver, esophageal, breast, and lung cancers. METHODS Patients with liver (144), esophageal (159), breast (124), and lung cancers (267), and healthy volunteers (362) were recruited for the study, and serum samples were collected for ELISA autoantibody analysis. RESULTS Compared with the control group, survivin autoantibody levels were significantly higher in serum from patients with breast cancer and lung cancer, but were significantly lower in serum from patients with liver cancer (p < 0.05). In stage I and II lung cancer, the best-fit areas under the receiver operating characteristic curve was 0.731 (standard error [SE] = 0.023; 95% confidence interval [CI] 0.687-0.776) and the sensitivity, with 90% specificity, was 23.7%. CONCLUSION Analysis across four types of malignancies revealed that the survivin autoantibody had good specificity and sensitivity in lung cancer. Circulating autoantibodies to survivin could be a potential biomarker for the early lung cancer diagnosis.
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Affiliation(s)
- Yuting Xiu
- 1 Department of Radiotherapy, Second Hospital of Jilin University , Changchun, China
| | - Baosheng Sun
- 2 Department of Radiotherapy, Tumor Hospital of Jilin Province , Changchun, China
| | - Yongli Jiang
- 3 Changchun International Travel Healthcare Center , Changchun, China
| | - Aifu Wang
- 1 Department of Radiotherapy, Second Hospital of Jilin University , Changchun, China
| | - Linlin Liu
- 1 Department of Radiotherapy, Second Hospital of Jilin University , Changchun, China
| | - Ying Liu
- 4 Department of Toxicology, School of Public Health, Jilin University , Changchun, China
| | - Shilong Sun
- 5 Ministry of Health Key Laboratory of Radiobiology, Jilin University , Changchun, China
| | - Mingmei Huangfu
- 6 Department of Thyroid Surgery, Second Hospital of Jilin University , Changchun, China
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Lee PY, Chin SF, Low TY, Jamal R. Probing the colorectal cancer proteome for biomarkers: Current status and perspectives. J Proteomics 2018; 187:93-105. [PMID: 29953962 DOI: 10.1016/j.jprot.2018.06.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/13/2018] [Accepted: 06/23/2018] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Biomarkers that can facilitate better clinical management of CRC are in high demand to improve patient outcome and to reduce mortality. In this regard, proteomic analysis holds a promising prospect in the hunt of novel biomarkers for CRC and in understanding the mechanisms underlying tumorigenesis. This review aims to provide an overview of the current progress of proteomic research, focusing on discovery and validation of diagnostic biomarkers for CRC. We will summarize the contributions of proteomic strategies to recent discoveries of protein biomarkers for CRC and also briefly discuss the potential and challenges of different proteomic approaches in biomarker discovery and translational applications.
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Affiliation(s)
- Pey Yee Lee
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia.
| | - Siok-Fong Chin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
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Du Q, Yu R, Wang H, Yan D, Yuan Q, Ma Y, Slamon D, Hou D, Wang H, Wang Q. Significance of tumor-associated autoantibodies in the early diagnosis of lung cancer. CLINICAL RESPIRATORY JOURNAL 2018; 12:2020-2028. [PMID: 29356386 DOI: 10.1111/crj.12769] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 10/16/2017] [Accepted: 01/09/2018] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Autoantibodies tumor-associated antigens (TAAs) could be a valuable tool for the diagnosis or early detection of cancer due to their relatively high specificity and stability. The purpose of this study is to detect the level of tumor-associated autoantibodies in lung cancer and assess the diagnostic potential of autoantibodies in screening strategy for early stage lung cancer. MATERIALS AND METHODS Levels of tumor-associated autoantibodies (AAbs) were measured against a panel of seven TAAs (p53, PGP9.5, SOX2, GAGE7, GBU4-5, CAGE and MAGEA1) in 397 patients with pulmonary lesions (305 with newly diagnosis of NSCLC, 47 with SCLC and 45 with benign nodule) and 74 control persons without any nodules in the lung after chest MDCT scan. The sensitivity, specificity for patients and control persons, positive rate of the panel in different pathology, stage, size of lesion, age and gender were compared and analyzed. RESULTS The AAbs panel could distinguish malignant lesions from benign lesions and control people, with sensitivity of 56.53% and specificity of 91.60%. The specificity could be further increased to 95.80%, when combined with CT. The AAbs also showed high diagnostic value of malignant nodule, and it would be a new method for judgment of malignant nodules that are less than 8 mm in diameter. No significant differences were seen based on pathology, NSCLC stages, tumor size, age or gender. CONCLUSION This assay confirms the value of AAbs panel as a diagnostic tool combined with CT scan.
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Affiliation(s)
- Qiang Du
- Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.,Department of Respiratory Medicine, The North Area of Suzhou Municipal Hospital, Suzhou, China
| | - Ruofei Yu
- Department of Oncology, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Han Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.,Department of Pharmacy, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Dong Yan
- Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Qi Yuan
- Department of Intensive Care Unit, People's Hospital of Liaoning Provincial, Shenyang, China
| | - Yixin Ma
- Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Dennis Slamon
- Department of Medicine, Division of Hematology Oncology, Medical School of University of California at Los Angeles, Los Angeles 90095, California
| | - Dongmei Hou
- Department of Medicine, Division of Hematology Oncology, Medical School of University of California at Los Angeles, Los Angeles 90095, California
| | - Huiling Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Qi Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
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39
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Challenges in Colorectal Cancer: From Vaccines to Macrophage Repolarization. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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40
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Teras LR, Gapstur SM, Maliniak ML, Jacobs EJ, Gansler T, Michel A, Pawlita M, Waterboer T, Campbell PT. Prediagnostic Antibodies to Serum p53 and Subsequent Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2017; 27:219-223. [PMID: 29254936 DOI: 10.1158/1055-9965.epi-17-0407] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/27/2017] [Accepted: 11/22/2017] [Indexed: 11/16/2022] Open
Abstract
Background: The presence of circulating antibodies to the p53 tumor suppressor protein is a potential early detection colorectal cancer biomarker. However, studies of prediagnostic measures of p53 seropositivity in relation to colorectal cancer risk are limited.Methods: We conducted a nested case-control study of serum p53 autoantibodies and risk of colorectal cancer within the Cancer Prevention Study-II Nutrition Cohort. Among cohort participants who were cancer free at the time of blood collection, 392 were subsequently diagnosed with colorectal cancer over 11 years of follow-up. Two controls were matched to each case on birth date, blood draw date, race, and sex. Autoantibodies to p53 were detected in 41 of the 392 cases (10.5%) and 49 of the 774 controls (6.3%).Results: Participants who were seropositive for p53 antibodies before diagnosis were more likely to be subsequently diagnosed with colorectal cancer [RR = 1.77; 95% confidence interval (CI), 1.12-2.78]. This association was strongest within 3 years of diagnosis (RR = 2.26; 95% CI, 1.06-4.83). An association was also suggested when colorectal cancer was diagnosed 4 to <6 years after p53 measurement (RR = 1.84; 95% CI, 0.89-3.79), but not 6 or more years later (RR = 1.15; 95% CI, 0.44-2.99).Conclusions: If these results are confirmed, serum p53 antibodies may be useful on a panel of early detection markers for colorectal cancer.Impact: Individuals who were seropositive for p53 antibodies were twice as likely to develop colorectal cancer within the next 3 years compared with those who were seronegative. This marker is a good candidate for inclusion on an early detection marker panel for colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(2); 219-23. ©2017 AACR.
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Affiliation(s)
- Lauren R Teras
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
| | - Susan M Gapstur
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
| | - Maret L Maliniak
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
| | - Eric J Jacobs
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
| | - Ted Gansler
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
| | - Angelika Michel
- Infection, Inflammation and Cancer Program, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany
| | - Michael Pawlita
- Infection, Inflammation and Cancer Program, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany
| | - Tim Waterboer
- Infection, Inflammation and Cancer Program, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany
| | - Peter T Campbell
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
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Somovilla VJ, Bermejo IA, Albuquerque IS, Martínez-Sáez N, Castro-López J, García-Martín F, Compañón I, Hinou H, Nishimura SI, Jiménez-Barbero J, Asensio JL, Avenoza A, Busto JH, Hurtado-Guerrero R, Peregrina JM, Bernardes GJL, Corzana F. The Use of Fluoroproline in MUC1 Antigen Enables Efficient Detection of Antibodies in Patients with Prostate Cancer. J Am Chem Soc 2017; 139:18255-18261. [PMID: 29166012 DOI: 10.1021/jacs.7b09447] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
A structure-based design of a new generation of tumor-associated glycopeptides with improved affinity against two anti-MUC1 antibodies is described. These unique antigens feature a fluorinated proline residue, such as a (4S)-4-fluoro-l-proline or 4,4-difluoro-l-proline, at the most immunogenic domain. Binding assays using biolayer interferometry reveal 3-fold to 10-fold affinity improvement with respect to the natural (glyco)peptides. According to X-ray crystallography and MD simulations, the fluorinated residues stabilize the antigen-antibody complex by enhancing key CH/π interactions. Interestingly, a notable improvement in detection of cancer-associated anti-MUC1 antibodies from serum of patients with prostate cancer is achieved with the non-natural antigens, which proves that these derivatives can be considered better diagnostic tools than the natural antigen for prostate cancer.
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Affiliation(s)
- Víctor J Somovilla
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain.,Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Bijvoet Center for Biomolecular Research, Utrecht University , Universiteitsweg 99, Utrecht, The Netherlands
| | - Iris A Bermejo
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain
| | - Inês S Albuquerque
- Instituto de Medicina Molecular, Faculdade de Medicina da, Universidade de Lisboa , Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
| | - Nuria Martínez-Sáez
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain.,Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Bijvoet Center for Biomolecular Research, Utrecht University , Universiteitsweg 99, Utrecht, The Netherlands
| | - Jorge Castro-López
- Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) , Zaragoza, Spain
| | - Fayna García-Martín
- Graduate School and Faculty of Advanced Life Science, Field of Drug Discovery Research, Hokkaido University , N21 W11, Sapporo 001-0021, Japan
| | - Ismael Compañón
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain
| | - Hiroshi Hinou
- Graduate School and Faculty of Advanced Life Science, Field of Drug Discovery Research, Hokkaido University , N21 W11, Sapporo 001-0021, Japan
| | - Shin-Ichiro Nishimura
- Graduate School and Faculty of Advanced Life Science, Field of Drug Discovery Research, Hokkaido University , N21 W11, Sapporo 001-0021, Japan
| | - Jesús Jiménez-Barbero
- (i) CIC bioGUNE, Bizkaia Technology Park, Building 801A, 48170 Derio, Spain; (ii) Ikerbasque, Basque Foundation for Science, Maria Diaz de Haro 13, 48009 Bilbao, Spain; (iii) Department of Organic Chemistry II, Faculty of Science & Technology, University of the Basque Country , 48940 Leioa, Spain
| | - Juan L Asensio
- Instituto de Química Orgánica General, IQOG-CSIC , 28006 Madrid, Spain
| | - Alberto Avenoza
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain
| | - Jesús H Busto
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain
| | - Ramón Hurtado-Guerrero
- Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) , Zaragoza, Spain.,Fundación ARAID , 50018 Zaragoza, Spain
| | - Jesús M Peregrina
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain
| | - Gonçalo J L Bernardes
- Instituto de Medicina Molecular, Faculdade de Medicina da, Universidade de Lisboa , Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal.,Department of Chemistry, University of Cambridge , Lensfield Road, CB2 1EW Cambridge, U.K
| | - Francisco Corzana
- Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain
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Dumstrei K, Chen H, Brenner H. A systematic review of serum autoantibodies as biomarkers for pancreatic cancer detection. Oncotarget 2017; 7:11151-64. [PMID: 26840568 PMCID: PMC4905464 DOI: 10.18632/oncotarget.7098] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 01/18/2016] [Indexed: 12/22/2022] Open
Abstract
Pancreatic cancer is a leading cause of cancer-related deaths in the western world. Patients with pancreatic cancer have poor prognosis, partly due to difficulties in detecting it at early stages. While different markers have been associated with pancreatic cancer, many of them show suboptimal sensitivity and specificity. Serum autoantibodies against tumor-associated antigens have recently emerged as early stage biomarkers for different types of cancers. Given the urgent need for early and reliable biomarkers for pancreatic cancer, we undertook a systematic review of the published literature to identify primary articles that evaluated serum autoantibodies in pancreatic cancer detection by searching PubMed and ISI Web of Knowledge. Two reviewers extracted data on study characteristics and results independently. Overall, 31 studies evaluating 124 individual serum autoantibodies in pancreatic cancer detection met the inclusion criteria. In general, single autoantibody markers showed relatively low sensitivities at high specificity. A combination of markers, either multiple serum autoantibodies or serum autoantibodies combined with tumor-associated markers, led to a better diagnostic performance. However, most of the analyzed autoantibodies have only been reported in single studies and therefore need to be independently validated. We conclude that serum autoantibodies might present an option as biomarkers for early detection of pancreatic cancer, but more work is needed to identify and validate autoantibody signatures that are associated with early stage pancreatic cancer.
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Affiliation(s)
- Karin Dumstrei
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.,European Molecular Biology Organization (EMBO), D-69117 Heidelberg, Germany
| | - Hongda Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.,Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), D-69120 Heidelberg, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
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Bhardwaj M, Gies A, Werner S, Schrotz-King P, Brenner H. Blood-Based Protein Signatures for Early Detection of Colorectal Cancer: A Systematic Review. Clin Transl Gastroenterol 2017; 8:e128. [PMID: 29189767 PMCID: PMC5717517 DOI: 10.1038/ctg.2017.53] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 10/10/2017] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES Blood-based proteins might be an attractive option for early detection of colorectal cancer (CRC), but individually they are unlikely to achieve the diagnostic performance required for population based screening. We aimed at summarizing current evidence of diagnostic performance of signatures based on multiple proteins for early detection of CRC. METHODS A systematic literature review adhering to the PRISMA (preferred reporting items for systematic reviews and meta-analysis) guidelines was performed. PubMed and Web of Science databases were searched for potentially relevant studies published until 28th August, 2017. Relevant studies were identified by predefined eligibility criteria. Estimates of indicators of diagnostic performance such as sensitivity, specificity, and the area under the curve (AUC), along with information on validation and other key methodological procedures were extracted. Study quality was assessed by a QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) instrument tool. RESULTS Thirty six eligible studies with numbers of CRC cases ranging from 23 to 512 and the number of proteins included in signatures ranged from 3 to 13 were identified. Reported Youden's Index and AUC ranged from 0.19 to 0.95 and from 0.62 to 0.996, respectively. However most studies, especially those reporting better diagnostic performance, were conducted in clinical rather than screening setting and many studies lacked any internal or external validation of identified algorithm. CONCLUSIONS Blood-based tests using signatures of multiple proteins may be a promising approach for non-invasive CRC screening. However, promising signatures identified in clinical settings still require rigorous evaluation in large studies conducted in true screening setting.
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Affiliation(s)
- Megha Bhardwaj
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Anton Gies
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Simone Werner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Petra Schrotz-King
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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Chen H, Werner S, Butt J, Zörnig I, Knebel P, Michel A, Eichmüller SB, Jäger D, Waterboer T, Pawlita M, Brenner H. Prospective evaluation of 64 serum autoantibodies as biomarkers for early detection of colorectal cancer in a true screening setting. Oncotarget 2017; 7:16420-32. [PMID: 26909861 PMCID: PMC4941325 DOI: 10.18632/oncotarget.7500] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 02/05/2016] [Indexed: 02/07/2023] Open
Abstract
Novel blood-based screening tests are strongly desirable for early detection of colorectal cancer (CRC). We aimed to identify and evaluate autoantibodies against tumor-associated antigens as biomarkers for early detection of CRC. 380 clinically identified CRC patients and samples of participants with selected findings from a cohort of screening colonoscopy participants in 2005–2013 (N=6826) were included in this analysis. Sixty-four serum autoantibody markers were measured by multiplex bead-based serological assays. A two-step approach with selection of biomarkers in a training set, and validation of findings in a validation set, the latter exclusively including participants from the screening setting, was applied. Anti-MAGEA4 exhibited the highest sensitivity for detecting early stage CRC and advanced adenoma. Multi-marker combinations substantially increased sensitivity at the price of a moderate loss of specificity. Anti-TP53, anti-IMPDH2, anti-MDM2 and anti-MAGEA4 were consistently included in the best-performing 4-, 5-, and 6-marker combinations. This four-marker panel yielded a sensitivity of 26% (95% CI, 13–45%) for early stage CRC at a specificity of 90% (95% CI, 83–94%) in the validation set. Notably, it also detected 20% (95% CI, 13–29%) of advanced adenomas. Taken together, the identified biomarkers could contribute to the development of a useful multi-marker blood-based test for CRC early detection.
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Affiliation(s)
- Hongda Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Simone Werner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Julia Butt
- Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Inka Zörnig
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), Internal Medicine VI, University of Heidelberg, Heidelberg, Germany
| | - Phillip Knebel
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Angelika Michel
- Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefan B Eichmüller
- GMP & T cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), Internal Medicine VI, University of Heidelberg, Heidelberg, Germany
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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45
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Chen H, Qian J, Werner S, Cuk K, Knebel P, Brenner H. Development and validation of a panel of five proteins as blood biomarkers for early detection of colorectal cancer. Clin Epidemiol 2017; 9:517-526. [PMID: 29184444 PMCID: PMC5672848 DOI: 10.2147/clep.s144171] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Objective Reliable noninvasive biomarkers for early detection of colorectal cancer (CRC) are highly desirable for efficient population-based screening with high adherence rates. We aimed to discover and validate blood-based protein markers for the early detection of CRC. Patients and methods A two-stage design with a discovery and a validation set was used. In the discovery phase, plasma levels of 92 protein markers and serum levels of TP53 autoantibody were measured in 226 clinically recruited CRC patients and 118 controls who were free of colorectal neoplasms at screening colonoscopy. An algorithm predicting the presence of CRC was derived by Lasso regression and validated in a validation set consisting of all available 41 patients with CRC and a representative sample of 106 participants with advanced adenomas and 107 controls free of neoplasm from a large screening colonoscopy cohort (N=6018). Receiver operating characteristic (ROC) analyses were conducted to evaluate the diagnostic performance of individual biomarkers and biomarker combinations. Results An algorithm based on growth differentiation factor 15 (GDF-15), amphiregulin (AREG), Fas antigen ligand (FasL), Fms-related tyrosine kinase 3 ligand (Flt3L) and TP53 autoantibody was constructed. In the validation set, the areas under the curves of this five-marker algorithm were 0.82 (95% CI, 0.74–0.90) for detecting CRC and 0.60 (95% CI, 0.52–0.69) for detecting advanced adenomas. At cutoffs yielding 90% specificity, the sensitivities (95% CI) for detecting CRC and advanced adenomas were 56.4% (38.4%–71.8%) and 22.0% (13.4%–35.4%), respectively. The five-marker panel showed similar diagnostic efficacy for the detection of early- and late-stage CRC. Conclusion The identified most promising biomarkers could contribute to the development of powerful blood-based tests for CRC screening in the future.
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Affiliation(s)
- Hongda Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Program Office for Cancer Screening in Urban China, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Jing Qian
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Simone Werner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katarina Cuk
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Phillip Knebel
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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46
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Fan CW, Kuo YB, Lin GP, Chen SM, Chang SH, Li BA, Chan EC. Development of a multiplexed tumor-associated autoantibody-based blood test for the detection of colorectal cancer. Clin Chim Acta 2017; 475:157-163. [PMID: 29074220 DOI: 10.1016/j.cca.2017.10.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 10/01/2017] [Accepted: 10/22/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies worldwide, and early diagnosis is vital to improving prognoses. We explored the diagnostic potential of a multiplex autoantibody panel as a biomarker for the detection of CRC by ELISA. METHODS In total, 192 serum samples (92 CRC and 100 matched controls) were tested against a panel of 12 tumor-associated antigens (TAAs): RPH3AL, RPL36, SLP2, p53, survivin, ANAXA4, SEC61B, CCCAP, NYCO16, NMDAR, PLSCR1, and HDAC5. Individual and combined autoantibody signatures were examined. RESULTS Compared to individual autoantibody markers, the combinations of TAAs provided better discrimination between tumorous and normal sera. The overall sensitivity of a selected panel of four antibodies (anti-SLP2, -p53, -SEC61B, and -PLSCR1) was 64.1%, with a specificity of 80% that increased to 83.7% when carcinoembryonic antigen (CEA) measurement was added. Furthermore, the sensitivity of the panel of four antibodies for early and advanced stages of CRC was 66.7% and 62%, increasing to 88.3% and 84%, respectively, when CEA was added. CONCLUSIONS We identified a panel of four antibodies as a promising diagnostic biomarker for the detection of CRC.
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Affiliation(s)
- Chung-Wei Fan
- Division of Colorectal Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | | | - Geng-Pin Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Si-Min Chen
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan
| | - Shih-Hsien Chang
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan
| | - Bo-An Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Err-Cheng Chan
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan.
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Li P, Shi JX, Xing MT, Dai LP, Li JT, Zhang JY. Evaluation of serum autoantibodies against tumor-associated antigens as biomarkers in lung cancer. Tumour Biol 2017; 39:1010428317711662. [DOI: 10.1177/1010428317711662] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Pei Li
- The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Jian-Xiang Shi
- The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
- Henan Key Laboratory for Tumor Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Meng-Tao Xing
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Li-Ping Dai
- The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
- Henan Key Laboratory for Tumor Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Ji-Tian Li
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Jian-Ying Zhang
- The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
- Henan Key Laboratory for Tumor Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, China
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48
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Giat E, Ehrenfeld M, Shoenfeld Y. Cancer and autoimmune diseases. Autoimmun Rev 2017; 16:1049-1057. [DOI: 10.1016/j.autrev.2017.07.022] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023]
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Fortner RT, Damms-Machado A, Kaaks R. Systematic review: Tumor-associated antigen autoantibodies and ovarian cancer early detection. Gynecol Oncol 2017; 147:465-480. [PMID: 28800944 DOI: 10.1016/j.ygyno.2017.07.138] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/20/2017] [Accepted: 07/24/2017] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Tumor-associated autoantibodies (AAbs), produced as an immune response to tumor-associated antigens (TAAs), are a novel pathway of early detection markers. METHODS We conducted a systematic review on AAbs and ovarian cancer to summarize the diagnostic performance of individual AAbs and AAb panels. A total of 29 studies including 85 AAbs were included; 27 of the studies were conducted in prevalent cases and cancer-free controls and 2 investigations included pre-diagnosis samples. The majority of studies were hypothesis-driven, evaluating AAbs to target TAAs; 10 studies used screening approaches such as serological expression cloning (SEREX) and nucleic acid-programmable protein arrays (NAPPA). RESULTS The highest sensitivities for individual AAbs were reported for RhoGDI-AAbs (89.5%) and TUBA1C-AAbs (89%); however, specificity levels were relatively low (80% and 75%, respectively). High sensitivities at high specificities were reported for HOXA7-AAbs for detection of moderately differentiated ovarian tumors (66.7% sensitivity at 100% specificity) and IL8-AAbs in stage I-II ovarian cancer (65.5% sensitivity at 98% specificity). A panel of 11 AAbs (ICAM3, CTAG2, p53, STYXL1, PVR, POMC, NUDT11, TRIM39, UHMK1, KSR1, and NXF3) provided 45% sensitivity at 98% specificity for serous ovarian cancer, when at least 2 AAbs were above a threshold of 95% specificity. Twelve of the AAbs identified in this review were investigated in more than one study. Data on diagnostic discrimination by tumor histology and stage at diagnosis are sparse. Limited data suggest select AAb markers improve diagnostic discrimination when combined with markers such as CA125 and HE4. CONCLUSIONS AAbs for ovarian cancer early detection is an emerging area, and large-scale, prospective investigations considering histology and stage are required for discovery and validation. However, data to date suggests panels of AAbs may eventually reach sufficient diagnostic discrimination to allow earlier detection of disease as a complement to existing markers and transvaginal ultrasound.
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Affiliation(s)
| | - Antje Damms-Machado
- Division of Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany.
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50
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Paul B, O'Neil BH, McRee AJ. Checkpoint inhibition for colorectal cancer: progress and possibilities. Immunotherapy 2017; 8:693-704. [PMID: 27197538 DOI: 10.2217/imt-2016-0013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most common cause of cancer death in the USA. Despite an increase in the repertoire of treatment options available for CRC, median overall survival has plateaued at approximately 2.5 years. Strategies that engage the patient's native immune system to overcome checkpoint inhibition have proven to be promising in subsets of CRCs, specifically those with mismatch repair deficiency. Further studies are required to determine combinations of standard therapies with immunotherapy drugs and to discover the best biomarkers to predict response. This review provides insight into the progress made in treating patients with advanced CRC with immunotherapeutics and the areas that demand further research to make these drugs more effective in this patient population.
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Affiliation(s)
- Barry Paul
- School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Bert H O'Neil
- Indiana University Melvin & Bren Simon Cancer Center, Indianapolis, IN, USA
| | - Autumn J McRee
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
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