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Hu Y, Lei S, Zhang Z, Wang K, Ji Z. Exploration of the current status and trends of pancreatic cancer immune cells in the past 30 years: a bibliometric analysis. Discov Oncol 2025; 16:1105. [PMID: 40517216 PMCID: PMC12167183 DOI: 10.1007/s12672-025-02886-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 06/02/2025] [Indexed: 06/16/2025] Open
Abstract
OBJECTIVE Immune cells are pivotal in progressing and treating pancreatic cancer. Over the past three decades, the complex interactions between pancreatic cancer and immune cells have garnered much attention, as evidenced by the increasing number of publications in this domain. This bibliometric study maps the global research landscape of pancreatic cancer immune cell interactions, emphasizing evolving trends, collaborative networks, and therapeutic innovation. METHOD Using VOSviewer and CiteSpace, we analyzed 2658 articles from the Web of Science Core Collection (2000-2024) to evaluate publication trends, collaborative networks, keyword dynamics, and highly cited works. RESULTS Annual publications surged from 4 (2000) to 453 (2024), with China (44.9%) and the U.S. (33.6%) dominating output. Key institutions included Fudan University (102 articles) and Zhejiang University (88 articles). Keyword evolution revealed three phases: antitumor mechanisms, clinical translation of checkpoint inhibitors, and recent emphasis on stromal-immune crosstalk. High-impact works by Brahmer (N Engl J Med 366:2455-2465, 2012) and Marabelle (J Clin Oncol 38:1-10, 2020) underscored immunotherapy milestones. CONCLUSION This bibliometric analysis highlights the dynamic nature of pancreatic cancer immune cell research, emphasizing the growing global interest and investment in this field. The findings underscore the need for ongoing monitoring of research trends to inform and propel innovative therapeutic strategies, ultimately improving patient outcomes.
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Affiliation(s)
- Yang Hu
- Department of Hepatobiliary, Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Simeng Lei
- Department of Hepatobiliary, Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zihan Zhang
- Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Kexin Wang
- Department of Hepatobiliary, Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhili Ji
- Department of Hepatobiliary, Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
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2
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Kökrek E, Pir P. Distinct deregulation trends of transcriptional protein complexes in aging naive T cells. J Leukoc Biol 2025; 117:qiae231. [PMID: 39437255 DOI: 10.1093/jleuko/qiae231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/19/2024] [Accepted: 10/21/2024] [Indexed: 10/25/2024] Open
Abstract
The impact of aging on T cell subsets, specifically CD4+ and CD8+ T cells, leading to immune system dysfunction has been the focus of scientific investigation due to its potential to reverse age-associated deterioration. Transcriptomic and epigenomic studies have identified the primary regulators in T cell aging. However, comprehending the underlying dynamic mechanisms requires studying these proteins with their interactors. Here, we integrated single-cell RNA sequencing data of naive CD4+ and CD8+ T cells obtained from 3 different age groups with protein-protein and domain-domain interaction networks to predict and compare the transcriptional protein complexes and identify their capacity to explain age-associated variances. Our novel approach revealed significant effects of aging on the repertoire of complexes, which remains unchanged in naive CD4+ T cells, while in naive CD8+ T cells, it diminishes. In both cell types, there was major deregulation of complexes with the same composition, involving a range of transcription factors. This aging-associated deregulation is characterized by a specific set of protein complexes in naive CD4+ T cells, but this pattern is not observed in naive CD8+ T cells. SMAD3 and BCL11A complexes emerge as key markers in defining a trajectory in aging naive CD4+ T cells. These complexes can accurately distinguish between 3 different age groups, indicating their potential as targets. The direct link between SMAD3 and FOS complexes whose regulatory role has been previously implicated in aging and MBD3 as the novel key link between SMAD3 and BCL11A complexes implicates a coordinated mechanism in age-associated deregulation.
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Affiliation(s)
- Emel Kökrek
- Department of Molecular Biology and Genetics, Kadir Has University, Cibali, Kadir Has Cd., 34083 Fatih/Istanbul, Turkey
- Department of Bioengineering, Gebze Technical University, Cumhuriyet, 2254. Sk. No:2, 41400 Gebze/Kocaeli, Turkey
| | - Pınar Pir
- Department of Bioengineering, Gebze Technical University, Cumhuriyet, 2254. Sk. No:2, 41400 Gebze/Kocaeli, Turkey
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3
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Pian LL, Song MH, Wang TF, Qi L, Peng TL, Xie KP. Identification and analysis of pancreatic intraepithelial neoplasia: opportunities and challenges. Front Endocrinol (Lausanne) 2025; 15:1401829. [PMID: 39839479 PMCID: PMC11746065 DOI: 10.3389/fendo.2024.1401829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 12/17/2024] [Indexed: 01/23/2025] Open
Abstract
Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions. PanINs are classified into PanIN 1, PanIN 2, and PanIN 3, with PanIN 3 having the highest likelihood of developing into invasive PDAC. Differentiating between PanIN 2 and PanIN 3 is clinically significant. Genetic alterations found in PDAC are also present in PanIN and increase with the grade of PanIN. Imaging methods alone are insufficient for distinguishing PanIN, necessitating the use of genetic and molecular tests for identification. In addition, metabolomics technologies and miRNAs are playing an increasingly important role in the field of cancer diagnosis, offering more possibilities for efficient identification of PanIN. Although detecting and stratifying the risk of PanIN poses challenges, the combined utilization of imaging, genetics, and metabolomics holds promise for improving patient survival in this field.
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Affiliation(s)
- Ling-ling Pian
- School of Medicine, The South China University of Technology, Guangzhou, Guangdong, China
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Mei-hui Song
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Teng-fei Wang
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
| | - Ling Qi
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Tie-li Peng
- Division of Gastroenterology, Institute of Digestive Disease, Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China
| | - Ke-ping Xie
- School of Medicine, The South China University of Technology, Guangzhou, Guangdong, China
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Nair ST, Abhi C, Kamalasanan K, Pavithran K, Unni AR, Sithara MS, Sarma M, Mangalanandan TS. Pathophysiology-Driven Approaches for Overcoming Nanomedicine Resistance in Pancreatic Cancer. Mol Pharm 2024; 21:5960-5988. [PMID: 39561094 DOI: 10.1021/acs.molpharmaceut.4c00801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
Tumor heterogeneity poses a significant challenge in cancer therapy. To address this, we analyze pharmacotherapeutic challenges by categorizing them into static and dynamic barriers, reframing these challenges to improve drug delivery, efficacy, and the development of controlled-release nanomedicines (CRNMs). This pathophysiology-driven approach facilitates the design of novel therapeutics tailored to overcome obstacles in pancreatic ductal adenocarcinoma (PDAC) using nanotechnology. Advanced biomaterials in nanodrug delivery systems offer innovative solutions by combining controlled release, stimuli sensitivity, and smart design strategies. CRNMs are engineered to modulate spatiotemporal signaling and control drug release in PDAC, where resistance to conventional therapies is particularly high. This review explores pharmacokinetic considerations for nanomedicine design, RNA interference (RNAi) for stromal modulation, and the development of targeted nanomedicine strategies. Additionally, we highlight the limitations of current animal models in capturing the complexities of PDAC and discuss notable clinical failures, such as PEGylated hyaluronidase (Phase III HALO 109-301 trial) and evofosfamide (TH-302) with gemcitabine (MAESTRO trial), underscoring the need for improved models and treatment strategies. By targeting pathways like Notch and Hedgehog and incorporating stimuli-sensitive and pathway-modulating agents, CRNMs offer a promising avenue to enhance drug penetration and efficacy, reshaping the paradigm of pancreatic cancer treatment.
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Affiliation(s)
- Sreejith Thrivikraman Nair
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - C Abhi
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Kaladhar Kamalasanan
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - K Pavithran
- Department of Medical Oncology and Hematology, School of Medicine, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Ashok R Unni
- Department of Veterinary Medicine, Central Animal Facility, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - M S Sithara
- Department of Veterinary Medicine, Central Animal Facility, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Manjit Sarma
- Department of Nuclear Medicine, Amrita School of Medicine, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - T S Mangalanandan
- Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
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5
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Xu Y, Wang Y, Höti N, Clark DJ, Chen SY, Zhang H. The next "sweet" spot for pancreatic ductal adenocarcinoma: Glycoprotein for early detection. MASS SPECTROMETRY REVIEWS 2023; 42:822-843. [PMID: 34766650 PMCID: PMC9095761 DOI: 10.1002/mas.21748] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 10/07/2021] [Accepted: 10/24/2021] [Indexed: 05/02/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common neoplastic disease of the pancreas, accounting for more than 90% of all pancreatic malignancies. As a highly lethal malignancy, PDAC is the fourth leading cause of cancer-related deaths worldwide with a 5-year overall survival of less than 8%. The efficacy and outcome of PDAC treatment largely depend on the stage of disease at the time of diagnosis. Surgical resection followed by adjuvant chemotherapy remains the only possibly curative therapy, yet 80%-90% of PDAC patients present with nonresectable PDAC stages at the time of clinical presentation. Despite our advancing knowledge of PDAC, the prognosis remains strikingly poor, which is primarily due to the difficulty of diagnosing PDAC at the early stages. Recent advances in glycoproteomics and glycomics based on mass spectrometry have shown that aberrations in protein glycosylation plays a critical role in carcinogenesis, tumor progression, metastasis, chemoresistance, and immuno-response of PDAC and other types of cancers. A growing interest has thus been placed upon protein glycosylation as a potential early detection biomarker for PDAC. We herein take stock of the advancements in the early detection of PDAC that were carried out with mass spectrometry, with special focus on protein glycosylation.
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Affiliation(s)
- Yuanwei Xu
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Yuefan Wang
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Naseruddin Höti
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - David J Clark
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Shao-Yung Chen
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Hui Zhang
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
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6
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Applications of mass spectroscopy in understanding cancer proteomics. Proteomics 2023. [DOI: 10.1016/b978-0-323-95072-5.00007-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
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7
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Yu WW, Fu XL, Cai XW, Sun MH, Guo YM. Identification of differentially expressed proteins in the locoregional recurrent esophageal squamous cell carcinoma by quantitative proteomics. J Gastrointest Oncol 2021; 12:991-1006. [PMID: 34295551 DOI: 10.21037/jgo-21-278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/15/2021] [Indexed: 11/06/2022] Open
Abstract
Background This study aimed to identify potential biomarkers associated with locoregional recurrence in patients with esophageal squamous cell carcinoma (ESCC) after radical resection. Methods We performed a quantitative proteomics analysis using isobaric tags for relative and absolute quantification (iTRAQ) with reversed-phase liquid chromatography-mass spectrometry (RPLC-MS) to identify differential expression proteins (DEPs) between a locoregional recurrence group and good prognosis group of ESCC after radical esophagectomy. The bioinformatics analysis was performed with ingenuity pathway analysis software (IPA) and Gene Ontology (GO) database using the software of MAS 3.0. Kaplan-Meier (KM) Plotter Online Tool (http://www.kmplot.com) was used to evaluate the relationship between the differential expression of proteins and survival in patients with ESCC. Results More than 400 proteins were quantitated of which 27 proteins had upregulated expression and 55 proteins had downregulated expression in the locoregional recurrence group compared to the good prognosis group. These 82 DEPs were associated with biological procession of cancer development including cellular movement, cellular assembly and organization, cellular function and maintenance, cellular growth and proliferation, cell death and survival, DNA replication recombination and repair, and so on. Of these DEPs, SPTAN1 and AGT proteins were identified to be associated with RFS in ESCC. SPTAN1 was positively associated with RFS and AGT was negatively associated with RFS. Expression of SPTAN1 tended to have favorable OS while expression of AGT tended to have poor OS. Conclusions Our results demonstrated that quantitative proteomics is an effective discovery tool to identify biomarkers for prognosis prediction in ESCC. However, it needs more studies with large populations of ESCC to validate these potential biomarkers.
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Affiliation(s)
- Wei-Wei Yu
- Department of Radiation Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiao-Long Fu
- Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xu-Wei Cai
- Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Meng-Hong Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yan-Mei Guo
- Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai, China
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8
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Tao L, Zhong L, Li Y, Li D, Xiu D, Zhou J. Integrated proteomics and phosphoproteomics reveal perturbed regulative pathways in pancreatic ductal adenocarcinoma. Mol Omics 2021; 17:230-240. [PMID: 33355329 DOI: 10.1039/d0mo00125b] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to its inefficient diagnosis, rapid progress, and tenacious drug resistance. Here, we aimed to analyze the expressive patterns of proteins and phosphorylation in PDAC tissue samples and compare them to normal pancreatic tissue to investigate the underlying mechanisms and to reveal potential protein targets for diagnosis and drug development. Liquid chromatography coupled to mass spectrometry (LC-MS) based proteomics and phosphoproteomics analyses were performed using 20 pairs of patient-derived PDAC tissue and normal pancreatic tissue samples. Protein identification and quantification were conducted using MaxQuant software. Bioinformatics analysis was used to retrieve PDAC-relevant pathways and gene ontology (GO) terms. 4985 proteins and 3643 phosphoproteins were identified with high confidence; of these, 322 proteins and 235 phosphoproteins were dysregulated in PDAC. Several pathways, including several extracellular matrix-related pathways, were found to be strongly associated with PDAC. Further, the expression levels of filamin A (FLNA), integrin alpha-V (ITGAV), thymidine phosphorylase (TYMP), medium-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADM), short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS), and acetyl-CoA acetyltransferase, mitochondrial (ACAT1) were examined through western blot and immunohistochemistry analysis, and the results confirmed the validity of the proteomics analysis results. These findings provide comprehensive insight into the dysregulated regulative networks in PDAC tissue samples at the protein and phosphorylation levels, and they provide clues for further pathological studies and drug-target development.
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Affiliation(s)
- Lianyuan Tao
- Department of General Surgery, Peking University Third Hospital, No. 49, Hua Yuan North Rd, Hai Dian District, Beijing 100191, China. and Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China
| | - Lijun Zhong
- Medical and Health Analytical Center, Peking University Health Science Center, Beijing 100191, China
| | - Yang Li
- Department of Pathology, Peking University Health Science Center, Beijing 100191, China
| | - Deyu Li
- Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China
| | - Dianrong Xiu
- Department of General Surgery, Peking University Third Hospital, No. 49, Hua Yuan North Rd, Hai Dian District, Beijing 100191, China.
| | - Juntuo Zhou
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing 100083, China.
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9
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Stromal expression of hemopexin is associated with lymph-node metastasis in pancreatic ductal adenocarcinoma. PLoS One 2020; 15:e0235904. [PMID: 32663208 PMCID: PMC7360047 DOI: 10.1371/journal.pone.0235904] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive types of cancer. Certain proteins in the tumor microenvironment have attracted considerable attention owing to their association with tumor invasion and metastasis. Here, we used proteomics to identify proteins associated with lymph-node metastasis, which is one of the prognostic factors. We selected lymph node metastasis-positive and -negative patients (n = 5 each) who underwent pancreatectomy between 2005 and 2015 and subjected to comprehensive proteomic profiling of tumor stroma. A total of 490 proteins were detected by mass spectrometry. Software analysis revealed that nine of these proteins were differentially expressed between the two patient groups. We focused on hemopexin and ferritin light chain based on immunohistochemistry results. We assessed the clinicopathological data of 163 patients and found that hemopexin expression was associated with UICC N2 (p = 0.0399), lymph node ratio (p = 0.0252), venous invasion (p = 0.0096), and lymphatic invasion (p = 0.0232). Notably, in vitro assays showed that hemopexin promotes invasion of the pancreatic cancer cells. Our findings suggest that hemopexin is a lymph node metastasis-associated protein that could potentially serve as a useful therapeutic target or biomarker of pancreatic ductal adenocarcinoma.
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Larson K, Kannaiyan R, Pandey R, Chen Y, Babiker HM, Mahadevan D. A Comparative Analysis of Tumors and Plasma Circulating Tumor DNA in 145 Advanced Cancer Patients Annotated by 3 Core Cellular Processes. Cancers (Basel) 2020; 12:E701. [PMID: 32188081 PMCID: PMC7140098 DOI: 10.3390/cancers12030701] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/06/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
Matched-targeted and immune checkpoint therapies have improved survival in cancer patients, but tumor heterogeneity contributes to drug resistance. Our study categorized gene mutations from next generation sequencing (NGS) into three core processes. This annotation helps decipher complex biologic interactions to guide therapy. We collected NGS data on 145 patients who have failed standard therapy (2016 to 2018). One hundred and forty two patients had data for tissue (Caris MI/X) and plasma cell-free circulating tumor DNA (Guardant360) platforms. The mutated genes were categorized into cell fate (CF), cell survival (CS), and genome maintenance (GM). Comparative analysis was performed for concordance and discordance, unclassified mutations, trends in TP53 alterations, and PD-L1 expression. Two gene mutation maps were generated to compare each NGS platform. Mutated genes predominantly matched to CS with concordance between Guardant360 (64.4%) and Caris (51.5%). TP53 alterations comprised a significant proportion of the mutation pool in Caris and Guardant360, 14.7% and 13.1%, respectively. Twenty-six potentially actionable gene alterations were detected from matching ctDNA to Caris unclassified alterations. The CS core cellular process was the most prevalent in our study population. Clinical trials are warranted to investigate biomarkers for the three core cellular processes in advanced cancer patients to define the next best therapies.
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Affiliation(s)
- Kristian Larson
- University of Arizona College of Medicine, 1501 N Campbell Ave, Tucson, AZ 85724, USA;
| | | | - Ritu Pandey
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA;
| | - Yuliang Chen
- University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA;
| | - Hani M. Babiker
- Early Phase Clinical Trials Program, University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA;
| | - Daruka Mahadevan
- Early Phase Clinical Trials Program, University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA;
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11
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Pan S, Brentnall TA, Chen R. Proteome alterations in pancreatic ductal adenocarcinoma. Cancer Lett 2020; 469:429-436. [PMID: 31734355 PMCID: PMC9017243 DOI: 10.1016/j.canlet.2019.11.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023]
Abstract
Proteins are the essential functional biomolecules profoundly implicated in all aspects of pancreatic tumorigenesis and its progression. While common genomic factors, such as KRAS, TP53, SMAD4, and CDKN2A have been well recognized in association of pancreatic ductal adenocarcinoma (PDAC), our understanding of functional changes at the proteome level merits further investigation. Malignance associated proteome alterations can be attributed to the convoluted outcomes from genetic, epigenetic and environmental factors in initiating and progressing PDAC, and may reflect on changes in protein expressional level, structure, localization, as well as post-translational modifications (PTMs) status. The study of localized or systemic proteome alterations in PDAC, as well as its precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN) and mucinous pancreatic cystic neoplasm, would provide unique perspectives in elucidating functional molecular events underlying PDAC. While efforts have been made, challenges still exist to comprehensively integrate much of the proteomic discovery to the perspectives gained from genomic studies in the context of biomarker discovery. Novel approaches and data from well-defined longitudinal clinical studies and experimental models are needed to facilitate the study of PDAC and precursor lesions for early detection and intervention.
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12
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González-Borja I, Viúdez A, Goñi S, Santamaria E, Carrasco-García E, Pérez-Sanz J, Hernández-García I, Sala-Elarre P, Arrazubi V, Oyaga-Iriarte E, Zárate R, Arévalo S, Sayar O, Vera R, Fernández-Irigoyen J. Omics Approaches in Pancreatic Adenocarcinoma. Cancers (Basel) 2019; 11:cancers11081052. [PMID: 31349663 PMCID: PMC6721316 DOI: 10.3390/cancers11081052] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 07/10/2019] [Accepted: 07/22/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.
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Affiliation(s)
- Iranzu González-Borja
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA) Irunlarrea 3, 31008 Pamplona, Spain
| | - Antonio Viúdez
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA) Irunlarrea 3, 31008 Pamplona, Spain.
- Medical Oncology Department, Complejo Hospitalario de Navarra, Irunlarrea 3, 31008 Pamplona, Spain.
| | - Saioa Goñi
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA) Irunlarrea 3, 31008 Pamplona, Spain
| | - Enrique Santamaria
- Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain
- Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Estefania Carrasco-García
- Grupo de Oncología Celular, Instituto de Investigación Sanitaria Biodonostia, 20014 San Sebastián, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
| | - Jairo Pérez-Sanz
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA) Irunlarrea 3, 31008 Pamplona, Spain
| | - Irene Hernández-García
- Medical Oncology Department, Complejo Hospitalario de Navarra, Irunlarrea 3, 31008 Pamplona, Spain
| | - Pablo Sala-Elarre
- Medical Oncology Department, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Complejo Hospitalario de Navarra, Irunlarrea 3, 31008 Pamplona, Spain
| | | | - Ruth Zárate
- OncobionaTras Lab, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA) Irunlarrea 3, 31008 Pamplona, Spain
| | - Sara Arévalo
- Grupo de Oncología Celular, Instituto de Investigación Sanitaria Biodonostia, 20014 San Sebastián, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
| | | | - Ruth Vera
- Medical Oncology Department, Complejo Hospitalario de Navarra, Irunlarrea 3, 31008 Pamplona, Spain
| | - Joaquin Fernández-Irigoyen
- Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain
- Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
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13
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He Y, Mohamedali A, Huang C, Baker MS, Nice EC. Oncoproteomics: Current status and future opportunities. Clin Chim Acta 2019; 495:611-624. [PMID: 31176645 DOI: 10.1016/j.cca.2019.06.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/05/2019] [Accepted: 06/05/2019] [Indexed: 02/07/2023]
Abstract
Oncoproteomics is the systematic study of cancer samples using omics technologies to detect changes implicated in tumorigenesis. Recent progress in oncoproteomics is already opening new avenues for the identification of novel biomarkers for early clinical stage cancer detection, targeted molecular therapies, disease monitoring, and drug development. Such information will lead to new understandings of cancer biology and impact dramatically on the future care of cancer patients. In this review, we will summarize the advantages and limitations of the key technologies used in (onco)proteogenomics, (the Omics Pipeline), explain how they can assist us in understanding the biology behind the overarching "Hallmarks of Cancer", discuss how they can advance the development of precision/personalised medicine and the future directions in the field.
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Affiliation(s)
- Yujia He
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, PR China
| | - Abidali Mohamedali
- Department of Molecular Sciences, Faculty of Science and Engineering, Macquarie University, New South Wales 2109, Australia
| | - Canhua Huang
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, PR China
| | - Mark S Baker
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, New South Wales 2109, Australia.
| | - Edouard C Nice
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, PR China; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, New South Wales 2109, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
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14
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Rostami-Nejad M, Rezaei-Tavirani M, Mansouri V, Akbari Z, Abdi S. Impact of proteomics investigations on gastric cancer treatment and diagnosis. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2019; 12:S1-S7. [PMID: 32099594 PMCID: PMC7011056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/08/2019] [Indexed: 11/16/2022]
Abstract
Gastric cancer is one of the epidemics diseases with a high mortality rate in different countries. It causes many health problems in the world every year. It affects the digestive tract, and in advanced cases, its treatment has many difficulties. Early detection of cancer in different parts of the gastrointestinal tract can be accompanied by inexpensive treatment. As cancer cells make different biomarkers during different stages of the disease, researchers are looking for different biomarkers for gastrointestinal cancers detection. On the other hand, with the advent of advanced techniques such as proteomics and the discovery of a large number of proteins related to gastrointestinal cancer, finding the role of these proteins is essential. Indeed, the function of large amounts of these proteins has remained unknown. Data from databases such as genes and proteins associated with gastrointestinal cancers were collected and the proteomic data of these databases were analyzed to find a clear perspective of the impact of proteomics in gastric cancer management. The role of heat shock proteins, metabolic proteins, membrane binding proteins, galectins, prohibitins, S100 proteins, and many different types of proteins in gastric cancer was highlighted. This article reviewed proteomic researches in cancer-related areas of the gastric cancer in order to evaluate the findings of researchers.
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Affiliation(s)
- Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Mansouri
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Akbari
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Abdi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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15
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Sanh N, Fadul H, Hussein N, Lyn-Cook BD, Hammons G, Ramos-Cardona XE, Mohamed K, Mohammed SI. Proteomics Profiling of Pancreatic Cancer and Pancreatitis for Biomarkers Discovery. ACTA ACUST UNITED AC 2018; 9. [PMID: 31032145 DOI: 10.4172/2157-7013.1000287] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer is one of the most aggressive malignancies with an increase in incidence predicted, particularly in African Americans. Pancreatic cancer is considered a silent disease with poor prognosis and a lack of early biomarkers for detection. Proteomics has been applied in many diseases for identifying or discovering biomarkers. It has long been suggested that chronic pancreatitis may be a risk factor for developing pancreatic cancer. This study identified proteins that are altered in expression in pancreatic cancer and pancreatitis compared to normal using proteomic technology. Proteins were extracted from laser captured micro-dissected tissues and separated in 2-DPAGE and imaged. The protein profiles of pancreatic cancer and pancreatitis are similar but differed with the protein profile of normal adjacent tissues. Representative proteins, overexpressed in tumor and pancreatitis but not normal tissues, were excised from gels, subjected to in-gel digestion, and analyzed by MALDI-TOF mass spectrometry. Proteins identified included transferrin, ER-60 protein, proapolipoprotein, tropomyosin 1, alpha 1 actin precursor, ACTB protein, and gamma 2 propeptide, aldehyde dehydrogenase 1A1, pancreatic lipase and annexin A1. Several proteins, which were shown in pancreatic cancer, were also observed in pancreatitis samples. Understanding the role of these specific proteins and their mechanistic action will give insights into their involvement in pancreatic cancers.
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Affiliation(s)
- N Sanh
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - H Fadul
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - N Hussein
- Franklin College, IUPUI- Indiana University Purdue University Indianapolis, Indianapolis, USA
| | - B D Lyn-Cook
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA
| | - G Hammons
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA
| | - X E Ramos-Cardona
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - K Mohamed
- Radiation and Isotopes Center Khartoum (RICK), Sudan
| | - S I Mohammed
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
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16
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Coleman O, Henry M, O'Neill F, Roche S, Swan N, Boyle L, Murphy J, Meiller J, Conlon NT, Geoghegan J, Conlon KC, Lynch V, Straubinger NL, Straubinger RM, McVey G, Moriarty M, Meleady P, Clynes M. A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts. Proteomes 2018; 6:proteomes6040045. [PMID: 30404163 PMCID: PMC6313850 DOI: 10.3390/proteomes6040045] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 11/01/2018] [Accepted: 11/02/2018] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide; it develops in a relatively symptom-free manner, leading to rapid disease progression and metastasis, leading to a 5-year survival rate of less than 5%. A lack of dependable diagnostic markers and rapid development of resistance to conventional therapies are among the problems associated with management of the disease. A better understanding of pancreatic tumour biology and discovery of new potential therapeutic targets are important goals in pancreatic cancer research. This study describes the comparative quantitative LC-MS/MS proteomic analysis of the membrane-enriched proteome of 10 human pancreatic ductal adenocarcinomas, 9 matched adjacent-normal pancreas and patient-derived xenografts (PDXs) in mice (10 at F1 generation and 10 F2). Quantitative label-free LC-MS/MS data analysis identified 129 proteins upregulated, and 109 downregulated, in PDAC, compared to adjacent-normal tissue. In this study, analysing peptide MS/MS data from the xenografts, great care was taken to distinguish species-specific peptides definitively derived from human sequences, or from mice, which could not be distinguished. The human-only peptides from the PDXs are of particular value, since only human tumour cells survive, and stromal cells are replaced during engraftment in the mouse; this list is, therefore, enriched in tumour-associated proteins, some of which might be potential therapeutic or diagnostic targets. Using human-specific sequences, 32 proteins were found to be upregulated, and 113 downregulated in PDX F1 tumours, compared to primary PDAC. Differential expression of CD55 between PDAC and normal pancreas, and expression across PDX generations, was confirmed by Western blotting. These data indicate the value of using PDX models in PDAC research. This study is the first comparative proteomic analysis of PDAC which employs PDX models to identify patient tumour cell-associated proteins, in an effort to find robust targets for therapeutic treatment of PDAC.
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Affiliation(s)
- Orla Coleman
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
| | - Michael Henry
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
| | - Fiona O'Neill
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
| | - Sandra Roche
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
| | - Niall Swan
- St. Vincent's University Hospital, Dublin 4, Ireland.
| | | | - Jean Murphy
- St. Vincent's University Hospital, Dublin 4, Ireland.
| | - Justine Meiller
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
| | - Neil T Conlon
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
| | | | - Kevin C Conlon
- St. Vincent's University Hospital, Dublin 4, Ireland.
- Trinity College Dublin, College Green, Dublin 2, Ireland.
| | - Vincent Lynch
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
- St. Vincent's University Hospital, Dublin 4, Ireland.
| | - Ninfa L Straubinger
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
| | - Robert M Straubinger
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
| | - Gerard McVey
- St. Vincent's University Hospital, Dublin 4, Ireland.
- St. Luke's Hospital, Highfield Road, Rathgar, Dublin 6, Ireland.
| | - Michael Moriarty
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
- St. Luke's Hospital, Highfield Road, Rathgar, Dublin 6, Ireland.
| | - Paula Meleady
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
| | - Martin Clynes
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
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17
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18
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Jedinak A, Loughlin KR, Moses MA. Approaches to the discovery of non-invasive urinary biomarkers of prostate cancer. Oncotarget 2018; 9:32534-32550. [PMID: 30197761 PMCID: PMC6126692 DOI: 10.18632/oncotarget.25946] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/23/2018] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PCa) continues to be one of the most common cancers in men worldwide. Prostate specific antigen (PSA) measured in blood has been used for decades as an aid for physicians to detect the presence of prostate cancer. However, the PSA test has limited sensitivity and specificity, leading to unnecessary biopsies, overdiagnosis and overtreatment of patients. For these reasons, there is an urgent need for more accurate PCa biomarkers that can detect PCa with high sensitivity and specificity. Urine is a unique source of potential protein biomarkers that can be measured in a non-invasive way. This review comprehensively summarizes state of the art approaches used in the discovery and validation of urinary biomarkers for PCa. Numerous strategies are currently being used in the discovery of urinary biomarkers for prostate cancer including gel-based separation techniques, mass spectrometry, activity-based proteomic assays and software approaches. Antibody-based approaches remain preferred method for validation of candidate biomarkers with rapidly advancing multiplex immunoassays and MS-based targeted approaches. In the last decade, there has been a dramatic acceleration in the development of new techniques and approaches in the discovery of protein biomarkers for prostate cancer including computational, statistical and data mining methods. Many urinary-based protein biomarkers have been identified and have shown significant promise in initial studies. Examples of these potential biomarkers and the methods utilized in their discovery are also discussed in this review.
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Affiliation(s)
- Andrej Jedinak
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA.,Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Kevin R Loughlin
- Department of Surgery, Harvard Medical School, Boston, MA, USA.,Department of Urology, Brigham and Women's Hospital, Boston, MA, USA
| | - Marsha A Moses
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA.,Department of Surgery, Harvard Medical School, Boston, MA, USA
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19
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Huang R, Chen Z, He L, He N, Xi Z, Li Z, Deng Y, Zeng X. Mass spectrometry-assisted gel-based proteomics in cancer biomarker discovery: approaches and application. Theranostics 2017; 7:3559-3572. [PMID: 28912895 PMCID: PMC5596443 DOI: 10.7150/thno.20797] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Accepted: 07/12/2017] [Indexed: 12/13/2022] Open
Abstract
There is a critical need for the discovery of novel biomarkers for early detection and targeted therapy of cancer, a major cause of deaths worldwide. In this respect, proteomic technologies, such as mass spectrometry (MS), enable the identification of pathologically significant proteins in various types of samples. MS is capable of high-throughput profiling of complex biological samples including blood, tissues, urine, milk, and cells. MS-assisted proteomics has contributed to the development of cancer biomarkers that may form the foundation for new clinical tests. It can also aid in elucidating the molecular mechanisms underlying cancer. In this review, we discuss MS principles and instrumentation as well as approaches in MS-based proteomics, which have been employed in the development of potential biomarkers. Furthermore, the challenges in validation of MS biomarkers for their use in clinical practice are also reviewed.
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Affiliation(s)
- Rongrong Huang
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Zhongsi Chen
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Lei He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Nongyue He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Economical Forest Cultivation and Utilization of 2011 Collaborative Innovation Center in Hunan Province, Hunan Key Laboratory of Green Chemistry and Application of Biological Nanotechnology; Hunan University of Technology, Zhuzhou 412007, China
| | - Zhijiang Xi
- School of Medicine, Yangtze University, Jingzhou 434023, China
| | - Zhiyang Li
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Department of Clinical Laboratory, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Yan Deng
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Economical Forest Cultivation and Utilization of 2011 Collaborative Innovation Center in Hunan Province, Hunan Key Laboratory of Green Chemistry and Application of Biological Nanotechnology; Hunan University of Technology, Zhuzhou 412007, China
| | - Xin Zeng
- Nanjing Maternity and Child Health Medical Institute, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing 210004, China
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20
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Dick JM. Chemical composition and the potential for proteomic transformation in cancer, hypoxia, and hyperosmotic stress. PeerJ 2017; 5:e3421. [PMID: 28603672 PMCID: PMC5463988 DOI: 10.7717/peerj.3421] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 05/16/2017] [Indexed: 12/19/2022] Open
Abstract
The changes of protein expression that are monitored in proteomic experiments are a type of biological transformation that also involves changes in chemical composition. Accompanying the myriad molecular-level interactions that underlie any proteomic transformation, there is an overall thermodynamic potential that is sensitive to microenvironmental conditions, including local oxidation and hydration potential. Here, up- and down-expressed proteins identified in 71 comparative proteomics studies were analyzed using the average oxidation state of carbon (ZC) and water demand per residue (\documentclass[12pt]{minimal}
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}{}${\overline{n}}_{{\mathrm{H}}_{2}\mathrm{O}}$\end{document}n¯H2O), calculated using elemental abundances and stoichiometric reactions to form proteins from basis species. Experimental lowering of oxygen availability (hypoxia) or water activity (hyperosmotic stress) generally results in decreased ZC or \documentclass[12pt]{minimal}
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}{}${\overline{n}}_{{\mathrm{H}}_{2}\mathrm{O}}$\end{document}n¯H2O of up-expressed compared to down-expressed proteins. This correspondence of chemical composition with experimental conditions provides evidence for attraction of the proteomes to a low-energy state. An opposite compositional change, toward higher average oxidation or hydration state, is found for proteomic transformations in colorectal and pancreatic cancer, and in two experiments for adipose-derived stem cells. Calculations of chemical affinity were used to estimate the thermodynamic potentials for proteomic transformations as a function of fugacity of O2 and activity of H2O, which serve as scales of oxidation and hydration potential. Diagrams summarizing the relative potential for formation of up- and down-expressed proteins have predicted equipotential lines that cluster around particular values of oxygen fugacity and water activity for similar datasets. The changes in chemical composition of proteomes are likely linked with reactions among other cellular molecules. A redox balance calculation indicates that an increase in the lipid to protein ratio in cancer cells by 20% over hypoxic cells would generate a large enough electron sink for oxidation of the cancer proteomes. The datasets and computer code used here are made available in a new R package, canprot.
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21
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Coleman O, Henry M, McVey G, Clynes M, Moriarty M, Meleady P. Proteomic strategies in the search for novel pancreatic cancer biomarkers and drug targets: recent advances and clinical impact. Expert Rev Proteomics 2016; 13:383-94. [PMID: 26985644 DOI: 10.1586/14789450.2016.1167601] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers; despite a low incidence rate it is the fourth leading cause of cancer-related death in the world. Improvement of the diagnosis, prognosis and treatment remains the main focus of pancreatic cancer research. Rapid developments in proteomic technologies has improved our understanding of the pancreatic cancer proteome. Here, the authors summarise the recent proteomic strategies undertaken in the search for: novel biomarkers for early diagnosis, pancreatic cancer-specific proteins which may be used for novel targeted therapies and proteins which may be useful for monitoring disease progression post-therapy. Recent advances and findings discussed here provide great promise of having a significant clinical impact and improving the outcome of patients with this malignancy.
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Affiliation(s)
- Orla Coleman
- a Department of Proteomics, National Institute for Cellular Biotechnology , Dublin City University , Glasnevin , Dublin 9 , Ireland
| | - Michael Henry
- a Department of Proteomics, National Institute for Cellular Biotechnology , Dublin City University , Glasnevin , Dublin 9 , Ireland
| | - Gerard McVey
- b St. Lukes Hospital , Rathgar , Dublin 6 , Ireland
| | - Martin Clynes
- a Department of Proteomics, National Institute for Cellular Biotechnology , Dublin City University , Glasnevin , Dublin 9 , Ireland
| | - Michael Moriarty
- a Department of Proteomics, National Institute for Cellular Biotechnology , Dublin City University , Glasnevin , Dublin 9 , Ireland.,b St. Lukes Hospital , Rathgar , Dublin 6 , Ireland
| | - Paula Meleady
- a Department of Proteomics, National Institute for Cellular Biotechnology , Dublin City University , Glasnevin , Dublin 9 , Ireland
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22
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Pan S, Brentnall TA, Chen R. Glycoproteins and glycoproteomics in pancreatic cancer. World J Gastroenterol 2016; 22:9288-9299. [PMID: 27895417 PMCID: PMC5107693 DOI: 10.3748/wjg.v22.i42.9288] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/23/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
Aberrations in protein glycosylation and polysaccharides play a pivotal role in pancreatic tumorigenesis, influencing cancer progression, metastasis, immuno-response and chemoresistance. Abnormal expression in sugar moieties can impact the function of various glycoproteins, including mucins, surface receptors, adhesive proteins, proteoglycans, as well as their effectors and binding ligands, resulting in an increase in pancreatic cancer invasiveness and a cancer-favored microenvironment. Recent advance in glycoproteomics, glycomics and other chemical biology techniques have been employed to better understand the complex mechanism of glycosylation events and how they orchestrate molecular activities in genomics, proteomics and metabolomics implicated in pancreatic adenocarcinoma. A variety of strategies have been demonstrated targeting protein glycosylation and polysaccharides for diagnostic and therapeutic development.
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23
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Abstract
As our knowledge of the mechanisms underlying cancer development and progression has increased, so too have more effective, less toxic, and targeted therapies begun to reach the clinic. However, the full impact of these clinical advances and the practical success of the emerging field of precision medicine are dependent on the discovery and validation of sensitive and accurate biomarkers that can enable appropriate and rigorous sample type and patient selection, reliable longitudinal monitoring of therapeutic efficacy, and even risk assessment and early detection. Within the context of this review, we examine state-of-the-art approaches to the discovery and validation of noninvasive cancer biomarkers, with a specific emphasis on those that are protein or protein-associated ones. We also review sample selection strategies, currently utilized proteomic approaches for both discovery and validation requirements, and data analysis standards. Finally, we provide examples of these elements of biomarker discovery and validation from our own biomarker research.
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24
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Xiao H, Zhang Y, Kim Y, Kim S, Kim JJ, Kim KM, Yoshizawa J, Fan LY, Cao CX, Wong DTW. Differential Proteomic Analysis of Human Saliva using Tandem Mass Tags Quantification for Gastric Cancer Detection. Sci Rep 2016; 6:22165. [PMID: 26911362 PMCID: PMC4766442 DOI: 10.1038/srep22165] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 02/04/2016] [Indexed: 02/07/2023] Open
Abstract
Novel biomarkers and non-invasive diagnostic methods are urgently needed for the screening of gastric cancer to reduce its high mortality. We employed quantitative proteomics approach to develop discriminatory biomarker signatures from human saliva for the detection of gastric cancer. Salivary proteins were analyzed and compared between gastric cancer patients and matched control subjects by using tandem mass tags (TMT) technology. More than 500 proteins were identified with quantification, and 48 of them showed significant difference expression (p < 0.05) between normal controls and gastric cancer patients, including 7 up-regulated proteins and 41 down-regulated proteins. Five proteins were selected for initial verification by ELISA and three were successfully verified, namely cystatin B (CSTB), triosephosphate isomerase (TPI1), and deleted in malignant brain tumors 1 protein (DMBT1). All three proteins could differentiate gastric cancer patients from normal control subjects, dramatically (p < 0.05). The combination of these three biomarkers could reach 85% sensitivity and 80% specificity for the detection of gastric cancer with accuracy of 0.93. This study provides the proof of concept of salivary biomarkers for the non-invasive detection of gastric cancer. It is highly encouraging to turn these biomarkers into an applicable clinical test after large scale validation.
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Affiliation(s)
- Hua Xiao
- State Key Laboratory of Microbial Metabolism, Laboratory of Bioseparation and Analytical Biochemistry, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yan Zhang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yong Kim
- Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, California, 90095, USA
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 030031, Korea
| | - Jae Joon Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 030031, Korea
| | - Kyoung Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 030031, Korea
| | - Janice Yoshizawa
- Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, California, 90095, USA
| | - Liu-Yin Fan
- State Key Laboratory of Microbial Metabolism, Laboratory of Bioseparation and Analytical Biochemistry, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Cheng-Xi Cao
- State Key Laboratory of Microbial Metabolism, Laboratory of Bioseparation and Analytical Biochemistry, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - David T W Wong
- Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, California, 90095, USA
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Majumder S, Chari ST, Ahlquist DA. Molecular detection of pancreatic neoplasia: Current status and future promise. World J Gastroenterol 2015; 21:11387-11395. [PMID: 26526068 PMCID: PMC4616215 DOI: 10.3748/wjg.v21.i40.11387] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/15/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is usually diagnosed at an advanced stage and curative resection is feasible in only a small minority of patients at the time of diagnosis. Diagnosis at an early stage is unequivocally associated with better long-term survival. Several candidate molecular markers for early detection are currently under investigation in different phases of discovery and validation. Recent advances in the technology for whole genome, methylome, ribonucleome, and proteome interrogation has enabled rapid advancements in the field of biomarker discovery. In this review we discuss the current status of molecular markers for detection of pancreatic cancer in blood, pancreatic cyst fluid, pancreatic juice and stool and briefly highlight some promising preliminary results of new approaches that have the potential of advancing this field in the near future.
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Pan S, Brentnall TA, Chen R. Proteomics analysis of bodily fluids in pancreatic cancer. Proteomics 2015; 15:2705-15. [PMID: 25780901 DOI: 10.1002/pmic.201400476] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 02/06/2015] [Accepted: 03/13/2015] [Indexed: 12/12/2022]
Abstract
Proteomics study of pancreatic cancer using bodily fluids emphasizes biomarker discovery and clinical application, presenting unique prospect and challenges. Depending on the physiological nature of the bodily fluid and its proximity to pancreatic cancer, the proteomes of bodily fluids, such as pancreatic juice, pancreatic cyst fluid, blood, bile, and urine, can be substantially different in terms of protein constitution and the dynamic range of protein concentration. Thus, a comprehensive discovery and specific detection of cancer-associated proteins within these varied fluids is a complex task, requiring rigorous experiment design and a concerted approach. While major challenges still remain, fluid proteomics studies in pancreatic cancer to date have provided a wealth of information in revealing proteome alterations associated with pancreatic cancer in various bodily fluids.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington, Seattle, WA, USA
| | | | - Ru Chen
- Department of Medicine, University of Washington, Seattle, WA, USA
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Ansari D, Aronsson L, Sasor A, Welinder C, Rezeli M, Marko-Varga G, Andersson R. The role of quantitative mass spectrometry in the discovery of pancreatic cancer biomarkers for translational science. J Transl Med 2014; 12:87. [PMID: 24708694 PMCID: PMC3998064 DOI: 10.1186/1479-5876-12-87] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
In the post-genomic era, it has become evident that genetic changes alone are not sufficient to understand most disease processes including pancreatic cancer. Genome sequencing has revealed a complex set of genetic alterations in pancreatic cancer such as point mutations, chromosomal losses, gene amplifications and telomere shortening that drive cancerous growth through specific signaling pathways. Proteome-based approaches are important complements to genomic data and provide crucial information of the target driver molecules and their post-translational modifications. By applying quantitative mass spectrometry, this is an alternative way to identify biomarkers for early diagnosis and personalized medicine. We review the current quantitative mass spectrometric technologies and analyses that have been developed and applied in the last decade in the context of pancreatic cancer. Examples of candidate biomarkers that have been identified from these pancreas studies include among others, asporin, CD9, CXC chemokine ligand 7, fibronectin 1, galectin-1, gelsolin, intercellular adhesion molecule 1, insulin-like growth factor binding protein 2, metalloproteinase inhibitor 1, stromal cell derived factor 4, and transforming growth factor beta-induced protein. Many of these proteins are involved in various steps in pancreatic tumor progression including cell proliferation, adhesion, migration, invasion, metastasis, immune response and angiogenesis. These new protein candidates may provide essential information for the development of protein diagnostics and targeted therapies. We further argue that new strategies must be advanced and established for the integration of proteomic, transcriptomic and genomic data, in order to enhance biomarker translation. Large scale studies with meta data processing will pave the way for novel and unexpected correlations within pancreatic cancer, that will benefit the patient, with targeted treatment.
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Affiliation(s)
- Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Linus Aronsson
- Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Agata Sasor
- Department of Pathology, Clinical Sciences Lund, Lund University, and Skåne University Hospital, Lund, Sweden
| | - Charlotte Welinder
- Department of Oncology, Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Melinda Rezeli
- Clinical Protein Science & Imaging, Biomedical Center, Department of Measurement Technology and Industrial Electrical Engineering, Lund University, Lund, Sweden
| | - György Marko-Varga
- Clinical Protein Science & Imaging, Biomedical Center, Department of Measurement Technology and Industrial Electrical Engineering, Lund University, Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden
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Iuga C, Seicean A, Iancu C, Buiga R, Sappa PK, Völker U, Hammer E. Proteomic identification of potential prognostic biomarkers in resectable pancreatic ductal adenocarcinoma. Proteomics 2014; 14:945-955. [PMID: 24459066 DOI: 10.1002/pmic.201300402] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 12/16/2013] [Accepted: 12/24/2013] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer is a devastating disease with a mortality rate almost identical with its incidence. In this context, the investigation of the pancreatic cancer proteome has gained considerable attention because profiles of proteins may be able to identify disease states and progression more accurately. Therefore, our objective was to investigate the changes in the proteome of patients suffering from pancreatic ductal adenocarcinoma (PDAC) by a comprehensive quantitative approach. Comparative proteomic profiling by label-free LC-MS/MS analysis of nine matched pairs of tumor and nontumor pancreas samples was used to identify differences in protein levels characteristic for PDAC. In this analysis, 488 proteins were quantified by at least two peptides of which 99 proteins displayed altered levels in PDAC (p < 0.01, fold change >1.3). Screening of data revealed a number of molecules that had already been related to PDAC such as galectin-1 (LEG1), major vault protein, adenylyl cyclase-associated protein 1 (CAP1), but also a potential new prognostic biomarker prolargin (PRELP). The Kaplan-Meier survival analysis revealed a significant correlation of protein abundance of PRELP with postoperative survival of patients with PDAC. For selected proteins the findings were verified by targeted proteomics (SRM), validated by immunohistochemistry and Western blotting and their value as candidate biomarkers is discussed.
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Affiliation(s)
- Cristina Iuga
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, University of Medicine and Pharmacy "Iuliu Haţieganu", Cluj-Napoca, Romania; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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Maryáš J, Faktor J, Dvořáková M, Struhárová I, Grell P, Bouchal P. Proteomics in investigation of cancer metastasis: Functional and clinical consequences and methodological challenges. Proteomics 2014; 14:426-40. [DOI: 10.1002/pmic.201300264] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Revised: 09/16/2013] [Accepted: 10/04/2013] [Indexed: 01/05/2023]
Affiliation(s)
- Josef Maryáš
- Department of Biochemistry; Faculty of Science; Masaryk University; Brno Czech Republic
| | - Jakub Faktor
- Department of Biochemistry; Faculty of Science; Masaryk University; Brno Czech Republic
- Regional Centre for Applied Molecular Oncology; Masaryk Memorial Cancer Institute; Brno Czech Republic
| | - Monika Dvořáková
- Department of Biochemistry; Faculty of Science; Masaryk University; Brno Czech Republic
- Regional Centre for Applied Molecular Oncology; Masaryk Memorial Cancer Institute; Brno Czech Republic
| | - Iva Struhárová
- Department of Biochemistry; Faculty of Science; Masaryk University; Brno Czech Republic
- Regional Centre for Applied Molecular Oncology; Masaryk Memorial Cancer Institute; Brno Czech Republic
| | - Peter Grell
- Department of Comprehensive Cancer Care; Masaryk Memorial Cancer Institute; Brno Czech Republic
| | - Pavel Bouchal
- Department of Biochemistry; Faculty of Science; Masaryk University; Brno Czech Republic
- Regional Centre for Applied Molecular Oncology; Masaryk Memorial Cancer Institute; Brno Czech Republic
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Pan S, Chen R, Brentnall TA. Proteomics in Pancreatic Cancer Translational Research. MOLECULAR DIAGNOSTICS AND TREATMENT OF PANCREATIC CANCER 2014:197-219. [DOI: 10.1016/b978-0-12-408103-1.00009-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ballehaninna UK, Chamberlain RS. Biomarkers for pancreatic cancer: promising new markers and options beyond CA 19-9. Tumour Biol 2013; 34:3279-92. [PMID: 23949878 DOI: 10.1007/s13277-013-1033-3] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 07/18/2013] [Indexed: 12/11/2022] Open
Abstract
Pancreatic adenocarcinoma accounts for nearly 90-95% of exocrine malignant tumors of the pancreas. Traditionally, overexpressed proteins/epitopes such as CA 19-9, CA-50, CEA, and many others were being used as pancreatic cancer tumor markers. The main utility of these biomarkers was in the diagnosis of pancreatic cancer as well as to assess response to chemotherapy and to determine prognosis and to predict tumor recurrence. However, these markers had significant limitations such as lack of sensitivity, false-negative results in certain blood groups, as well as false-positive elevation in the presence of obstructive jaundice. To circumvent these limitations, an extraordinary amount of research is being performed to identify an accurate tumor marker or a panel of markers that could aid in the management of the pancreatic cancer. Although this research has identified a large number and different variety of biomarkers, few hold future promise as a preferred marker for pancreatic cancer. This review provides an insight into exciting new areas of pancreatic biomarker research such as salivary, pancreatic juice, and stool markers that can be used as a noninvasive test to identify pancreatic cancer. This manuscript also provides a discussion on newer biomarkers, the role of microRNAs, and pancreatic cancer proteomics, which have the potential to identify a preferred tumor marker for pancreatic adenocarcinoma. This review further elaborates on important genetic changes associated with the development and progression of pancreatic cancer that holds the key for the identification of a sensitive biomarker and which could also serve as a therapeutic target.
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Affiliation(s)
- Umashankar K Ballehaninna
- Department of Surgery, Saint Barnabas Medical Center, 94, Old Short Hills Road, Livingston, NJ, 07039, USA
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Zhou W, Liotta LA, Petricoin EF. Cancer metabolism and mass spectrometry-based proteomics. Cancer Lett 2013; 356:176-83. [PMID: 24262660 DOI: 10.1016/j.canlet.2013.11.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 10/25/2013] [Accepted: 11/11/2013] [Indexed: 12/17/2022]
Abstract
Cancer metabolism has been extensively investigated by various tools, and the fact of diverse metabolic reprogramming in cancer cells has been gradually unveiled. In this review, we discuss some contributions in cancer metabolism by general proteomic analysis and post-translational modification analysis using mass spectrometry (MS) technique. Instead of following one or several metabolic enzymes/pathways, the current MS approach can quickly identify a large number of proteins and compare their expression levels in different samples, providing a potentially comprehensive picture of cancer metabolism. The MS analyses from pancreatic cancer cells support a hypothesis that hypoxia promotes cells in solid tumor to reprogram metabolic pathways in order to minimize the oxygen consumption. The oxidative stress in pancreatic cancer cells is lower than that in normal duct cells, and the cancer cells adaptively express less antioxidant proteins, contrary to claims that oxidative stress is higher in cancer cells. Separately, the MS analyses confirm that pyruvate kinase isoform 2 (PKM2) can be detected in both cancer and normal cells, disagreeing with report that tumor cells express exclusively PKM2. In addition, MS analyses from pancreatic cancer cells demonstrate that lactate dehydrogenase-B is significantly upregulated in pancreatic cancer cells, whereas previous reports show that lactate dehydrogenase-A is overexpressed and is responsible for lactate production in cancer cells. Lastly, the result from MS analysis suggests that the glutaminolysis in pancreatic cancer cells is different from that observed in glioblastoma cells.
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Affiliation(s)
- Weidong Zhou
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
| | - Lance A Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
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Jiang Y, DiVittore NA, Young MM, Jia Z, Xie K, Ritty TM, Kester M, Fox TE. Altered sphingolipid metabolism in patients with metastatic pancreatic cancer. Biomolecules 2013; 3:435-48. [PMID: 24970174 PMCID: PMC4030952 DOI: 10.3390/biom3030435] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 07/10/2013] [Accepted: 07/24/2013] [Indexed: 01/28/2023] Open
Abstract
Although numerous genetic mutations and amplifications have been identified in pancreatic cancer, much of the molecular pathogenesis of the disease remains undefined. While proteomic and transcriptomic analyses have been utilized to probe and characterize pancreatic tumors, lipidomic analyses have not been applied to identify perturbations in pancreatic cancer patient samples. Thus, we utilized a mass spectrometry-based lipidomic approach, focused towards the sphingolipid class of lipids, to quantify changes in human pancreatic cancer tumor and plasma specimens. Subgroup analysis revealed that patients with positive lymph node metastasis have a markedly higher level of ceramide species (C16:0 and C24:1) in their tumor specimens compared to pancreatic cancer patients without nodal disease or to patients with pancreatitis. Also of interest, ceramide metabolites, including phosphorylated (sphingosine- and sphinganine-1-phosphate) and glycosylated (cerebroside) species were elevated in the plasma, but not the pancreas, of pancreatic cancer patients with nodal disease. Analysis of plasma level of cytokine and growth factors revealed that IL-6, IL-8, CCL11 (eotaxin), EGF and IP10 (interferon inducible protein 10, CXCL10) were elevated in patients with positive lymph nodes metastasis, but that only IP10 and EGF directly correlated with several sphingolipid changes. Taken together, these data indicate that sphingolipid metabolism is altered in human pancreatic cancer and associated with advanced disease. Assessing plasma and/or tissue sphingolipids could potentially risk stratify patients in the clinical setting.
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Affiliation(s)
- Yixing Jiang
- Pennsylvania state Hershey cancer institute, Hershey, PA17033, USA.
| | | | | | - Zhiliang Jia
- Department of gastrointestinal medical oncology, the University of Texas MD Anderson cancer center, Houston, TX77030, USA.
| | - Keping Xie
- Department of gastrointestinal medical oncology, the University of Texas MD Anderson cancer center, Houston, TX77030, USA.
| | - Timothy M Ritty
- Department of orthopedics Pennsylvania state college of medicine, 500 University Drive, Hershey, PA 17033, USA.
| | - Mark Kester
- Pennsylvania state Hershey cancer institute, Hershey, PA17033, USA.
| | - Todd E Fox
- Department of pharmacology, Hershey, PA17033, USA.
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Jiang JX, Gao S, Pan YZ, Sun CY. Quantitative proteomic analysis of differentially expressed proteins in pancreatic cancer stem cells. Shijie Huaren Xiaohua Zazhi 2013; 21:145-152. [DOI: 10.11569/wcjd.v21.i2.145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To screen and identify differentially expressed proteins in pancreatic cancer stem cells.
METHODS: MIA-PaCa2 (TIChigh) and BxPc-3 (TIClow) were used in the study. Differentially expressed proteins between MIA-PaCa2 (TIChigh) and BxPc-3 (TIClow) cells were isolated and screened by 2D-DIGE analysis. Protein identification was performed by peptide mass fingerprinting with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF). Western blot was performed to verify the differential expression of TRIM28.
RESULTS: Fluorescent differential protein expression patterns were obtained between MIA-PaCa2 (TIChigh) and BxPc-3 (TIClow) cells. Analyses with DeCyder v6.5 software showed a total of 23 differentially expressed protein spots (>1.5 folds), and these protein spots were identified by mass spectrometry as 19 proteins, which are involved in cell communication and signal transduction, immune response, transcription and cell cycle regulation, adipocyte differentiation and lipid droplet formation, cytoskeletal formation, cell adhesion, transport, and translation. Western blot analysis revealed that TRIM28 was highly expressed in MIA-PaCa2 (TIChigh) cells but not expressed in BxPc-3 (TIClow) cells. Among the 19 identified proteins, 8 were up-regulated and 11 down-regulated in MIA-PaCa2 (TIChigh) cells.
CONCLUSION: The identified differentially expressed proteins, such as TRIM28, are associated with the genesis, development and regulation of pancreatic cancer stem cells. They may become new therapeutic targets for pancreatic cancer.
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