|
1
|
Guan B, Lu Q, Chen J, Fang J, Liu Z, Li W, Zhang L, Xu G. FLOT1 Is a Novel Serum Biomarker of Ovarian Cancer Targeted by N6-methyladenosine Modification Inhibition. Cell Biol Int 2025; 49:674-691. [PMID: 40066501 PMCID: PMC12070024 DOI: 10.1002/cbin.70015] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/19/2025] [Accepted: 02/27/2025] [Indexed: 05/14/2025]
Abstract
Ovarian cancer (OC) is a deadly disease and lacks a precise marker for diagnosis worldwide. Our previous work has shown the overexpression of flotillin-1 (FLOT1) in OC tissue. To improve diagnostic sensitivity and accuracy, we evaluated the serum level of FLOT1 in OC patients and found that the serum concentration of FLOT1 as well as CA125 was significantly increased in patients with OC compared with healthy control (p < 0.01) and those with benign tumors (p < 0.05). The detection rate (above the upper limit of a cut-off value) of FLOT1 and CA125 was 77.78% and 72.22%, respectively, in patients with OC, which was increased to 88.89% in combination. The elevation of FLOT1 was confirmed in the serum of nude mice after the implantation of human OC cells. A high level of FLOT1 protein in the serum was positively correlated with the overexpression of FLOT1 protein in OC tissues. Furthermore, the level of m6A modification of FLOT1 mRNA was significantly high in OC cells compared with normal ovarian epithelial cells, leading to an increase in FLOT1 mRNA expression. Application of a methylation inhibitor, 3-deazaadenosine, decreased FLOT1 mRNA expression in OC cells and suppressed tumor formation in a xenograft mouse model. In conclusion, the current study demonstrated that FLOT1 is a novel serum biomarker of OC and can be targeted by m6A modification inhibition. These data highlight the potential application of FLOT1 as a diagnostic marker and a therapeutic target for patients with OC.
Collapse
Affiliation(s)
- Bin Guan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
| | - Qi Lu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Department of Obstetrics and GynecologyJinshan Hospital, Fudan UniversityShanghaiChina
| | - Junyu Chen
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
| | - Jingyi Fang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
| | - Zhenyu Liu
- Shanghai Yizhi Medical Technology Co. LtdShanghaiChina
| | - Wei Li
- Shanghai Yizhi Medical Technology Co. LtdShanghaiChina
| | - Lingyun Zhang
- Department of Medical OncologyShanghai Geriatric Medical CenterShanghaiChina
- Department of Medical OncologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
| |
Collapse
|
|
2
|
Fan S, Zhao K, Lei J, Ge Y. Preoperative total bile acid can be used as a prognostic biomarker in patients with operable biliary tract cancers. Discov Oncol 2025; 16:696. [PMID: 40338467 PMCID: PMC12061807 DOI: 10.1007/s12672-025-02527-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 04/28/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Biliary tract cancers (BTCs) are highly invasive malignancies with poor prognoses. However, reliable biomarkers for survival prediction remain lacking. Notably, abnormal lipid metabolism has elicited increasing interest in digestive tract tumors, with the liver playing an important role in lipid metabolism. OBJECTIVE To explore the relationship between hepatic lipid metabolism-related indicators, assessed through routine clinical biochemical testing and survival prognosis in patients with BTCs. METHODS Overall, 109 patients with a pathological diagnosis of BTC from 2017 to 2023 were included in this study. Univariate and multivariate Cox regression analyses were performed using R Studio software, and survival curves were plotted. RESULTS Univariate analysis revealed that tumor location and preoperative total bile acid (TBA), carcinoembryonic antigen, cancer antigen (CA)125, and CA19-9 levels were correlated with patient survival (P < 0.05). Multivariate Cox regression analysis identified increased TBA level [hazard ratio (HR) = 0.445, P = 0.004] as an independent prognostic factor for longer survival. Conversely, tumor location [intrahepatic cholangiocarcinoma (iCCA) and/or extrahepatic cholangiocarcinoma (eCCA)] (HR = 2.463, P = 0.036) and increased CA125 and CA19-9 levels (HR = 2.549, P = 0.008 and HR = 2.100, P = 0.019) were independent prognostic factors for shorter survival. Additionally, Kaplan‒Meier survival curves revealed significantly longer survival in patients with increased TBA levels than those in the normal group (P = 0.012). Conversely, patients with iCCA and/or eCCA tumor location and increased CA125 and CA19-9 levels had significantly shorter median survival (P = 0.044, P = 0.013, and P = 0.012, respectively). CONCLUSION TBA may be a biomarker for predicting survival in patients with operable BTC, highlighting its clinical significance and application potential.
Collapse
Affiliation(s)
- Shanshan Fan
- Department of Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
| | - Kexin Zhao
- The Third Clinical School of Medicine, Capital Medical University, Beijing, China
| | - Jiabao Lei
- The Third Clinical School of Medicine, Capital Medical University, Beijing, China
| | - Yang Ge
- Department of Oncology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| |
Collapse
|
|
3
|
He W, Cui J, Wang XY, Siu RHP, Tanner JA. Early-Stage Pancreatic Cancer Diagnosis: Serum Biomarkers and the Potential for Aptamer-Based Biosensors. Molecules 2025; 30:2012. [PMID: 40363817 PMCID: PMC12073606 DOI: 10.3390/molecules30092012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/25/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Pancreatic cancer has a high mortality rate, and both the incidence and mortality are continuing to increase in many countries globally. The poor prognosis of pancreatic cancer is in part due to the challenges in early diagnosis. Improving early-stage pancreatic cancer diagnosis would improve survival outcomes. Aptamer-based biosensors provide an alternative technological approach for the analysis of serum biomarkers with several potential advantages. This review summarizes the major pancreatic cancer serum biomarkers, as well as discusses recent progress in biomarker exploration and aptasensor development. Here, we review both established and novel serum biomarkers identified recently, emphasizing their potential for early-stage pancreatic cancer diagnosis. We also propose strategies for further expanding multiplex biomarker panels beyond the established CA19-9 biomarker to enhance diagnostic performance. We discuss technological advancements in aptamer-based sensors for pancreatic cancer-related biomarkers over the last decade. Optical and electrochemical sensors are highlighted as two primary modalities in aptasensor design, each offering unique advantages. Finally, we propose steps towards clinical application using aptamer-based sensors with multiplexed biomarker detection for improved pancreatic cancer diagnostics.
Collapse
Affiliation(s)
- Weisi He
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (W.H.); (J.C.); (X.-Y.W.); (R.H.P.S.)
| | - Jingyu Cui
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (W.H.); (J.C.); (X.-Y.W.); (R.H.P.S.)
| | - Xue-Yan Wang
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (W.H.); (J.C.); (X.-Y.W.); (R.H.P.S.)
| | - Ryan H. P. Siu
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (W.H.); (J.C.); (X.-Y.W.); (R.H.P.S.)
| | - Julian A. Tanner
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (W.H.); (J.C.); (X.-Y.W.); (R.H.P.S.)
- Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Hong Kong SAR, China
- Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen 518057, China
| |
Collapse
|
|
4
|
Zhang XY, Hong LL, Ling ZQ. MUC16/CA125 in cancer: new advances. Clin Chim Acta 2025; 565:119981. [PMID: 39368688 DOI: 10.1016/j.cca.2024.119981] [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: 02/08/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/07/2024]
Abstract
MUC16/CA125 is a common diagnostic marker for many types of cancer. However, due to the widespread expression of MUC16 in cancer, its specificity and sensitivity as a target are poor, which severely limits its clinical application. In recent years, various studies have shown that the clinical application potential of MUC16/CA125 has been greatly improved. The update of detection technology improves the accuracy and range of detection, and improves the early diagnosis rate of cancer. Targeting MUC16/CA125 is an important strategy for tumor therapy. Targeting residual amino acids, n-glycoylation structures or other targets on the surface of MUC16 cells can greatly improve the accuracy of detection and therapy. The new drug delivery method broke through the original technical shackles, targeted MUC16 positive cells more specifically and improved the drug efficacy. In this paper, the technological advances in detecting and identifying MUC16 targets and the great progress in cancer screening and treatment based on MUC16 as a target are described in detail, revealing the great potential of MUC16 as a target in cancer screening and treatment, and illustrating the potential clinical application value of MUC16.
Collapse
Affiliation(s)
- Xin-Yu Zhang
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No. 1 Banshan East Rd., Gongshu District, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; The Second Clinical Medical College of Zhejiang Chinese Medicine University, Hangzhou 310053, People's Republic of China
| | - Lian-Lian Hong
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No. 1 Banshan East Rd., Gongshu District, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China
| | - Zhi-Qiang Ling
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No. 1 Banshan East Rd., Gongshu District, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
| |
Collapse
|
|
5
|
Malik S, Sikander M, Bell N, Zubieta D, Bell MC, Yallapu MM, Chauhan SC. Emerging role of mucins in antibody drug conjugates for ovarian cancer therapy. J Ovarian Res 2024; 17:161. [PMID: 39118097 PMCID: PMC11308542 DOI: 10.1186/s13048-024-01485-2] [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: 05/15/2024] [Accepted: 07/24/2024] [Indexed: 08/10/2024] Open
Abstract
Ovarian cancer stands as the deadliest gynecologic malignancy, responsible for nearly 65% of all gynecologic cancer-related deaths. The challenges in early detection and diagnosis, coupled with the widespread intraperitoneal spread of cancer cells and resistance to chemotherapy, contribute significantly to the high mortality rate of this disease. Due to the absence of specific symptoms and the lack of effective screening methods, most ovarian cancer cases are diagnosed at advanced stages. While chemotherapy is a common treatment, it often leads to tumor recurrence, necessitating further interventions. In recent years, antibody-drug conjugates (ADCs) have emerged as a valuable tool in targeted cancer therapy. These complex biotherapeutics combine an antibody that specifically targets tumor specific/associated antigen(s) with a high potency anti-cancer drug through a linker, offering a promising approach for ovarian cancer treatment. The identification of molecular targets in various human tumors has paved the way for the development of targeted therapies, with ADCs being at the forefront of this innovation. By delivering cytotoxic agents directly to tumors and metastatic lesions, ADCs show potential in managing chemo-resistant ovarian cancers. Mucins such as MUC16, MUC13, and MUC1 have shown significantly higher expression in ovarian tumors as compared to normal and/or benign samples, thus have become promising targets for ADC generation. While traditional markers are limited by their elevated levels in non-cancerous conditions, mucins offer a new possibility for targeted treatment in ovarian cancer. This review comprehensively described the potential of mucins for the generation of ADC therapy, highlighting their importance in the quest to improve the outcome of ovarian cancer patients.
Collapse
Affiliation(s)
- Shabnam Malik
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Mohammed Sikander
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Natasha Bell
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Daniel Zubieta
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Maria C Bell
- Sanford Health, Sanford Gynecologic Oncology Clinic, Sioux Falls, SD, 57104, USA
| | - Murali M Yallapu
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Subhash C Chauhan
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA.
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA.
| |
Collapse
|
|
6
|
Shringi S, Agrawal AK, Gadkari P. A Review of Pseudomyxoma Peritonei: Insights Into Diagnosis, Management, and Prognosis. Cureus 2024; 16:e61244. [PMID: 38939264 PMCID: PMC11210681 DOI: 10.7759/cureus.61244] [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: 05/08/2024] [Accepted: 05/28/2024] [Indexed: 06/29/2024] Open
Abstract
Pseudomyxoma peritonei (PMP) is a rare and complex clinical syndrome characterized by the accumulation of mucinous ascites within the peritoneal cavity, typically associated with mucinous tumours of appendiceal origin. Despite its rarity, PMP poses significant challenges in diagnosis and management due to its indolent yet locally aggressive nature. This comprehensive review provides insights into the diagnosis, management, and prognosis of PMP, synthesizing current evidence and emerging trends in the field. Challenges and opportunities in PMP management are discussed, along with recommendations for clinical practice emphasizing the importance of a multidisciplinary approach and specialized care. Despite ongoing challenges, advances in surgical techniques, perioperative chemotherapy, and emerging therapies offer hope for improved outcomes and quality of life for PMP patients.
Collapse
Affiliation(s)
- Siddhi Shringi
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Anil K Agrawal
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Pravin Gadkari
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| |
Collapse
|
|
7
|
Lee SH, Brianna. Association of microRNA-21 expression with breast cancer subtypes and its potential as an early biomarker. Pathol Res Pract 2024; 254:155073. [PMID: 38218039 DOI: 10.1016/j.prp.2023.155073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/29/2023] [Indexed: 01/15/2024]
Abstract
Breast cancer has become the most diagnosed cancer worldwide in 2020 with high morbidity and mortality rates. The alarming increase in breast cancer incidence has sprung many researchers to focus on developing novel screening tests to identify early breast cancer which will allow clinicians to provide timely and effective treatments. With much evidence supporting the notion that the deregulation of miRNAs (a class of non-coding RNA) greatly contributes to cancer initiation and progression, the promising role of miRNAs as cancer biomarkers is gaining traction in the research world. Among the upregulated miRNAs identified in breast carcinogenesis, miR-21 was shown to be significantly expressed in breast cancer tissues and bodily fluids of breast cancer patients. Therein, this review paper aims to provide an overview of breast cancer, the role and significance of miR-21 in breast cancer pathogenesis, and its potential as a breast cancer biomarker. The paper also discusses the current types of tumor biomarkers and their limitations, the presence of miR-21 in extracellular vesicles and plasma, screening methods available for miRNA detection along with some challenges faced in developing diagnostic miR-21 testing for breast cancer to provide readers with a comprehensive outlook based on using miR-21 in clinical settings.
Collapse
Affiliation(s)
- Sau Har Lee
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia; Digital Health and Medical Advancements Impact Lab, Taylor's University, Subang Jaya 47500, Malaysia.
| | - Brianna
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Darul Ehsan, Selangor 47500, Malaysia
| |
Collapse
|
|
8
|
Wang CW, Weaver SD, Boonpattrawong N, Schuster-Little N, Patankar M, Whelan RJ. A Revised Molecular Model of Ovarian Cancer Biomarker CA125 (MUC16) Enabled by Long-read Sequencing. CANCER RESEARCH COMMUNICATIONS 2024; 4:253-263. [PMID: 38197671 PMCID: PMC10829539 DOI: 10.1158/2767-9764.crc-23-0327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 12/01/2023] [Accepted: 01/04/2024] [Indexed: 01/11/2024]
Abstract
The biomarker CA125, a peptide epitope located in several tandem repeats of the mucin MUC16, is the gold standard for monitoring regression and recurrence of high-grade serous ovarian cancer in response to therapy. However, the CA125 epitope along with several structural features of the MUC16 molecule are ill defined. One central aspect still unresolved is the number of tandem repeats in MUC16 and how many of these repeats contain the CA125 epitope. Studies from the early 2000s assembled short DNA reads to estimate that MUC16 contained 63 repeats.Here, we conduct Nanopore long-read sequencing of MUC16 transcripts from three primary ovarian tumors and established cell lines (OVCAR3, OVCAR5, and Kuramochi) for a more exhaustive and accurate estimation and sequencing of the MUC16 tandem repeats.The consensus sequence derived from these six sources was confirmed by proteomics validation and agrees with recent additions to the NCBI database. We propose a model of MUC16 containing 19-not 63-tandem repeats. In addition, we predict the structure of the tandem repeat domain using the deep learning algorithm, AlphaFold.The predicted structure displays an SEA domain and unstructured linker region rich in proline, serine, and threonine residues in all 19 tandem repeats. These studies now pave the way for a detailed characterization of the CA125 epitope. Sequencing and modeling of the MUC16 tandem repeats along with their glycoproteomic characterization, currently underway in our laboratories, will help identify novel epitopes in the MUC16 molecule that improve on the sensitivity and clinical utility of the current CA125 assay. SIGNIFICANCE Despite its crucial role in clinical management of ovarian cancer, the exact molecular sequence and structure of the biomarker, CA125, are not defined. Here, we combine long-read sequencing, mass spectrometry, and in silico modeling to provide the foundational dataset for a more complete characterization of the CA125 epitope.
Collapse
Affiliation(s)
- Chien-Wei Wang
- Department of Chemistry, University of Kansas, Lawrence, Kansas
| | - Simon D. Weaver
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, Indiana
| | - Nicha Boonpattrawong
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin
| | | | - Manish Patankar
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin
| | | |
Collapse
|
|
9
|
Feng R, Zhang Z, Fan Q. Carbohydrate antigen 125 in congestive heart failure: ready for clinical application? Front Oncol 2023; 13:1161723. [PMID: 38023127 PMCID: PMC10644389 DOI: 10.3389/fonc.2023.1161723] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Congestion is the permanent mechanism driving disease progression in patients with acute heart failure (AHF) and also is an important treatment target. However, distinguishing between the two different phenotypes (intravascular congestion and tissue congestion) for personalized treatment remains challenging. Historically, carbohydrate antigen 125 (CA125) has been a frequently used biomarker for the screening, diagnosis, and prognosis of ovarian cancer. Interestingly, CA125 is highly sensitive to tissue congestion and shows potential for clinical monitoring and optimal treatment of congestive heart failure (HF). Furthermore, in terms of right heart function parameters, CA125 levels are more advantageous than other biomarkers of HF. CA125 is expected to become a new biological alternative marker for congestive HF and thereby is expected be widely used in clinical practice.
Collapse
Affiliation(s)
- Rui Feng
- Department of Laboratory Medicine, Wuhan Asian Heart Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
- School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Zhenlu Zhang
- Department of Laboratory Medicine, Wuhan Asian Heart Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Qingkun Fan
- Department of Laboratory Medicine, Wuhan Asian Heart Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| |
Collapse
|
|
10
|
Meng J, Weng J, Wu J, Mao H, Huang P, Chen S, Liu L. Preoperative serum CA125 level is a good prognostic predictor in patients with intrahepatic cholangiocarcinoma after hepatectomy: A single-center retrospective study. Medicine (Baltimore) 2023; 102:e34839. [PMID: 37682202 PMCID: PMC10489453 DOI: 10.1097/md.0000000000034839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 07/28/2023] [Indexed: 09/09/2023] Open
Abstract
Serum carbohydrate antigen 125 (CA125) is associated with the prognosis of various malignancies, including ovarian and pancreatic cancer. The relationship between preoperative serum CA125 level and the survival of patients with intrahepatic cholangiocarcinoma (ICC) has not been fully studied. The aim of this study was to explore the prognostic value of CA125 in ICC after hepatectomy. We retrospectively reviewed the clinicopathological data of 178 ICC patients who underwent hepatic resection. Receiver operating characteristic analyses were performed to estimate the relationships of serum CA125, α-fetoprotein, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 with the prognosis of ICC. The predictive value of CA125 for the prognosis of ICC patients was demonstrated by univariate analyses and Cox proportional hazards models. CA125 was correlated with tumor size, differentiation, capsulation, tumor node-metastasis stage, recurrence, and CEA. Univariate analysis indicated that CA125, sex, tumor number, tumor size, differentiation, surgical resection margin, tumor node metastasis stage, and CEA were risk factors for both the overall survival and the disease-free survival of ICC patients. Cox proportional hazards models showed that preoperative elevated CA125, a tumor size > 5 cm, and an R1 surgical resection margin were independent prognostic predictors of overall survival and disease-free survival. CA125 also had strong predictive value for the prognosis of different ICC subgroups, including patients without lymph node metastasis and with elevated carbohydrate antigen 19-9 levels. Preoperative elevated serum CA125 level is a noninvasive, simple, and reliable indicator of the prognosis of ICC patients after hepatectomy.
Collapse
Affiliation(s)
- Jie Meng
- Department of Health Management Center, The Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jun Weng
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jian Wu
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Han Mao
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Peilu Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Shule Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Lingyun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Laboratory of Hepatobiliary and Pancreatic Surgery, Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, China
| |
Collapse
|
|
11
|
Yue S, Wang X, Ge W, Li J, Yang C, Zhou Z, Zhang P, Yang X, Xiao W, Yang S. Deciphering Protein O-GalNAcylation: Method Development and Disease Implication. ACS OMEGA 2023; 8:19223-19236. [PMID: 37305274 PMCID: PMC10249083 DOI: 10.1021/acsomega.3c01653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 04/20/2023] [Indexed: 06/13/2023]
Abstract
Mucin-type O-glycosylation is an important protein post-translational modification that is abundantly expressed on cell surface proteins. Protein O-glycosylation plays a variety of roles in cellular biological functions including protein structure and signal transduction to the immune response. Cell surface mucins are highly O-glycosylated and are the main substance of the mucosal barrier that protects the gastrointestinal or respiratory tract from infection by pathogens or microorganisms. Dysregulation of mucin O-glycosylation may impair mucosal protection against pathogens that can invade cells to trigger infection or immune evasion. Truncated O-glycosylation, also known as Tn antigen or O-GalNAcylation, is highly upregulated in diseases such cancer, autoimmune disorders, neurodegenerative diseases, and IgA nephropathy. Characterization of O-GalNAcylation helps decipher the role of Tn antigen in physiopathology and therapy. However, the analysis of O-glycosylation, specifically the Tn antigen, remains challenging due to the lack of reliable enrichment and identification assays compared to N-glycosylation. Here, we summarize recent advances in analytical methods for O-GalNAcylation enrichment and identification and highlight the biological role of the Tn antigen in various diseases and the clinical implications of identifying aberrant O-GalNAcylation.
Collapse
Affiliation(s)
- Shuang Yue
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
- Department
of Endocrinology, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Xiaotong Wang
- Department
of Hepatology and Gastroenterology, The
Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu 215004, China
- Department
of Endocrinology, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Wei Ge
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
| | - Jiajia Li
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
| | - Chuanlai Yang
- Scientific
Research Department, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Zeyang Zhou
- Department
of General Surgery, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Peng Zhang
- Department
of Orthopedics, The Second Affiliated Hospital
of Soochow University, Suzhou, Jiangsu 215004, China
| | - Xiaodong Yang
- Department
of General Surgery, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Wenjin Xiao
- Department
of Endocrinology, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Shuang Yang
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
| |
Collapse
|
|
12
|
Wang CW, Hanson EK, Minkoff L, Whelan RJ. Individual recombinant repeats of MUC16 display variable binding to CA125 antibodies. Cancer Biomark 2023:CBM220191. [PMID: 37248884 DOI: 10.3233/cbm-220191] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
BACKGROUND Despite its importance in the clinical management of ovarian cancer, the CA125 biomarker - located on the mucin protein MUC16 - is still not completely understood. Questions remain about MUC16's function and structure, specifically the identity and location of the CA125 epitopes. OBJECTIVE The goal of this study was to characterize the interaction of individual recombinant repeats from the tandem repeat domain of MUC16 with antibodies used in the clinical CA125 II test. METHODS Using E. coli expression, we isolated nine repeats from the putative antigenic domain of CA125. Amino acid composition of recombinant repeats was confirmed by high-resolution mass spectrometry. We characterized the binding of four antibodies - OC125, M11, "OC125-like," and "M11-like" - to nine recombinant repeats using Western blotting, indirect enzyme-linked immunosorbent assay (ELISA), and localized surface plasmon resonance (SPR) spectroscopy. RESULTS Each recombinant repeat was recognized by a different combination of CA125 antibodies. OC125 and "OC125-like" antibodies did not bind the same set of recombinant repeats, nor did M11 and "M11-like" antibodies. CONCLUSIONS Characterization of the interactions between MUC16 recombinant repeats and CA125 antibodies will contribute to ongoing efforts to identify the CA125 epitopes and improve our understanding of this important biomarker.
Collapse
Affiliation(s)
- Chien-Wei Wang
- Department of Chemistry, University of Kansas, Lawrence, KS, USA
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
| | - Eliza K Hanson
- Department of Chemistry, University of Kansas, Lawrence, KS, USA
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
| | - Lisa Minkoff
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
| | - Rebecca J Whelan
- Department of Chemistry, University of Kansas, Lawrence, KS, USA
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
| |
Collapse
|
|
13
|
Ren AH, Filippou PS, Soosaipillai A, Dimitrakopoulos L, Korbakis D, Leung F, Kulasingam V, Bernardini MQ, Diamandis EP. Mucin 13 (MUC13) as a candidate biomarker for ovarian cancer detection: potential to complement CA125 in detecting non-serous subtypes. Clin Chem Lab Med 2023; 61:464-472. [PMID: 36380677 DOI: 10.1515/cclm-2022-0491] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 11/07/2022] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Ovarian cancer is the most lethal gynecological malignancy in developed countries. One of the key associations with the high mortality rate is diagnosis at late stages. This clinical limitation is primarily due to a lack of distinct symptoms and detection at the early stages. The ovarian cancer biomarker, CA125, is mainly effective for identifying serous ovarian carcinomas, leaving a gap in non-serous ovarian cancer detection. Mucin 13 (MUC13) is a transmembrane, glycosylated protein with aberrant expression in malignancies, including ovarian cancer. We explored the potential of MUC13 to complement CA125 as an ovarian cancer biomarker, by evaluating its ability to discriminate serous and non-serous subtypes of ovarian cancer at FIGO stages I-IV from benign conditions. METHODS We used our newly developed, high sensitivity ELISA to measure MUC13 protein in a large, well-defined cohort of 389 serum samples from patients with ovarian cancer and benign conditions. RESULTS MUC13 and CA125 serum levels were elevated in malignant compared to benign cases (p<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of 0.74 (MUC13) and 0.76 (CA125). MUC13 concentrations were significantly higher in mucinous adenocarcinomas compared to benign controls (p=0.0005), with AUC of 0.80. MUC13 and CA125 showed significant elevation in early-stage cases (stage I-II) in relation to benign controls (p=0.0012 and p=0.014, respectively). CONCLUSIONS We report the novel role of MUC13 as a serum ovarian cancer biomarker, where it could complement CA125 for detecting some subtypes of non-serous ovarian carcinoma and early-stage disease.
Collapse
Affiliation(s)
- Annie H Ren
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Panagiota S Filippou
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Antoninus Soosaipillai
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Lampros Dimitrakopoulos
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Dimitrios Korbakis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Felix Leung
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Marcus Q Bernardini
- Division of Gynecologic Oncology, University Health Network, Toronto, ON, Canada
| | - Eleftherios P Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada.,Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| |
Collapse
|
|
14
|
Wang CW, Hanson EK, Minkoff L, Whelan RJ. Individual recombinant repeats of MUC16 display variable binding to CA125 antibodies. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.08.527749. [PMID: 36798296 PMCID: PMC9934600 DOI: 10.1101/2023.02.08.527749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
BACKGROUND Despite its importance in the clinical management of ovarian cancer, the CA125 biomarker-located on the mucin protein MUC16-is still not completely understood. Questions remain about MUC16's function and structure, specifically the identity and location of the CA125 epitopes. OBJECTIVE The goal of this study was to characterize the interaction of individual recombinant repeats from the tandem repeat domain of MUC16 with antibodies used in the clinical CA125 II test. METHODS Using E. coli expression, we isolated nine repeats from the putative antigenic domain of CA125. Amino acid composition of recombinant repeats was confirmed by high-resolution mass spectrometry. We characterized the binding of four antibodies-OC125, M11, "OC125-like," and "M11-like"-to nine recombinant repeats using Western blotting, indirect enzyme-linked immunosorbent assay (ELISA), and localized surface plasmon resonance (SPR) spectroscopy. RESULTS Each recombinant repeat was recognized by a different combination of CA125 antibodies. OC125 and "OC125-like" antibodies did not bind the same set of recombinant repeats, nor did M11 and "M11-like" antibodies. CONCLUSIONS Characterization of the interactions between MUC16 recombinant repeats and CA125 antibodies will contribute to ongoing efforts to identify the CA125 epitopes and improve our understanding of this important biomarker.
Collapse
Affiliation(s)
- Chien-Wei Wang
- Department of Chemistry, University of Kansas, Lawrence, KS, United States of America,Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, United States of America
| | - Eliza K. Hanson
- Department of Chemistry, University of Kansas, Lawrence, KS, United States of America,Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, United States of America
| | - Lisa Minkoff
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, United States of America
| | - Rebecca J. Whelan
- Department of Chemistry, University of Kansas, Lawrence, KS, United States of America,Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, United States of America,Corresponding author: Rebecca J. Whelan, University of Kansas, Multidisciplinary Research Building 220E, University of Kansas, Lawrence, KS, United States of America. Tel.: + 1-785-864-4670;
| |
Collapse
|
|
15
|
Non-invasive diagnosis of endometriosis: Immunologic and genetic markers. Clin Chim Acta 2023; 538:70-86. [PMID: 36375526 DOI: 10.1016/j.cca.2022.11.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/13/2022]
Abstract
Endometriosis, a benign gynecologic and chronic inflammatory disease, is defined by the presence of endometrial tissue outside the uterus characterized mainly by pelvic pain and infertility. Because endometriosis affects approximately 10% of females, it represents a significant socioeconomic burden worldwide having tremendous impact on daily quality of life. Accurate and prompt diagnosis is crucial for the management of this debilitating disorder. Unfortunately, diagnosis is typically delayed to lack of specific symptoms and readily accessible biomarkers. Although histopathologic examination remains the current gold standard, this approach is highly invasive and not applicable for early screening. Recent work has focused on the identification of reliable biomarkers including immunologic, ie, immune cells, antibodies and cytokines, as well as genetic and biochemical markers, ie, microRNAs, lncRNAs, circulating and mitochondrial nucleic acids, along with some hormones, glycoproteins and signaling molecules. Confirmatory research studies are, however, needed to more fully establish these markers in the diagnosis, progression and staging of these endometrial lesions.
Collapse
|
|
16
|
de Alcântara AL, Pastana LF, Gellen LPA, Vieira GM, Dobbin EAF, Silva TA, Pereira EEB, Rodrigues JCG, Guerreiro JF, Fernandes MR, de Assumpção PP, Cohen-Paes ADN, Santos SEBD, dos Santos NPC. Mucin (MUC) Family Influence on Acute Lymphoblastic Leukemia in Cancer and Non-Cancer Native American Populations from the Brazilian Amazon. J Pers Med 2022; 12:jpm12122053. [PMID: 36556273 PMCID: PMC9853325 DOI: 10.3390/jpm12122053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/05/2022] [Accepted: 11/10/2022] [Indexed: 12/15/2022] Open
Abstract
The mucin (MUC) family includes several genes aberrantly expressed in multiple carcinomas and mediates diverse pathways essentials for oncogenesis, in both solid and hematological malignancies. Acute Lymphoblastic Leukemia (ALL) can have its course influenced by genetic variants, and it seems more frequent in the Amerindian population, which has been understudied. Therefore, the present work aimed to investigate the MUC family exome in Amerindian individuals from the Brazilian Amazon, in a sample containing healthy Native Americans (NAMs) and indigenous subjects with ALL, comparing the frequency of polymorphisms between these two groups. The population was composed of 64 Amerindians from the Brazilian Amazon, from 12 different isolated tribes, five of whom were diagnosed with ALL. We analyzed 16 genes from the MUC family and found a total of 1858 variants. We compared the frequency of each variant in the ALL vs. NAM group, which led to 77 variants with a significant difference and, among these, we excluded those with a low impact, resulting in 63 variants, which were distributed in nine genes, concentrated especially in MUC 19 (n = 30) and MUC 3A (n = 18). Finally, 11 new variants were found in the NAM population. This is the first work with a sample of native Americans with cancer, a population which is susceptible to ALL, but remains understudied. The MUC family seems to have an influence on the development of ALL in the Amerindian population and especially MUC19 and MUC3A are shown as possible hotspots. In addition, the 11 new variants found point to the need to have their clinical impact analyzed.
Collapse
Affiliation(s)
| | - Lucas Favacho Pastana
- Oncology Research Nucleus, Universidade Federal do Pará, Belém 66075-110, PA, Brazil
| | | | | | | | - Thays Amâncio Silva
- Oncology Research Nucleus, Universidade Federal do Pará, Belém 66075-110, PA, Brazil
| | | | | | - João Farias Guerreiro
- Human and Medical Genetics Laboratory, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém 66077-830, PA, Brazil
| | | | | | | | | | | |
Collapse
|
|
17
|
Ward TM, Cauley CE, Stafford CE, Goldstone RN, Bordeianou LG, Kunitake H, Berger DL, Ricciardi R. Tumour genotypes account for survival differences in right- and left-sided colon cancers. Colorectal Dis 2022; 24:601-610. [PMID: 35142008 DOI: 10.1111/codi.16060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023]
Abstract
AIM We sought to identify genetic differences between right- and left-sided colon cancers and using these differences explain lower survival in right-sided cancers. METHOD A retrospective review of patients diagnosed with colon cancer was performed using The Cancer Genome Atlas, a cancer genetics registry with patient and tumour data from 20 North American institutions. The primary outcome was 5-year overall survival. Predictors for survival were identified using directed acyclic graphs and Cox proportional hazards models. RESULTS A total of 206 right- and 214 left-sided colon cancer patients with 84 recorded deaths were identified. The frequency of mutated alleles differed significantly in 12 of 25 genes between right- and left-sided tumours. Right-sided tumours had worse survival with a hazard ratio of 1.71 (95% confidence interval 1.10-2.64, P = 0.017). The total effect of the genetic loci on survival showed five genes had a sizeable effect on survival: DNAH5, MUC16, NEB, SMAD4, and USH2A. Lasso-penalized Cox regression selected 13 variables for the highest-performing model, which included cancer stage, positive resection margin, and mutated alleles at nine genes: MUC16, USH2A, SMAD4, SYNE1, FLG, NEB, TTN, OBSCN, and DNAH5. Post-selection inference demonstrated that mutations in MUC16 (P = 0.01) and DNAH5 (P = 0.02) were particularly predictive of 5-year overall survival. CONCLUSIONS Our study showed that genetic mutations may explain survival differences between tumour sites. Further studies on larger patient populations may identify other genes, which could form the foundation for more precise prognostication and treatment decisions beyond current rudimentary TNM staging.
Collapse
Affiliation(s)
- Thomas M Ward
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Christy E Cauley
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Caitlin E Stafford
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Robert N Goldstone
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Liliana G Bordeianou
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hiroko Kunitake
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David L Berger
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rocco Ricciardi
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| |
Collapse
|
|
18
|
Recent Advances in Ovarian Cancer: Therapeutic Strategies, Potential Biomarkers, and Technological Improvements. Cells 2022; 11:cells11040650. [PMID: 35203301 PMCID: PMC8870715 DOI: 10.3390/cells11040650] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/10/2022] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Aggressive and recurrent gynecological cancers are associated with worse prognosis and a lack of effective therapeutic response. Ovarian cancer (OC) patients are often diagnosed in advanced stages, when drug resistance, angiogenesis, relapse, and metastasis impact survival outcomes. Currently, surgical debulking, radiotherapy, and/or chemotherapy remain the mainstream treatment modalities; however, patients suffer unwanted side effects and drug resistance in the absence of targeted therapies. Hence, it is urgent to decipher the complex disease biology and identify potential biomarkers, which could greatly contribute to making an early diagnosis or predicting the response to specific therapies. This review aims to critically discuss the current therapeutic strategies for OC, novel drug-delivery systems, and potential biomarkers in the context of genetics and molecular research. It emphasizes how the understanding of disease biology is related to the advancement of technology, enabling the exploration of novel biomarkers that may be able to provide more accurate diagnosis and prognosis, which would effectively translate into targeted therapies, ultimately improving patients’ overall survival and quality of life.
Collapse
|
|
19
|
Chagovets VV, Vasil'ev VG, Iurova MV, Khabas GN, Pavlovich SV, Starodubtseva NL, Mayboroda OA. Metabolic “footprints” of the circulating cancer mucins: CA125 in the high-grade ovarian cancer. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2021. [DOI: 10.24075/brsmu.2021.065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Mucins are large glycoproteins characterized by the abundant O-linked oligosaccharides (O-glycans) clustered on a protein backbone. Most of the circulating mucins are rapidly cleared by glycan-recognizing hepatic clearance receptors in the liver. Those mucins that remain in the bloodstream are most commonly used as markers in clinical diagnostics. One of such circulating mucins is MUC16; a peptide epitope of which is known as CA125 antigen — a marker for ovarian cancer. Here, using a targeted 1H-NMR profiling of plasma we are exploring a link between the measured CA125 values and the systemic metabolism of the patients within a group with confirmed high-grade ovarian cancer. The study allowed identifying statistically significant associations between the measured values of CA125 epitope and the plasma concentrations of glucose, glutamine, alanine, betaine and serine. The significance of the identified associations for the listed compounds is below 0.01. This, in turn, enables us to hypothesize about a possibility of including the metabolic measures into a composite score of the ovarian cancer based on the CA125 epitope of MUC16.
Collapse
Affiliation(s)
- VV Chagovets
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - VG Vasil'ev
- Peoples' Friendship University of Russia, Moscow, Russia
| | - MV Iurova
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - GN Khabas
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - SV Pavlovich
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - NL Starodubtseva
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - OA Mayboroda
- Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
20
|
El Bairi K, Al Jarroudi O, Afqir S. Revisiting antibody-drug conjugates and their predictive biomarkers in platinum-resistant ovarian cancer. Semin Cancer Biol 2021; 77:42-55. [PMID: 33812984 DOI: 10.1016/j.semcancer.2021.03.031] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/07/2021] [Accepted: 03/27/2021] [Indexed: 02/05/2023]
Abstract
Until to date, platinum derived drugs are still the backbone of treating ovarian cancer (OC). Most patients treated with platinum-based chemotherapy develop resistance during the course of their management. The treatment of platinum-resistant ovarian cancer (PROC) is challenging. Few therapeutic options are available for patients with this aggressive disease. Besides, there are liminal advances regarding new anticancer drugs as well as validated predictive biomarkers of clinical outcomes in this setting. The enrollment of PROC patients in interventional studies is limited as compared to newly launched clinical trials for platinum-sensitive OC. Enthusiastically, the emergence of antibody-drug conjugates (ADCs) has provided promising findings for further clinical development in PROC. ADCs have the advantage to selectively deliver cytotoxic drugs to cancer cells expressing several of antigens using specific monoclonal antibodies based on the concept of immune bioconjugation. This innovative class of therapeutics showed encouraging early signs of clinical efficacy in PROC particularly mirvetuximab soravtansine that has been successfully introduced into three randomized and controlled phase III studies. In this review, the evidence from clinical trials supporting the development of ADCs targeting folate receptor alpha, sodium-dependent phosphate transporter 2B, dipeptidase 3, mesothelin, mucin 16, and tissue factor using various cytotoxic payloads in PROC is reviewed.
Collapse
Affiliation(s)
- Khalid El Bairi
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco.
| | - Ouissam Al Jarroudi
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Said Afqir
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| |
Collapse
|
|
21
|
Stergiou N, Urschbach M, Gabba A, Schmitt E, Kunz H, Besenius P. The Development of Vaccines from Synthetic Tumor-Associated Mucin Glycopeptides and their Glycosylation-Dependent Immune Response. CHEM REC 2021; 21:3313-3331. [PMID: 34812564 DOI: 10.1002/tcr.202100182] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 10/31/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022]
Abstract
Tumor-associated carbohydrate antigens are overexpressed as altered-self in most common epithelial cancers. Their glycosylation patterns differ from those of healthy cells, functioning as an ID for cancer cells. Scientists have been developing anti-cancer vaccines based on mucin glycopeptides, yet the interplay of delivery system, adjuvant and tumor associated MUC epitopes in the induced immune response is not well understood. The current state of the art suggests that the identity, abundancy and location of the glycans on the MUC backbone are all key parameters in the cellular and humoral response. This review shares lessons learned by us in over two decades of research in glycopeptide vaccines. By bridging synthetic chemistry and immunology, we discuss efforts in designing synthetic MUC1/4/16 vaccines and focus on the role of glycosylation patterns. We provide a brief introduction into the mechanisms of the immune system and aim to promote the development of cancer subunit vaccines.
Collapse
Affiliation(s)
- Natascha Stergiou
- Radionuclide Center, Radiology and Nuclear medicine Amsterdam UMC, VU University, De Boelelaan 1085c, 1081 HV, Amsterdam, the Netherlands
| | - Moritz Urschbach
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
| | - Adele Gabba
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
| | - Edgar Schmitt
- Institute of Immunology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Horst Kunz
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
| | - Pol Besenius
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
| |
Collapse
|
|
22
|
Hegde P, B R S, Ballal S, Swamy BM, Inamdar SR. Rhizoctonia bataticola lectin induces apoptosis and inhibits metastasis in ovarian cancer cells by interacting with CA 125 antigen differentially expressed on ovarian cells. Glycoconj J 2021; 38:669-688. [PMID: 34748163 DOI: 10.1007/s10719-021-10027-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/15/2021] [Accepted: 10/14/2021] [Indexed: 10/19/2022]
Abstract
A N-glycan specific lectin from Rhizoctonia bataticola [RBL] was shown to induce growth inhibitory and apoptotic effect in human ovarian, colon and leukemic cells but mitogenic effect on normal PBMCs as reported earlier, revealing its clinical potential. RBL has unique specificity for high mannose tri and tetra antennary N-glycans, expressed in ovarian cancer and also recognizes glycans which are part of CA 125 antigen, a well known ovarian cancer marker. Hence, in the present study diagnostic and therapeutic potential of RBL was investigated using human ovarian epithelial cancer SKOV3 and OVCAR3 cells known for differentially expressing CA 125. RBL binds differentially to human ovarian normal, cyst and cancer tissues. Flow cytometry, western blot analysis of membrane proteins showed the competitive binding of RBL and CA 125 antibody for the same binding sites on SKOV3 and OVCAR3 cells. RBL has strong binding to both SKOV3 and OVCAR3 cells with MFI of 173 and 155 respectively. RBL shows dose and time dependent growth inhibitory effect with IC50 of 2.5 and 8 μg/mL respectively for SKOV3 and OVCAR3 cells. RBL induces reproductive cell death, morphological changes, nuclear degradation and increased release of ROS in SKOV3 and OVCAR3 cells leading to cell death. This is also supported by increase in hypodiploid population, altered MMP leading to apoptosis possibly involving intrinsic pathway. Adhesion, wound healing, invasion and migration assays demonstrated anti-metastasis effect of RBL apart from its growth inhibitory effect. These results show the promising potential of RBL both as a diagnostic and therapeutic agent.
Collapse
Affiliation(s)
- Prajna Hegde
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Sindhura B R
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Suhas Ballal
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Bale M Swamy
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Shashikala R Inamdar
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India.
| |
Collapse
|
|
23
|
Hunt AL, Bateman NW, Barakat W, Makohon-Moore S, Hood BL, Conrads KA, Zhou M, Calvert V, Pierobon M, Loffredo J, Litzi TJ, Oliver J, Mitchell D, Gist G, Rojas C, Blanton B, Robinson EL, Odunsi K, Sood AK, Casablanca Y, Darcy KM, Shriver CD, Petricoin EF, Rao UN, Maxwell GL, Conrads TP. Extensive three-dimensional intratumor proteomic heterogeneity revealed by multiregion sampling in high-grade serous ovarian tumor specimens. iScience 2021; 24:102757. [PMID: 34278265 PMCID: PMC8264160 DOI: 10.1016/j.isci.2021.102757] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/19/2021] [Accepted: 06/17/2021] [Indexed: 12/15/2022] Open
Abstract
Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten high-grade serous ovarian carcinomas (HGSOCs) and analyzed by mass spectrometry, reverse phase protein arrays, and RNA sequencing. Unsupervised analyses of protein abundance data revealed independent clustering of an enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering driven by overall tumor "purity." Comparing these data to previously defined prognostic HGSOC molecular subtypes revealed protein and transcript expression from tumor epithelium correlated with the differentiated subtype, whereas stromal proteins (and transcripts) correlated with the mesenchymal subtype. Protein and transcript abundance in the tumor epithelium and stroma exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial tumor microenvironment protein heterogeneity that directly bears on prognostic signatures, biomarker discovery, and cancer pathophysiology and underscore the need to enrich cellular subpopulations for expression profiling.
Collapse
Affiliation(s)
- Allison L. Hunt
- Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Road, Annandale, VA 22042, USA
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Nicholas W. Bateman
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Waleed Barakat
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Sasha Makohon-Moore
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Brian L. Hood
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Kelly A. Conrads
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Ming Zhou
- Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Road, Annandale, VA 22042, USA
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Valerie Calvert
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Mariaelena Pierobon
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Jeremy Loffredo
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Tracy J. Litzi
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Julie Oliver
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Dave Mitchell
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Glenn Gist
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - Christine Rojas
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Brian Blanton
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Emma L. Robinson
- Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Road, Annandale, VA 22042, USA
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Kunle Odunsi
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Anil K. Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA
| | - Yovanni Casablanca
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Kathleen M. Darcy
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Craig D. Shriver
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Emanuel F. Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Uma N.M. Rao
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, Suite 100, Bethesda, MD 20817, USA
| | - G. Larry Maxwell
- Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Road, Annandale, VA 22042, USA
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| | - Thomas P. Conrads
- Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Road, Annandale, VA 22042, USA
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
| |
Collapse
|
|
24
|
Giamougiannis P, Martin-Hirsch PL, Martin FL. The evolving role of MUC16 (CA125) in the transformation of ovarian cells and the progression of neoplasia. Carcinogenesis 2021; 42:327-343. [PMID: 33608706 DOI: 10.1093/carcin/bgab010] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/19/2021] [Accepted: 02/15/2021] [Indexed: 12/23/2022] Open
Abstract
MUC16 (the cancer antigen CA125) is the most commonly used serum biomarker in epithelial ovarian cancer, with increasing levels reflecting disease progression. It is a transmembrane glycoprotein with multiple isoforms, undergoing significant changes through the metastatic process. Aberrant glycosylation and cleavage with overexpression of a small membrane-bound fragment consist MUC16-related mechanisms that enhance malignant potential. Even MUC16 knockdown can induce an aggressive phenotype but can also increase susceptibility to chemotherapy. Variable MUC16 functions help ovarian cancer cells avoid immune cytotoxicity, survive inside ascites and form metastases. This review provides a comprehensive insight into MUC16 transformations and interactions, with description of activated oncogenic signalling pathways, and adds new elements on the role of its differential glycosylation. By following the journey of the molecule from pre-malignant states to advanced stages of disease it demonstrates its behaviour, in relation to the phenotypic shifts and progression of ovarian cancer. Additionally, it presents proposed differences of MUC16 structure in normal/benign conditions and epithelial ovarian malignancy.
Collapse
Affiliation(s)
- Panagiotis Giamougiannis
- Department of Gynaecological Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.,School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, UK
| | - Pierre L Martin-Hirsch
- Department of Gynaecological Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | | |
Collapse
|
|
25
|
Evaluating Lung Cancer with Tumor Markers: CEA, CA 19-9 and CA 125. JOURNAL OF CONTEMPORARY MEDICINE 2021. [DOI: 10.16899/jcm.840949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
|
|
26
|
Schuster-Little N, Fritz-Klaus R, Etzel M, Patankar N, Javeri S, Patankar MS, Whelan RJ. Affinity-free enrichment and mass spectrometry analysis of the ovarian cancer biomarker CA125 (MUC16) from patient-derived ascites. Analyst 2021; 146:85-94. [PMID: 33141132 DOI: 10.1039/d0an01701a] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Developing a mass spectrometry-based assay for the ovarian cancer biomarker CA125 (MUC16) is a desirable goal, because it may enable detection of molecular regions that are not recognized by antibodies and are therefore analytically silent in the current immunoassay. Additionally, the ability to characterize the CA125 proteoforms expressed by individuals may offer clinical insight. Enrichment of CA125 from malignant ascites may provide a high-quality source of this important ovarian cancer biomarker, but a reliable strategy for such enrichment is currently lacking. Beginning with crude ascites isolated from three individual patients with high grade serous ovarian cancer, we enriched for MUC16 using filtration, ion exchange, and size exclusion chromatography and then performed bottom-up proteomics on the isolated proteins. This approach of enrichment and analysis reveals that the peptides detected via mass spectrometry map to the SEA domain and C-loop regions within the tandem repeat domains of CA125 and that peptide abundance correlates with clinical CA125 counts.
Collapse
Affiliation(s)
- Naviya Schuster-Little
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Yeku OO, Rao TD, Laster I, Kononenko A, Purdon TJ, Wang P, Cui Z, Liu H, Brentjens RJ, Spriggs D. Bispecific T-Cell Engaging Antibodies Against MUC16 Demonstrate Efficacy Against Ovarian Cancer in Monotherapy and in Combination With PD-1 and VEGF Inhibition. Front Immunol 2021; 12:663379. [PMID: 33936101 PMCID: PMC8079980 DOI: 10.3389/fimmu.2021.663379] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/23/2021] [Indexed: 11/29/2022] Open
Abstract
Immunotherapy for ovarian cancer is an area of intense investigation since the majority of women with relapsed disease develop resistance to conventional cytotoxic therapy. The paucity of safe and validated target antigens has limited the development of clinically relevant antibody-based immunotherapeutics for this disease. Although MUC16 expression is almost universal in High Grade Serous Ovarian Cancers, engagement of the shed circulating MUC16 antigen (CA-125) presents a theoretical risk of systemic activation and toxicity. We designed and evaluated a series of bispecific tandem single-chain variable fragments specific to the retained portion of human MUC16 ectodomain (MUC16ecto) and human CD3. These MUC16ecto- BiTEDs retain binding in the presence of soluble MUC16 (CA-125) and show cytotoxicity against a panel of ovarian cancer cells in vitro. MUC16ecto- BiTEDs delay tumor progression in vivo and significantly prolong survival in a xenograft model of ovarian peritoneal carcinomatosis. This effect was significantly enhanced by antiangiogenic (anti-VEGF) therapy and immune checkpoint inhibition (anti-PD1). However, the combination of BiTEDs with anti-VEGF was superior to combination with anti-PD1, based on findings of decreased peritoneal tumor burden and ascites with the former. This study shows the feasibility and efficacy of MUC16ecto- specific BiTEDs and provides a basis for the combination with anti-VEGF therapy for ovarian cancer.
Collapse
Affiliation(s)
- Oladapo O Yeku
- Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, United States.,Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
| | - Thapi Dharma Rao
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Ian Laster
- Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, United States
| | - Artem Kononenko
- Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, United States
| | - Terence J Purdon
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Pei Wang
- Eureka Therapeutics Inc., Emeryville, California, United States
| | - Ziyou Cui
- Eureka Therapeutics Inc., Emeryville, California, United States
| | - Hong Liu
- Eureka Therapeutics Inc., Emeryville, California, United States
| | - Renier J Brentjens
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - David Spriggs
- Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, United States.,Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
| |
Collapse
|
|
28
|
Wang S, You L, Dai M, Zhao Y. Quantitative assessment of the diagnostic role of mucin family members in pancreatic cancer: a meta-analysis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:192. [PMID: 33708819 PMCID: PMC7940915 DOI: 10.21037/atm-20-5606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background The use of mucins (MUC) as specific biomarkers for various malignancies has recently emerged. MUC1, MUC4, MUC5AC, and MUC16 can be detected at different stages of pancreatic cancer (PC), and can be valuable for indicating the initiation and progression of this disease. However, the diagnostic significance of the mucin family in patients with PC remains disputed. Herein, we assessed the diagnostic accuracy of mucins in PC using a meta-analysis. Methods We searched the PubMed, Cochrane Library, Institute for Scientific Information (ISI) Web of Science, Embase, and Chinese databases from their date of inception to June 1, 2020 to identify studies assessing the diagnostic performance of mucins in PC. The estimations of diagnostic indicators in selected studies were extracted for further analysis by Meta-DiSc software. Publication bias was assessed using Deeks’ funnel plot asymmetry test. Results Our meta-analysis included 34 studies. The pooled accuracy indicators of MUC1 in PC including the sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) (with 95% confidence intervals) were 0.84 (0.82–0.86), 0.60 (0.56–0.64), 18.37 (9.18–36.78), 2.62 (1.79–3.86), and 0.22 (0.15–0.33), respectively. The area under the summary receiver operating characteristic (SROC) curve was 0.8875 and the Q index was 0.8181. Quantitative random-effects meta-analysis of MUC4 in PC using the summary (ROC) curve model revealed a pooled sensitivity of 0.86 (95% confidence interval, 0.82–0.89) and specificity of 0.88 (95% confidence interval, 0.85–0.91). In addition, the meta-analysis of MUC5AC in PC diagnosis also showed a high sensitivity and specificity of 0.71 (95% confidence interval, 0.65–0.76) and 0.60 (95% confidence interval, 0.53–0.66), respectively. Regarding MUC16, the area under the summary ROC curve and Q index were 0.9185 and 0.8516, respectively. Conclusions In summary, our results suggested a good diagnostic accuracy of several crucial mucins in PC. Mucins may serve as optional indicators in PC examination, and further research is warranted to investigate the role of mucins as potential clinical biomarkers.
Collapse
Affiliation(s)
- Shunda Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
29
|
Zhang M, Cheng S, Jin Y, Zhao Y, Wang Y. Roles of CA125 in diagnosis, prediction, and oncogenesis of ovarian cancer. Biochim Biophys Acta Rev Cancer 2021; 1875:188503. [PMID: 33421585 DOI: 10.1016/j.bbcan.2021.188503] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/03/2021] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
After it was discovered approximately 40 years ago, carbohydrate antigen 125 (CA125) became the most widely used and concerning biomarker in ovarian cancer screening. However, there is still controversy about its role in clinical practice. CA125 is not sufficiently reliable in diagnosis to screen for early-stage ovarian cancer. On the other hand, CA125 has been a valuable indicator for evaluating chemotherapeutic efficacy and prognosis. We still do not know much about its biological role, and several studies have indicated that this marker participates in the occurrence and development of ovarian cancer. Currently, an increasing number of scholars have begun to pay attention to CA125-targeted treatment strategies. In the interest of better design and development of anticancer therapies, a renewed and systematic understanding of the roles of CA125 in diagnosis, prediction, and tumorigenesis is warranted.
Collapse
Affiliation(s)
- Minghai Zhang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Shanshan Cheng
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Yue Jin
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Yaqian Zhao
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Yu Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, China.
| |
Collapse
|
|
30
|
Insights into Bioinformatic Applications for Glycosylation: Instigating an Awakening towards Applying Glycoinformatic Resources for Cancer Diagnosis and Therapy. Int J Mol Sci 2020; 21:ijms21249336. [PMID: 33302373 PMCID: PMC7762546 DOI: 10.3390/ijms21249336] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/26/2020] [Accepted: 12/01/2020] [Indexed: 01/10/2023] Open
Abstract
Glycosylation plays a crucial role in various diseases and their etiology. This has led to a clear understanding on the functions of carbohydrates in cell communication, which eventually will result in novel therapeutic approaches for treatment of various disease. Glycomics has now become one among the top ten technologies that will change the future. The direct implication of glycosylation as a hallmark of cancer and for cancer therapy is well established. As in proteomics, where bioinformatics tools have led to revolutionary achievements, bioinformatics resources for glycosylation have improved its practical implication. Bioinformatics tools, algorithms and databases are a mandatory requirement to manage and successfully analyze large amount of glycobiological data generated from glycosylation studies. This review consolidates all the available tools and their applications in glycosylation research. The achievements made through the use of bioinformatics into glycosylation studies are also presented. The importance of glycosylation in cancer diagnosis and therapy is discussed and the gap in the application of widely available glyco-informatic tools for cancer research is highlighted. This review is expected to bring an awakening amongst glyco-informaticians as well as cancer biologists to bridge this gap, to exploit the available glyco-informatic tools for cancer.
Collapse
|
|
31
|
Wang S, You L, Dai M, Zhao Y. Mucins in pancreatic cancer: A well-established but promising family for diagnosis, prognosis and therapy. J Cell Mol Med 2020; 24:10279-10289. [PMID: 32745356 PMCID: PMC7521221 DOI: 10.1111/jcmm.15684] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/12/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
Mucins are a family of multifunctional glycoproteins that mostly line the surface of epithelial cells in the gastrointestinal tract and exert pivotal roles in gut lubrication and protection. Pancreatic cancer is a lethal disease with poor early diagnosis, limited therapeutic effects, and high numbers of cancer‐related deaths. In this review, we introduce the expression profiles of mucins in the normal pancreas, pancreatic precursor neoplasia and pancreatic cancer. Mucins in the pancreas contribute to biological processes such as the protection, lubrication and moisturization of epithelial tissues. They also participate in the carcinogenesis of pancreatic cancer and are used as diagnostic biomarkers and therapeutic targets. Herein, we discuss the important roles of mucins that lead to the lethality of pancreatic adenocarcinoma, particularly MUC1, MUC4, MUC5AC and MUC16 in disease progression, and present a comprehensive analysis of the clinical application of mucins and their promising roles in cancer treatment to gain a better understanding of the role of mucins in pancreatic cancer.
Collapse
Affiliation(s)
- Shunda Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| |
Collapse
|
|
32
|
Fung K, Sharma SK, Keinänen O, Roche KL, Lewis JS, Zeglis BM. A Molecularly Targeted Intraoperative Near-Infrared Fluorescence Imaging Agent for High-Grade Serous Ovarian Cancer. Mol Pharm 2020; 17:3140-3147. [PMID: 32644804 DOI: 10.1021/acs.molpharmaceut.0c00437] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ovarian cancer is the fifth leading cause of cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. The foundation of its management consists of cytoreductive surgery (CRS) followed by systemic chemotherapy, with the completeness of surgical resection consistently identified as one of the most important prognostic factors for the disease. The goal of our investigation is the development of a near-infrared fluorescence (NIRF) imaging agent for the intraoperative imaging of high-grade serous ovarian cancer (HGSOC). As surgeons are currently limited to the visual and manual assessment of tumor tissue during CRS, this technology could facilitate more complete resections as well as serve important functions at other points in the surgical management of the disease. Elevated levels of cancer antigen 125 (CA125) have proven a useful biomarker of HGSOC, and the CA125-targeting antibody B43.13 has shown potential as a platform for immunoPET imaging in murine models of ovarian cancer. Herein, we report the development of a NIRF imaging agent based on B43.13: ssB43.13-IR800. We site-specifically modified the heavy chain glycans of B43.13 with the near-infrared dye IRDye 800CW using a chemoenzymatic approach developed in our laboratories. SDS-PAGE analysis confirmed the specificity of the conjugation reaction, and flow cytometry, immunostaining, and fluorescence microscopy verified the specific binding of ssB43.13-IR800 to CA125-expressing OVCAR3 human ovarian cancer cells. NIRF imaging studies demonstrated that ssB43.13-IR800 can be used to image CA125-expressing HGSOC tumors in subcutaneous, orthotopic, and patient-derived xenograft mouse models. Finally, ex vivo analyses confirmed that ssB43.13-IR800 can bind and identify CA125-expressing cells in primary tumor and metastatic lymph node samples from human patients with HGSOC.
Collapse
Affiliation(s)
- Kimberly Fung
- Department of Chemistry, Hunter College, City University of New York, New York, New York 10021, United States.,Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, United States
| | | | - Outi Keinänen
- Department of Chemistry, Hunter College, City University of New York, New York, New York 10021, United States
| | - Kara Long Roche
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
| | | | - Brian M Zeglis
- Department of Chemistry, Hunter College, City University of New York, New York, New York 10021, United States.,Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, United States
| |
Collapse
|
|
33
|
Ding L, Zhou YX, He C, Ai JY, Lan GL, Xiong HF, He WH, Xia L, Zhu Y, Lu NH. Elevated CA125 levels are associated with adverse clinical outcomes in acute pancreatitis: A propensity score-matched study. Pancreatology 2020; 20:789-794. [PMID: 32660761 DOI: 10.1016/j.pan.2020.06.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/02/2020] [Accepted: 06/13/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Glycosylation alterations are indicative of tissue inflammation and neoplasia. However, there are no large-sample, real-world studies assessing the levels of serum carbohydrate antigen 125 (CA125) in patients with acute pancreatitis (AP). We aimed to identify the association between elevated CA125 levels and adverse clinical outcomes in AP. METHODS This was a retrospective cohort study with an analysis of 3939 patients with AP who were admitted to the First Affiliated Hospital of Nanchang University between January 2015 and September 2019 that used data from a prospectively maintained database. Multivariate logistic regression analysis and a propensity score-matched analysis were conducted to reveal the relationship between elevated CA125 levels and poor prognosis. RESULTS The overall prevalence of elevated CA125 (>35 U/mL) levels was 38.51% (1517/3939) in AP patients. Elevated CA125 levels were independently associated with higher risks of mortality (adjusted odds ratio (AdjOR), 1.82; 95% confidence interval (CI), 1.30-2.54; P < 0.001), severe acute pancreatitis (SAP) (AdjOR, 2.40; 95% CI, 2.00-2.88; P < 0.001), and infected pancreatic necrosis (IPN) (AdjOR, 3.54; 95% CI, 2.65-4.71; P < 0.001). The propensity score-matched cohort analysis also demonstrated that mortality (OR, 1.57; 95% CI, 1.06-2.23; P < 0.05), SAP (OR, 2.20; 95% CI, 1.77-2.73; P < 0.001), and IPN (OR, 2.79; 95% CI, 1.98-3.92; P < 0.001) were more common in the elevated CA125 group than in the normal CA125 group. CONCLUSIONS Elevated CA125 levels (>35 U/mL) are independently associated with adverse clinical outcomes in AP patients. These observations justify ongoing efforts to understand the role of CA125 in the pathogenesis and prognosis of AP.
Collapse
Affiliation(s)
- Ling Ding
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Yi-Xin Zhou
- Joint Program of Nanchang University and Queen Mary University of London, Medical College of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Cong He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Jiao-Yu Ai
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Gui-Lian Lan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Hui-Fang Xiong
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Wen-Hua He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Liang Xia
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| |
Collapse
|
|
34
|
Abstract
Generating the barriers that protect our inner surfaces from bacteria and other challenges requires large glycoproteins called mucins. These come in two types, gel-forming and transmembrane, all characterized by large, highly O-glycosylated mucin domains that are diversely decorated by Golgi glycosyltransferases to become extended rodlike structures. The general functions of mucins on internal epithelial surfaces are to wash away microorganisms and, even more importantly, to build protective barriers. The latter function is most evident in the large intestine, where the inner mucus layer separates the numerous commensal bacteria from the epithelial cells. The host's conversion of MUC2 to the outer mucus layer allows bacteria to degrade the mucin glycans and recover the energy content that is then shared with the host. The molecular nature of the mucins is complex, and how they construct the extracellular complex glycocalyx and mucus is poorly understood and a future biochemical challenge.
Collapse
Affiliation(s)
- Gunnar C Hansson
- Department of Medical Biochemistry, University of Gothenburg, SE 405 30 Gothenburg, Sweden;
| |
Collapse
|
|
35
|
Nemieboka B, Sharma SK, Rao TD, Edwards KJ, Yan S, Wang P, Ragupathi A, Piersigilli A, Spriggs DR, Lewis JS. Radiopharmacologic screening of antibodies to the unshed ectodomain of MUC16 in ovarian cancer identifies a lead candidate for clinical translation. Nucl Med Biol 2020; 86-87:9-19. [PMID: 32403071 DOI: 10.1016/j.nucmedbio.2020.04.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 04/01/2020] [Accepted: 04/29/2020] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Despite its limitations, CA125 remains the most widely used biomarker for the diagnosis and treatment monitoring of ovarian cancer. Targeting the unshed portion of serum biomarkers such as CA125/MUC16 may afford more specific imaging and targeting of MUC16-positive tumors in High Grade Serous Ovarian Cancer (HGSOC) patients. METHODS Six monoclonal antibodies raised against the 58 amino acid sequence between the extracellular cleavage site and the transmembrane region of MUC16 were radiolabeled with [89Zr]Zr4+. The radioimmunoconjugates were evaluated in vitro for molar activities, target binding affinity, cellular internalization and serum stability. In vivo characterization was performed via longitudinal positron emission tomography (PET) imaging and ex vivo biodistribution studies in mice bearing subcutaneous xenografts of SKOV3 cells transfected with the proximal 114 amino-acids of MUC16 carboxy-terminus (SKOV3+). RESULTS In vitro screening identified 9C9 and 4H11 as the lead antibody candidates based on their comparable binding affinities, serum stability and cellular internalization profiles. Despite an identical molecular footprint for binding to MUC16, [89Zr]Zr-DFO-4H11 yielded a more favorable in vivo radiopharmacologic profile. Furthermore, a humanized variant of 4H11 capable of binding MUC16 in vitro also yielded excellent in vivo profile in subcutaneous xenograft models of SKOV3+, OVCAR3 tumors and a patient-derived xenograft model representative of HGSOC. CONCLUSION Radiopharmacologic screening of antibodies early during their development can provide crucial information pertinent to the in vitro characterization and in vivo pharmacokinetics. The favorable in vivo profile demonstrated by humanized 4H11 combined with the use of its murine predecessor for immunohistochemical staining of biopsied tumor tissues from HGSOC patients makes a unique pair of antibodies that is poised for clinical translation.
Collapse
Affiliation(s)
- Brandon Nemieboka
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, NY, USA
| | - Sai Kiran Sharma
- Department of Radiology, Memorial Sloan Kettering Cancer Center, NY, USA
| | - Thapi Dharma Rao
- Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, USA
| | - Kimberly J Edwards
- Department of Radiology, Memorial Sloan Kettering Cancer Center, NY, USA
| | - Su Yan
- Eureka Therapeutics Inc., CA, USA
| | - Pei Wang
- Eureka Therapeutics Inc., CA, USA
| | - Ashwin Ragupathi
- Department of Radiology, Memorial Sloan Kettering Cancer Center, NY, USA
| | - Alessandra Piersigilli
- Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College and The Rockefeller University, NY, USA
| | - David R Spriggs
- Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, USA; Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA
| | - Jason S Lewis
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA; Department of Radiology, Weill Cornell Medical College, New York, NY, USA; Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| |
Collapse
|
|
36
|
Reynolds IS, Fichtner M, McNamara DA, Kay EW, Prehn JHM, Burke JP. Mucin glycoproteins block apoptosis; promote invasion, proliferation, and migration; and cause chemoresistance through diverse pathways in epithelial cancers. Cancer Metastasis Rev 2020; 38:237-257. [PMID: 30680581 DOI: 10.1007/s10555-019-09781-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Overexpression of mucin glycoproteins has been demonstrated in many epithelial-derived cancers. The significance of this overexpression remains uncertain. The aim of this paper was to define the association of mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers by performing a systematic review of all published data. A systematic review of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify all papers that evaluated the association between mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers. PRISMA guidelines were adhered to. Results of individual studies were extracted and pooled together based on the organ in which the cancer was derived from. The initial search revealed 2031 papers, of which 90 were deemed eligible for inclusion in the study. The studies included details on MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16. The majority of studies evaluated MUC1. MUC1 overexpression was consistently associated with resistance to apoptosis and resistance to chemotherapy. There was also evidence that overexpression of MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16 conferred resistance to apoptosis in epithelial-derived cancers. The overexpression of mucin glycoproteins is associated with resistance to apoptosis in numerous epithelial cancers. They cause resistance through diverse signaling pathways. Targeting the expression of mucin glycoproteins represents a potential therapeutic target in the treatment of epithelial-derived cancers.
Collapse
Affiliation(s)
- Ian S Reynolds
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Michael Fichtner
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Deborah A McNamara
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland
- Department of Surgery, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Elaine W Kay
- Department of Pathology, Beaumont Hospital, Dublin 9, Ireland
- Department of Pathology, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Jochen H M Prehn
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland.
| |
Collapse
|
|
37
|
Chu X, Xue Y, Huo X, Wei J, Chen Y, Han R, Chen H, Su X, Zhang H, Gong Y, Chen J. Establishment and characterization of a novel cell line (cc‑006cpm8) of moderately/poorly differentiated colorectal adenocarcinoma derived from a primary tumor of a patient. Int J Oncol 2019; 55:243-256. [PMID: 31115570 DOI: 10.3892/ijo.2019.4806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 05/14/2019] [Indexed: 11/06/2022] Open
Abstract
In the present study, the cc‑006cpm8 novel colon cell line was established from a sample of right colorectal adenocarcinoma obtained from a woman with liver metastasis. It was possible to culture this cell line for ≥100 passages in vitro with vigorous growth. Morphologically, the cells grew as several layers with tight adhesion to the surface of the culture plate. The morphological, immunological and ultrastructural features of these cells suggested their epithelial origin. The characterization of this cell line indicated a doubling time of 27 h, a colony forming efficiency of 73.2% in semisolid media and a plate efficiency of 66.5% in liquid culture. The modal number of chromosomes was 50. In vivo, the cc‑006cpm8 cells underwent tumorigenesis in all nude mice used. Immunohistochemical analysis demonstrated that mutS homolog 2 (MSH2) and MSH6 were expressed; however, mutL homolog 1 and postmeiotic segregation 2 were downregulated in cc‑006cpm8 cells. To determine the mutation profile of the cell line analyzed, exome capture DNA sequencing was performed. The results revealed 20 hypermutated exons comprising single nucleotide polymorphisms, and insertion and deletions (InDels), including single nucleotide variants of mucin (MUC)19, MUC16, MUC12, filaggrin and AHNAK nucleoprotein 2, and InDels of β defensin‑126, microRNA‑3665, WNK lysine deficient protein kinase 1 and SLAIN motif‑containing protein 1. In addition, commonly mutated genes in colorectal cancer and exon mutations of genes in cc‑006cpm8 cells were analyzed, including adenomatous polyposis coli, tumor protein p53, Drosophila mothers against decapentaplegic 4, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α and Kirsten rat sarcoma, and genes associated with the DNA mismatch repair pathway were investigated.
Collapse
Affiliation(s)
- Xia Chu
- Cancer Center, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu 210046, P.R. China
| | - Yiqi Xue
- Cancer Center, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu 210046, P.R. China
| | - Xinying Huo
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Jingsun Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Yuetong Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Rongbo Han
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Hong Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Xinyu Su
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Honghong Zhang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Yang Gong
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210046, P.R. China
| | - Jinfei Chen
- Cancer Center, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu 210046, P.R. China
| |
Collapse
|
|
38
|
Matte I, Garde-Granger P, Bessette P, Piché A. Ascites from ovarian cancer patients stimulates MUC16 mucin expression and secretion in human peritoneal mesothelial cells through an Akt-dependent pathway. BMC Cancer 2019; 19:406. [PMID: 31039761 PMCID: PMC6492407 DOI: 10.1186/s12885-019-5611-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 04/12/2019] [Indexed: 12/14/2022] Open
Abstract
Background CA125 is a well-established ovarian cancer (OC) serum biomarker. The CA125 heavily glycosylated epitope is carried by the MUC16 mucin, a high molecular weight transmembrane mucin. Upon proteolytic cleavage, the extracellular domain of MUC16 is released from the cell surface into malignant ascites and blood vessels. Previous studies have shown that both tumor and surrounding mesothelial cells may express MUC16. Although little is known about the regulation of MUC16 expression in these cells, recent evidence suggest that inflammatory cytokines may stimulate MUC16 expression. Because malignant ascites is a pro-inflammatory environment, we investigated whether OC ascites stimulate the expression and release of MUC16 by human peritoneal mesothelial cells (HPMCs). Methods HPMCs were isolated from peritoneal lavages of women operated for conditions other than cancer. MUC16 protein expression was determined by immunoblot, immunofluorescence or immunohistochemistry depending on the experiments. The release of MUC16 from the cell surface was measured using EIA and MUC16 mRNA expression by ddPCR. Results We show that high-grade serous ascites from patients with OC (n = 5) enhance MUC16 expression in HPMCs. Malignant ascites, but not benign peritoneal fluids, stimulate the release of MUC16 in HPMCs in a dose-dependent manner, which is abrogated by heat inactivation. Moreover, we establish that ascites-induced MUC16 expression occurs at the post-transcriptional level and demonstrate that ascites-induced MUC16 expression is mediated, at least partially, through an Akt-dependent pathway. A cytokine array identified upregulation of several cytokines and chemokines in ascites that mediate MUC16 upregulation versus those that do not, including CCL7, CCL8, CCL16, CCL20, CXCL1, IL-6, IL-10, HGF and IL-1 R4. However, when individually tested, none of these factors affected MUC16 expression or secretion. Concentrations of CA125 in the serum of a given patient did not correlate with the ability of its corresponding ascites to stimulate MUC16 release in HPMCs. Conclusions Collectively, these data indicate that mesothelial cells are an important source of MUC16 in the context of ovarian cancer and malignant ascites is a strong modulator of MUC16 expression in HPMCs and uncover the Akt pathway as a driving factor for upregulation of MUC16. Factors in ascites associated with enhanced MUC16 expression and release remains to be identified.
Collapse
Affiliation(s)
- Isabelle Matte
- Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada
| | - Perrine Garde-Granger
- Département de Pathologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada
| | - Paul Bessette
- Département de Chirurgie, service de gynécologie-obstétrique, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada
| | - Alain Piché
- Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.
| |
Collapse
|
|
39
|
Zhang M, Zhang Y, Fu J, Zhang L. Serum CA125 levels are decreased in rectal cancer but increased in fibrosis-associated diseases and in most types of cancers. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 162:241-252. [DOI: 10.1016/bs.pmbts.2018.12.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
|
40
|
Song HJ, Yang ES, Kim JD, Park CY, Kyung MS, Kim YS. Best serum biomarker combination for ovarian cancer classification. Biomed Eng Online 2018; 17:152. [PMID: 30396341 PMCID: PMC6219009 DOI: 10.1186/s12938-018-0581-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Screening test using CA-125 is the most common test for detecting ovarian cancer. However, the level of CA-125 is diverse by variable condition other than ovarian cancer. It has led to misdiagnosis of ovarian cancer. METHODS In this paper, we explore the 16 serum biomarker for finding alternative biomarker combination to reduce misdiagnosis. For experiment, we use the serum samples that contain 101 cancer and 92 healthy samples. We perform two major tasks: Marker selection and Classification. For optimal marker selection, we use genetic algorithm, random forest, T-test and logistic regression. For classification, we compare linear discriminative analysis, K-nearest neighbor and logistic regression. RESULTS The final results show that the logistic regression gives high performance for both tasks, and HE4-ELISA, PDGF-AA, Prolactin, TTR is the best biomarker combination for detecting ovarian cancer. CONCLUSIONS We find the combination which contains TTR and Prolactin gives high performance for cancer detection. Early detection of ovarian cancer can reduce high mortality rates. Finding a combination of multiple biomarkers for diagnostic tests with high sensitivity and specificity is very important.
Collapse
Affiliation(s)
- Hye-Jeong Song
- Bio-IT Research Center, Hallym University, Chuncheon, South Korea.
| | - Eun-Suk Yang
- Department of Convergence Software, Hallym University, Chuncheon, South Korea.,Bio-IT Research Center, Hallym University, Chuncheon, South Korea
| | - Jong-Dae Kim
- Department of Convergence Software, Hallym University, Chuncheon, South Korea.,Bio-IT Research Center, Hallym University, Chuncheon, South Korea
| | - Chan-Young Park
- Department of Convergence Software, Hallym University, Chuncheon, South Korea.,Bio-IT Research Center, Hallym University, Chuncheon, South Korea
| | - Min-Sun Kyung
- Department of Obstetrics and Hynecology, Hallym University Medical Center, Hwaseong, South Korea
| | - Yu-Seop Kim
- Department of Convergence Software, Hallym University, Chuncheon, South Korea.,Bio-IT Research Center, Hallym University, Chuncheon, South Korea
| |
Collapse
|
|
41
|
Hilliard TS. The Impact of Mesothelin in the Ovarian Cancer Tumor Microenvironment. Cancers (Basel) 2018; 10:E277. [PMID: 30134520 PMCID: PMC6162689 DOI: 10.3390/cancers10090277] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/17/2018] [Accepted: 08/18/2018] [Indexed: 01/14/2023] Open
Abstract
Ovarian cancer is the deadliest gynecological disease among U.S. women. Poor 5-year survival rates (<30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. However, when diagnosed before metastatic propagation the overall 5-year survival rate is >90%. Metastasizing tumor cells grow rapidly and aggressively attach to the mesothelium of all organs within the peritoneal cavity, including the parietal peritoneum and the omentum, producing secondary lesions. In this review, the involvement of mesothelin (MSLN) in the tumor microenvironment is discussed. MSLN, a 40kDa glycoprotein that is overexpressed in many cancers including ovarian and mesotheliomas is suggested to play a role in cell survival, proliferation, tumor progression, and adherence. However, the biological function of MSLN is not fully understood as MSLN knockout mice do not present with an abnormal phenotype. Conversely, MSLN has been shown to bind to the ovarian cancer antigen, CA-125, and thought to play a role in the peritoneal diffusion of ovarian tumor cells. Although the cancer-specific expression of MSLN makes it a potential therapeutic target, more studies are needed to validate the role of MSLN in tumor metastasis.
Collapse
Affiliation(s)
- Tyvette S Hilliard
- Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA.
| |
Collapse
|
|
42
|
Hasanzadeh M, Sahmani R, Solhi E, Mokhtarzadeh A, Shadjou N, Mahboob S. Ultrasensitive immunoassay of carcinoma antigen 125 in untreated human plasma samples using gold nanoparticles with flower like morphology: A new platform in early stage diagnosis of ovarian cancer and efficient management. Int J Biol Macromol 2018; 119:913-925. [PMID: 30081127 DOI: 10.1016/j.ijbiomac.2018.08.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 07/28/2018] [Accepted: 08/02/2018] [Indexed: 12/25/2022]
Abstract
Ovarian cancer, as one of the most life-threatening malignancies among women worldwide, is usually diagnosed at the late stage despite up regulation of molecular markers such as carcinoma antigen 125 (CA 125) at the early stages of the malignancy. CA 125 is the only tumor marker recommended for clinical use in the diagnosis and management of ovarian cancer. The potential role of CA-125 for the early detection of ovarian cancer is controversial and has not yet been adopted for widespread screening efforts in asymptomatic women. Therefore, early detection of CA 125 in human biofluids is highly demanded. In the present study, a novel method was proposed for the fabrication of electrochemical immunosensor based reduced graphene oxide (RGO). Cysteamine capped gold nanoparticle (Cys-AuNPs) were deposited over the surface of ERGO probe using electrophoretic deposition method. These Cys-AuNPs/ERGO probes provide the favorable sites to attach the monoclonal antibody specific to CA 125 antigen. Cyclic voltammetry (CV), and square wave voltammetry (SWV) were applied for the electrochemical recognition of the biolayer. The represented signals demonstrates excellent figure of merits and good capability of the engineered immunosensor towards sensitive detection of CA 125. Quantitative measurements of CA 125 in human plasma samples have been demonstrated, showing the potential of the practical application of this novel immunosensor for the analysis of this biomarker in blood serum samples. This immunosensor has the ability of direct electron transfer as compared to earlier reported electrochemical immunosensors based electrochemical methods. Further, this immunosensor provides a very suitable and convenient alternative to replace the expensive commercially available methods such as immunohistochemistry. The following regression equation between the electrochemical current response and the CA 125 concentration range from 0.1 to 400 U/mL was found. The low limit of quantification for this immunosensor was 0.1 U/mL. To the best of our knowledge, this is the first reported on the direct immobilization of antibody on the surface of Cys-AuNPs/ERGO for fabrication of immunosensors.
Collapse
Affiliation(s)
- Mohammad Hasanzadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Rahimeh Sahmani
- Department of Biochemistry, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Elham Solhi
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasrin Shadjou
- Department of Nanochemistry, Nano Technology Research Center, Uremia University, Uremia 57154, Iran
| | - Soltanali Mahboob
- Department of Biochemistry, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| |
Collapse
|
|
43
|
Aithal A, Rauth S, Kshirsagar P, Shah A, Lakshmanan I, Junker WM, Jain M, Ponnusamy MP, Batra SK. MUC16 as a novel target for cancer therapy. Expert Opin Ther Targets 2018; 22:675-686. [PMID: 29999426 PMCID: PMC6300140 DOI: 10.1080/14728222.2018.1498845] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.
Collapse
Affiliation(s)
- Abhijit Aithal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Prakash Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Ashu Shah
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Wade M. Junker
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Moorthy P. Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States of America
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States of America
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, United States of America
| |
Collapse
|
|
44
|
Aithal A, Junker WM, Kshirsagar P, Das S, Kaur S, Orzechowski C, Gautam SK, Jahan R, Sheinin YM, Lakshmanan I, Ponnusamy MP, Batra SK, Jain M. Development and characterization of carboxy-terminus specific monoclonal antibodies for understanding MUC16 cleavage in human ovarian cancer. PLoS One 2018; 13:e0193907. [PMID: 29708979 PMCID: PMC5927449 DOI: 10.1371/journal.pone.0193907] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 02/21/2018] [Indexed: 12/28/2022] Open
Abstract
MUC16 is overexpressed in ovarian cancer and plays important roles in invasion and metastasis. Previously described monoclonal antibodies against cell surface expressed MUC16 recognize the N-terminal tandemly repeated epitopes present in cancer antigen 125 (CA125). MUC16 is cleaved at a specific location, thus, releasing CA125 into the extracellular space. Recent reports have indicated that the retained carboxy-terminal (CT) fragment of MUC16 might play an important role in tumorigenicity in diverse types of cancers. However, limited data is available on the fate and existence of CT fragment on the surface of the cancer cell. Herein, we characterize two monoclonal antibodies (mAbs) showing specificity to the retained juxtamembrane region of MUC16. For the first time, we demonstrate that MUC16 is cleaved in ovarian cancer cells (NIH:OVCAR-3 [OVCAR-3]) and that the cleaved MUC16 subunits remain associated with each other. Immunohistochemical analyses on different grades of ovarian tumor tissues indicated differential reactivity of CA125 and MUC16 CT mAbs. The CA125 (M11) mAb detected 32/40 (80%), while the CT mAb (5E6) detected 33/40 (82.5%) of total ovarian cancer cases. For serous and serous papillary cases, the CA125 (M11) mAb stained 27/31 cases (87%), while CT mAb (5E6) stained 29/31 cases (93.5%). The CT mAb(s) accurately predict expression of MUC16 since their epitopes are not tandemly repeated and their reactivity may not be dependent on O-linked glycosylation. These antibodies can serve as valuable reagents for understanding MUC16 cleavage and may also serve as potential therapeutic agents for treatment of ovarian cancer.
Collapse
Affiliation(s)
- Abhijit Aithal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Wade M. Junker
- Sanguine Diagnostics and Therapeutics Inc. Omaha, NE, United States of America
| | - Prakash Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Srustidhar Das
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Catherine Orzechowski
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Shailendra Kumar Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Rahat Jahan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Yuri M. Sheinin
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Moorthy P. Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States of America
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States of America
- * E-mail: (SKB); (MJ)
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States of America
- * E-mail: (SKB); (MJ)
| |
Collapse
|
|
45
|
Wang X, Hao B, Xu C, Zhao X, Liu C, Chu X, Lv Y, Zhao Y, Zhang S, Wang P, Wang Y. Involvement of erbB4 and tumor marker genes in renal carcinoma regulatory network. Saudi J Biol Sci 2018; 24:1787-1791. [PMID: 29551924 PMCID: PMC5851941 DOI: 10.1016/j.sjbs.2017.11.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 11/03/2017] [Accepted: 11/06/2017] [Indexed: 12/25/2022] Open
Abstract
Background Renal carcinoma is a common urologic tumor, and there is no ideal tumor marker for clinical diagnosis except for imaging diagnosis. This study aims to screen the serum tumor markers closely related with the benign and malignant of renal carcinoma out and chart out the regulatory network that involves renal carcinoma-related genes. Methods Based on 96 pathologically diagnosed renal cancer patients, factors strongly linked to renal carcinoma character were selected using Fisher discriminant analysis. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized to manipulate function annotation of erbB4 and the selected genes and pathway analysis. Results Four essential tumor markers CYFRA21-1, CA125, VHL and HIF-1β were successfully screened out. Using GO and KEGG databases, the regulatory network of renal cancer cell escaping apoptosis was charted out on the basis of erbB4 signaling pathway. Conclusion Serum tumor marker genes play a certain part in the genesis and development of renal carcinoma. We preliminarily illustrated the molecular mechanism of these markers to predict tumor, laying a foundation for further exploration in renal carcinoma.
Collapse
Affiliation(s)
- Xiaofu Wang
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Bin Hao
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Changbao Xu
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Xinghua Zhao
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Changwei Liu
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Xiaohan Chu
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Yuan Lv
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Yongli Zhao
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Shengwei Zhang
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Pengsen Wang
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| | - Youzhi Wang
- The Second Affiliated Hospital of Zhengzhou University (Institute of Urinary Surgery of Zhengzhou University; the Calculosis Diagnostic and Therapeutic Center of Henan Province), China
| |
Collapse
|
|
46
|
Bakrani M, Poor KS, Mehrzad V, Razmi N. Comparison of the Serum Level of Cancer Antigen 125 and Human Epididymis Protein 4 in Ovarian Cancer Patients and Healthy Groups in Isfahan City. Adv Biomed Res 2017; 6:124. [PMID: 29142887 PMCID: PMC5672644 DOI: 10.4103/2277-9175.216778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background: Ovarian cancer is the most common fatal malignancy of the gynecology tract. The purpose of this study was to compare serum levels of tumor markers cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in both healthy groups and patients with ovarian cancer. Materials and Methods: this case–control study was performed on Seyed Al-Shohada Hospital in Isfahan. Research on the treatment of 44 patients with ovarian cancer and 44 healthy controls was performed. CA125 and HE4 were measured in serum by sandwich ELISA method. Results: Average CA125 in ovarian cancer patients (83.30 ± 43.99 μ/ml) was significantly higher than in healthy controls (12.39 ± 5.50 μ/ml) (P < 0.001). Average HE4 in ovarian cancer patients (295.41 ± 133.33 PM) was significantly higher than in healthy controls (114.64 ± 17.31 PM) (P < 0.001). Conclusions: HE4 test is complementary of CA125 test in women with epithelial ovarian cancer. It is also used to study the disease process.
Collapse
Affiliation(s)
- Mahnaz Bakrani
- Department of Biochemistry, Shiraz Sciences and Research Branch, Islamic Azad University, Shiraz, Isfahan, Iran
| | - Kahin Shahani Poor
- Department of Biochemistry, Falavarjan Branch, Islamic Azad University, Isfahan, Iran
| | - Valiollah Mehrzad
- Department of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nematallah Razmi
- Department of Biochemistry, Shiraz Sciences and Research Branch, Islamic Azad University, Shiraz, Isfahan, Iran
| |
Collapse
|
|
47
|
Rao TD, Fernández-Tejada A, Axelrod A, Rosales N, Yan X, Thapi S, Wang A, Park KJ, Nemieboka B, Xiang J, Lewis JS, Olvera N, Levine DA, Danishefsky SJ, Spriggs DR. Antibodies Against Specific MUC16 Glycosylation Sites Inhibit Ovarian Cancer Growth. ACS Chem Biol 2017; 12:2085-2096. [PMID: 28617578 DOI: 10.1021/acschembio.7b00305] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Expression of the retained C-terminal extracellular portion of the ovarian cancer glycoprotein MUC16 induces transformation and tumor growth. However, the mechanisms of MUC16 oncogenesis related to glycosylation are not clearly defined. We establish that MUC16 oncogenic effects are mediated through MGAT5-dependent N-glycosylation of two specific asparagine sites within its 58 amino acid ectodomain. Oncogenic signaling from the C-terminal portion of MUC16 requires the presence of Galectin-3 and growth factor receptors colocalized on lipid rafts. These effects are blocked upon loss of either Galectin-3 expression or activity MGAT5. Using synthetic MUC16 glycopeptides, we developed novel N-glycosylation site directed monoclonal antibodies that block Galectin-3-mediated MUC16 interactions with cell surface signaling molecules. These antibodies inhibit invasion of ovarian cancer cells, directly blocking the in vivo growth of MUC16-bearing ovarian cancer xenografts, elucidating new therapeutic modalities.
Collapse
Affiliation(s)
| | - Alberto Fernández-Tejada
- Chemical
Immunology Laboratory, CIC bioGUNE, Biscay Science and Technology Park, 48160 Derio, Spain
- Ikerbasque, Basque Foundation for Science, Maria Diaz de Haro 13, 48009 Bilbao, Spain
| | | | | | | | | | | | | | | | - Jingyi Xiang
- Eureka Therapeutics Inc., 5858
Horton Street, Suite 362, Emeryville, California 94608, United States
| | - Jason S. Lewis
- Weill Cornell
Medical College, Cornell University, York Avenue, New York, New York 10021, United States
| | - Narciso Olvera
- Gynecologic
Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, 240 E. 38th Street, New York, New York 10016, United States
| | - Douglas A. Levine
- Gynecologic
Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, 240 E. 38th Street, New York, New York 10016, United States
| | - Samuel J. Danishefsky
- Department
of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, United States
| | - David R. Spriggs
- Weill Cornell
Medical College, Cornell University, York Avenue, New York, New York 10021, United States
| |
Collapse
|
|
48
|
Babic A, Cramer DW, Kelemen LE, Köbel M, Steed H, Webb PM, Johnatty SE, deFazio A, Lambrechts D, Goodman MT, Heitz F, Matsuo K, Hosono S, Karlan BY, Jensen A, Kjær SK, Goode EL, Pejovic T, Moffitt M, Høgdall E, Høgdall C, McNeish I, Terry KL. Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium. Cancer Causes Control 2017; 28:459-468. [PMID: 28050675 PMCID: PMC5593071 DOI: 10.1007/s10552-016-0841-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Accepted: 12/19/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE Cancer antigen 125 (CA125) is a glycoprotein expressed by epithelial cells of several normal tissue types and overexpressed by several epithelial cancers. Serum CA125 levels are mostly used as an aid in the diagnosis of ovarian cancer patients, to monitor response to treatment and detect cancer recurrence. Besides tumor characteristics, CA125 levels are also influenced by several epidemiologic factors, such as age, parity, and oral contraceptive use. Identifying factors that influence CA125 levels in ovarian cancer patients could aid in the interpretation of CA125 values for individuals. METHODS We evaluated predictors of pretreatment CA125 in 13 studies participating in the Ovarian Cancer Association Consortium. This analysis included a total of 5,091 women with invasive epithelial ovarian cancer with pretreatment CA125 measurements. We used probit scores to account for variability in CA125 between studies and linear regression to estimate the association between epidemiologic factors and tumor characteristics and pretreatment CA125 levels. RESULTS In age-adjusted models, older age, history of pregnancy, history of tubal ligation, family history of breast cancer, and family history of ovarian cancer were associated with higher CA125 levels while endometriosis was associated with lower CA125 levels. After adjusting for tumor-related characteristics (stage, histology, grade), body mass index (BMI) higher than 30 kg/m2 was associated with 10% (95% CI 2, 19%) higher CA125 levels, while race (non-white vs. white) was associated with 15% (95% CI 4, 27%) higher CA125 levels. CONCLUSION Our results suggest that high BMI and race may influence CA125 levels independent of tumor characteristics. Validation is needed in studies that use a single assay for CA125 measurement and have a diverse study population.
Collapse
Affiliation(s)
- Ana Babic
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Daniel W Cramer
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston, MA, 02115, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Linda E Kelemen
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada
| | - Helen Steed
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Royal Alexandra Hospital, Edmonton, AB, Canada
| | - Penelope M Webb
- Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia
- Australian Ovarian Cancer Study Group, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia
| | - Sharon E Johnatty
- Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia
| | - Anna deFazio
- Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Louvain, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Louvain, Belgium
| | - Marc T Goodman
- Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Florian Heitz
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
- Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
| | - Keitaro Matsuo
- Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | - Satoyo Hosono
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | - Beth Y Karlan
- Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Allan Jensen
- Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Susanne K Kjær
- Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ellen L Goode
- Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Tanja Pejovic
- Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
| | - Melissa Moffitt
- Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
| | - Estrid Høgdall
- Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
- Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Claus Høgdall
- The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Iain McNeish
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK
| | - Kathryn L Terry
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston, MA, 02115, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| |
Collapse
|
|
49
|
Rodriguez-Garcia A, Minutolo NG, Robinson JM, Powell DJ. T-cell target antigens across major gynecologic cancers. Gynecol Oncol 2017; 145:426-435. [PMID: 28377094 DOI: 10.1016/j.ygyno.2017.03.510] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 03/29/2017] [Accepted: 03/29/2017] [Indexed: 12/30/2022]
Abstract
Immunotherapies have achieved remarkable success in treating different forms of cancer including melanoma, non-small cell lung carcinoma, bladder cancer, synovial cell sarcoma, and multiple myeloma using immune checkpoint blockade or gene-engineered T-cells. Although gynecologic cancers have not been historically classified as immunogenic tumors, growing evidence has shown that they are in fact able to elicit endogenous antitumor immune responses suggesting that patients with these cancers may benefit from immunotherapy. Modest clinical success has been accomplished in early trials using immunotherapeutic modalities for major gynecologic cancers including ovarian, cervical, and endometrial cancer. Unlike solid cancers with high mutational burdens, or hematologic malignancies where target antigens are expressed homogenously and exclusively by tumor cells, identifying tumor-restricted antigens has been challenging when designing a T-cell targeted therapy for gynecologic tumors. Nevertheless, mounting preclinical and clinical evidence suggests that targeting shared, viral or patient-specific mutated antigens expressed by gynecologic tumors with T-cells may improve patient outcome. Here we review the strengths and weaknesses of targeting these various antigens, as well as provide insight into the future of immunotherapy for gynecologic cancers.
Collapse
Affiliation(s)
- Alba Rodriguez-Garcia
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas G Minutolo
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - John M Robinson
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Gynecologic Oncology, MD Anderson Cooper Cancer Center, Cooper University Hospital, Camden, NJ 08103, USA
| | - Daniel J Powell
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
50
|
Selvolini G, Marrazza G. MIP-Based Sensors: Promising New Tools for Cancer Biomarker Determination. SENSORS 2017; 17:s17040718. [PMID: 28353669 PMCID: PMC5421678 DOI: 10.3390/s17040718] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 03/24/2017] [Accepted: 03/27/2017] [Indexed: 12/12/2022]
Abstract
Detecting cancer disease at an early stage is one of the most important issues for increasing the survival rate of patients. Cancer biomarker detection helps to provide a diagnosis before the disease becomes incurable in later stages. Biomarkers can also be used to evaluate the progression of therapies and surgery treatments. In recent years, molecularly imprinted polymer (MIP) based sensors have been intensely investigated as promising analytical devices in several fields, including clinical analysis, offering desired portability, fast response, specificity, and low cost. The aim of this review is to provide readers with an overview on recent important achievements in MIP-based sensors coupled to various transducers (e.g., electrochemical, optical, and piezoelectric) for the determination of cancer biomarkers by selected publications from 2012 to 2016.
Collapse
Affiliation(s)
- Giulia Selvolini
- Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3, Sesto Fiorentino 50019, Italy.
| | - Giovanna Marrazza
- Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3, Sesto Fiorentino 50019, Italy.
| |
Collapse
|