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1
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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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2
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Senavirathna L, Ma C, Duong VA, Tsai HY, Chen R, Pan S. SLB-msSIM: a spectral library-based multiplex segmented SIM platform for single-cell proteomic analysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.22.618936. [PMID: 39484511 PMCID: PMC11526955 DOI: 10.1101/2024.10.22.618936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Mass spectrometry (MS)-based single-cell proteomics, while highly challenging, offers unique potential for a wide range of applications to interrogate cellular heterogeneity, trajectories, and phenotypes at a functional level. We report here the development of the spectral library-based multiplex segmented selected ion monitoring (SLB-msSIM) method, a conceptually unique approach with significantly enhanced sensitivity and robustness for single-cell analysis. The single-cell MS data is acquired by msSIM technique, which sequentially applies multiple isolation cycles with the quadrupole using a wide isolation window in each cycle to accumulate and store precursor ions in the C-trap for a single scan in the Orbitrap. Proteomic identification is achieved through spectral matching using a well-defined spectral library. We applied the SLB-msSIM method to interrogate cellular heterogeneity among multiple cell lines and to analyze cellular trajectories during epithelial-mesenchymal transition. Our results demonstrate that SLB-msSIM is a highly sensitive and robust platform applicable to a wide range of single-cell proteomic studies.
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3
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Sun X, Wang S, Wong CC. Mass spectrometry–based proteomics technology in pancreatic cancer research. JOURNAL OF PANCREATOLOGY 2024; 7:145-163. [DOI: 10.1097/jp9.0000000000000152] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has become a significant health concern with increasing incidence and mortality rates over the past few decades. Researchers have turned their attention to cutting-edge mass spectrometry (MS) technology due to its high-throughput and accurate detection capacity, which plays a vital role in understanding the mechanisms and discovering biomarkers for pancreatic diseases. In this review, we comprehensively investigate various methodologies of quantitative and qualitative proteomics MS technologies, alongside bioinformatical platforms employed in pancreatic cancer research. The integration of these optimized approaches provides novel insights into the molecular mechanisms underlying tumorigenesis and disease progression, ultimately facilitating the discovery of potential diagnostic, prognostic biomarkers, and therapeutic targets. The robust MS-based strategy shows promise in paving the way for early diagnosis and personalized medicine for pancreatic cancer patients.
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Affiliation(s)
- Xue Sun
- First School of Clinical Medicine, Peking University Health Science Center, Peking University, Beijing 100871, China
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Siyuan Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
| | - Catherine C.L. Wong
- First School of Clinical Medicine, Peking University Health Science Center, Peking University, Beijing 100871, China
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
- Tsinghua-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China
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4
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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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5
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Proteome-wide and matrisome-specific alterations during human pancreas development and maturation. Nat Commun 2021; 12:1020. [PMID: 33589611 PMCID: PMC7884717 DOI: 10.1038/s41467-021-21261-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 01/19/2021] [Indexed: 01/31/2023] Open
Abstract
The extracellular matrix (ECM) is unique to each tissue and capable of guiding cell differentiation, migration, morphology, and function. The ECM proteome of different developmental stages has not been systematically studied in the human pancreas. In this study, we apply mass spectrometry-based quantitative proteomics strategies using N,N-dimethyl leucine isobaric tags to delineate proteome-wide and ECM-specific alterations in four age groups: fetal (18-20 weeks gestation), juvenile (5-16 years old), young adults (21-29 years old) and older adults (50-61 years old). We identify 3,523 proteins including 185 ECM proteins and quantify 117 of them. We detect previously unknown proteome and matrisome features during pancreas development and maturation. We also visualize specific ECM proteins of interest using immunofluorescent staining and investigate changes in ECM localization within islet or acinar compartments. This comprehensive proteomics analysis contributes to an improved understanding of the critical roles that ECM plays throughout human pancreas development and maturation.
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6
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Parajón E, Surcel A, Robinson DN. The mechanobiome: a goldmine for cancer therapeutics. Am J Physiol Cell Physiol 2020; 320:C306-C323. [PMID: 33175572 DOI: 10.1152/ajpcell.00409.2020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancer progression is dependent on heightened mechanical adaptation, both for the cells' ability to change shape and to interact with varying mechanical environments. This type of adaptation is dependent on mechanoresponsive proteins that sense and respond to mechanical stress, as well as their regulators. Mechanoresponsive proteins are part of the mechanobiome, which is the larger network that constitutes the cell's mechanical systems that are also highly integrated with many other cellular systems, such as gene expression, metabolism, and signaling. Despite the altered expression patterns of key mechanobiome proteins across many different cancer types, pharmaceutical targeting of these proteins has been overlooked. Here, we review the biochemistry of key mechanoresponsive proteins, specifically nonmuscle myosin II, α-actinins, and filamins, as well as the partnering proteins 14-3-3 and CLP36. We also examined a wide range of data sets to assess how gene and protein expression levels of these proteins are altered across many different cancer types. Finally, we determined the potential of targeting these proteins to mitigate invasion or metastasis and suggest that the mechanobiome is a goldmine of opportunity for anticancer drug discovery and development.
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Affiliation(s)
- Eleana Parajón
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alexandra Surcel
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Douglas N Robinson
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
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7
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Hadden M, Mittal A, Samra J, Zreiqat H, Sahni S, Ramaswamy Y. Mechanically stressed cancer microenvironment: Role in pancreatic cancer progression. Biochim Biophys Acta Rev Cancer 2020; 1874:188418. [PMID: 32827581 DOI: 10.1016/j.bbcan.2020.188418] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/21/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in the world due to its insensitivity to current therapies and its propensity to metastases from the primary tumor mass. This is largely attributed to its complex microenvironment composed of unique stromal cell populations and extracellular matrix (ECM). The recruitment and activation of these cell populations cause an increase in deposition of ECM components, which highly influences the behavior of malignant cells through disrupted forms of signaling. As PDAC progresses from premalignant lesion to invasive carcinoma, this dynamic landscape shields the mass from immune defenses and cytotoxic intervention. This microenvironment influences an invasive cell phenotype through altered forms of mechanical signaling, capable of enacting biochemical changes within cells through activated mechanotransduction pathways. The effects of altered mechanical cues on malignant cell mechanotransduction have long remained enigmatic, particularly in PDAC, whose microenvironment significantly changes over time. A more complete and thorough understanding of PDAC's physical surroundings (microenvironment), mechanosensing proteins, and mechanical properties may help in identifying novel mechanisms that influence disease progression, and thus, provide new potential therapeutic targets.
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Affiliation(s)
- Matthew Hadden
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW 2006, Australia
| | - Anubhav Mittal
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia
| | - Jaswinder Samra
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia
| | - Hala Zreiqat
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW 2006, Australia; ARC Training Centre for Innovative Bioengineering, The University of Sydney, NSW 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia.
| | - Yogambha Ramaswamy
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW 2006, Australia.
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8
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Galectins in the Tumor Microenvironment: Focus on Galectin-1. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1259:17-38. [PMID: 32578169 DOI: 10.1007/978-3-030-43093-1_2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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9
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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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10
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Misiura M, Zińczuk J, Zaręba K, Kamińska D, Guzińska-Ustymowicz K, Pryczynicz A. Actin-Bundling Proteins (Actinin-4 and Fascin-1) are Involved in the Development of Pancreatic Intraepithelial Neoplasia (PanIN). Am J Med Sci 2019; 359:147-155. [PMID: 31889512 DOI: 10.1016/j.amjms.2019.11.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/09/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fascin-1 and actinin-4 are involved in key processes of tumor cell adhesion, migration and metastasis. Actinin-4 plays an important role in promotion of cell proliferation, whereas fascin-1 regulates cellular motility. Its over-expression leads to the loss of cell adhesion and metastasis. The aim of our study was to assess fascin-1 and actinin-4 expression in normal pancreatic ducts and in pancreatic intraepithelial neoplasia (PanIN) - precursor lesion of pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS The study involved 70 patients treated surgically due to PDAC, cysts and pancreatitis, who had also been diagnosed with pancreatic intraepithelial neoplasia. Fascin-1 and actinin-4 expressions were evaluated using the immunohistochemistry method. RESULTS A statistically significant relationship was observed between the expression of fascin-1 and actinin-4 (cytoplasmic) and patients' age (P = 0.01, P = 0.002, respectively). The expression of fascin-1 and actinin-4 was associated with the diagnosis (P <0.001, P = 0.04, respectively). Statistical analysis revealed correlations of fascin-1 and actinin-4 expressions with the presence and grade of PanIN (P < 0.001, P = 0.002, respectively). The expression of these proteins was observed in each degree of PanIN and increased with the pancreatic intraepithelial neoplasia progression. CONCLUSIONS The expression of fascin-1 and actinin-4 is connected with the degree of PanIN advancement and depends on the type of the primary disease. Overexpression of these proteins may be linked to cytological and architectural abnormalities observed in advanced PanIN. Elevated expression of fascin-1 and actinin-4 indicates the role of these proteins in the progression from PanIN to PDAC.
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Affiliation(s)
| | | | - Konrad Zaręba
- 2nd Clinical Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - Dorota Kamińska
- Department of Laboratory Diagnostics, Independent Public Health Care Unit of the Provincial Hospital Jędrzej Śniadecki in Bialystok, Bialystok, Poland
| | | | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Bialystok, Bialystok, Poland
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11
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Computer-aided drug repurposing for cancer therapy: Approaches and opportunities to challenge anticancer targets. Semin Cancer Biol 2019; 68:59-74. [PMID: 31562957 DOI: 10.1016/j.semcancer.2019.09.023] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/24/2019] [Accepted: 09/24/2019] [Indexed: 12/14/2022]
Abstract
Despite huge efforts made in academic and pharmaceutical worldwide research, current anticancer therapies achieve effective treatment in a limited number of neoplasia cases only. Oncology terms such as big killers - to identify tumours with yet a high mortality rate - or undruggable cancer targets, and chemoresistance, represent the current therapeutic debacle of cancer treatments. In addition, metastases, tumour microenvironments, tumour heterogeneity, metabolic adaptations, and immunotherapy resistance are essential features controlling tumour response to therapies, but still, lack effective therapeutics or modulators. In this scenario, where the pharmaceutical productivity and drug efficacy in oncology seem to have reached a plateau, the so-called drug repurposing - i.e. the use of old drugs, already in clinical use, for a different therapeutic indication - is an appealing strategy to improve cancer therapy. Opportunities for drug repurposing are often based on occasional observations or on time-consuming pre-clinical drug screenings that are often not hypothesis-driven. In contrast, in-silico drug repurposing is an emerging, hypothesis-driven approach that takes advantage of the use of big-data. Indeed, the extensive use of -omics technologies, improved data storage, data meaning, machine learning algorithms, and computational modeling all offer unprecedented knowledge of the biological mechanisms of cancers and drugs' modes of action, providing extensive availability for both disease-related data and drugs-related data. This offers the opportunity to generate, with time and cost-effective approaches, computational drug networks to predict, in-silico, the efficacy of approved drugs against relevant cancer targets, as well as to select better responder patients or disease' biomarkers. Here, we will review selected disease-related data together with computational tools to be exploited for the in-silico repurposing of drugs against validated targets in cancer therapies, focusing on the oncogenic signaling pathways activation in cancer. We will discuss how in-silico drug repurposing has the promise to shortly improve our arsenal of anticancer drugs and, likely, overcome certain limitations of modern cancer therapies against old and new therapeutic targets in oncology.
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12
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Ansari D, Torén W, Zhou Q, Hu D, Andersson R. Proteomic and genomic profiling of pancreatic cancer. Cell Biol Toxicol 2019; 35:333-343. [PMID: 30771135 PMCID: PMC6757097 DOI: 10.1007/s10565-019-09465-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 02/05/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer remains the most fatal human tumor type. The aggressive tumor biology coupled with the lack of early detection strategies and effective treatment are major reasons for the poor survival rate. Collaborative research efforts have been devoted to understand pancreatic cancer at the molecular level. Large-scale genomic studies have generated important insights into the genetic drivers of pancreatic cancer. In the post-genomic era, protein sequencing of tumor tissue, cell lines, pancreatic juice, and blood from patients with pancreatic cancer has provided a fundament for the development of new diagnostic and prognostic biomarkers. The integration of mass spectrometry and genomic sequencing strategies may help characterize protein identities and post-translational modifications that relate to a specific mutation. Consequently, proteomic and genomic techniques have become a compulsory requirement in modern medicine and health care. These types of proteogenomic studies may usher in a new era of precision diagnostics and treatment in patients with pancreatic cancer.
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Affiliation(s)
- Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden.
| | - William Torén
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
| | - Qimin Zhou
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dingyuan Hu
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
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13
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Munkley J. The glycosylation landscape of pancreatic cancer. Oncol Lett 2019; 17:2569-2575. [PMID: 30854032 PMCID: PMC6388511 DOI: 10.3892/ol.2019.9885] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 12/20/2018] [Indexed: 12/21/2022] Open
Abstract
Pancreatic adenocarcinoma is a lethal disease with a 5-year survival rate of <5%, the lowest of all types of cancer. The diagnosis of pancreatic cancer relies on imaging and tissue biopsy, and the only curative therapy is complete surgical resection. Pancreatic cancer has the propensity to metastasise at an early stage and the majority of patients are diagnosed when surgery is no longer an option. Hence, there is an urgent need to identify biomarkers to enable early diagnosis, and to develop new therapeutic strategies. One approach for this involves targeting cancer-associated glycans. The most widely used serological marker in pancreatic cancer is the carbohydrate antigen CA 19-9 which contains a glycan known as sialyl Lewis A (sLeA). The CA 19-9 assay is used routinely to monitor response to treatment, but concerns have been raised about its sensitivity and specificity as a diagnostic biomarker. In addition to sLeA, a wide range of alterations to other important glycans have been observed in pancreatic cancer. These include increases in the sialyl Lewis X antigen (sLex), an increase in truncated O-glycans (Tn and sTn), increased branched and fucosylated N-glycans, upregulation of specific proteoglycans and galectins, and increased O-GlcNAcylation. Growing evidence supports crucial roles for glycans in all stages of cancer progression, and it is well established that glycans regulate tumour proliferation, invasion and metastasis. The present review describes the biological significance of glycans in pancreatic cancer, and discusses the clinical value of exploiting aberrant glycosylation to improve the diagnosis and treatment of this deadly disease.
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Affiliation(s)
- Jennifer Munkley
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK
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14
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The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship. Cancers (Basel) 2018; 10:cancers10090316. [PMID: 30200666 PMCID: PMC6162452 DOI: 10.3390/cancers10090316] [Citation(s) in RCA: 194] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 08/31/2018] [Accepted: 09/02/2018] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has an extraordinarily dense fibrotic stroma that impedes tumor perfusion and delivery of anticancer drugs. Since the extracellular matrix (ECM) comprises the bulk of the stroma, it is primarily responsible for the increased interstitial tissue pressure and stiff mechanical properties of the stroma. Besides its mechanical influence, the ECM provides important biochemical and physical cues that promote survival, proliferation, and metastasis. By serving as a nutritional source, the ECM also enables PDAC cells to survive under the nutrient-poor conditions. While therapeutic strategies using stroma-depleting drugs have yielded disappointing results, an increasing body of research indicates the ECM may offer a variety of potential therapeutic targets. As preclinical studies of ECM-targeted drugs have shown promising effects, a number of clinical trials are currently investigating agents with the potential to advance the future treatment of PDAC. Thus, the present review seeks to give an overview of the complex relationship between the ECM and PDAC.
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15
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Martinez-Bosch N, Barranco LE, Orozco CA, Moreno M, Visa L, Iglesias M, Oldfield L, Neoptolemos JP, Greenhalf W, Earl J, Carrato A, Costello E, Navarro P. Increased plasma levels of galectin-1 in pancreatic cancer: potential use as biomarker. Oncotarget 2018; 9:32984-32996. [PMID: 30250644 PMCID: PMC6152472 DOI: 10.18632/oncotarget.26034] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 08/16/2018] [Indexed: 01/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is the most frequent type of pancreatic cancer and one of the deadliest diseases overall. New biomarkers are urgently needed to allow early diagnosis, one of the only factors that currently improves prognosis. Here we analyzed whether the detection of circulating galectin-1 (Gal-1), a soluble carbohydrate-binding protein overexpressed in PDA tissue samples, can be used as a biomarker for PDA. Gal-1 levels were determined by ELISA in plasma from healthy controls and patients diagnosed with PDA, using three independent cohorts. Patients with chronic pancreatitis (CP) were also included in the study to analyze the potential of Gal-1 to discriminate between cancer and inflammatory process. Plasma Gal-1 levels were significantly increased in patients with PDA as compared to controls in all three cohorts. Gal-1 sensitivity and specificity values were similar to that of the CA19-9 biomarker (the only FDA-approved blood test biomarker for PDA), and the combination of Gal-1 and CA19-9 significantly improved their individual discriminatory powers. Moreover, high levels of Gal-1 were associated with lower survival in patients with non-resected tumors. Collectively, our data indicate a strong potential of using circulating Gal-1 levels as a biomarker for detection and prognostics of patients with PDA.
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Affiliation(s)
- Neus Martinez-Bosch
- Cancer Research Program, IMIM, Hospital del Mar Medical Research Institute, Unidad Asociade CSIC, Barcelona, Spain
| | - Luis E Barranco
- Cancer Research Program, IMIM, Hospital del Mar Medical Research Institute, Unidad Asociade CSIC, Barcelona, Spain
- Department of Gastroenterology, Universidad Autonoma de Barcelona, Hospital del Mar, Barcelona, Spain
| | - Carlos A Orozco
- Cancer Research Program, IMIM, Hospital del Mar Medical Research Institute, Unidad Asociade CSIC, Barcelona, Spain
| | - Mireia Moreno
- Cancer Research Program, IMIM, Hospital del Mar Medical Research Institute, Unidad Asociade CSIC, Barcelona, Spain
| | - Laura Visa
- Department of Medical Oncology, Hospital del Mar, Barcelona, Spain
| | - Mar Iglesias
- Department of Pathology, Universidad Autonoma de Barcelona, Hospital del Mar, CIBERONC, Barcelona, Spain
| | - Lucy Oldfield
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - John P Neoptolemos
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
| | - William Greenhalf
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Julie Earl
- Department of Medical Oncology, Ramon y Cajal University Hospital, CIBERONC, IRYCIS, Alcala University, Madrid, Spain
| | - Alfredo Carrato
- Department of Medical Oncology, Ramon y Cajal University Hospital, CIBERONC, IRYCIS, Alcala University, Madrid, Spain
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Pilar Navarro
- Cancer Research Program, IMIM, Hospital del Mar Medical Research Institute, Unidad Asociade CSIC, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, Spain
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16
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Bacigalupo ML, Carabias P, Troncoso MF. Contribution of galectin-1, a glycan-binding protein, to gastrointestinal tumor progression. World J Gastroenterol 2017; 23:5266-5281. [PMID: 28839427 PMCID: PMC5550776 DOI: 10.3748/wjg.v23.i29.5266] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 05/04/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly metastasize, thus identifying effective targets is crucial for treatment. Galectin-1 (Gal-1) belongs to a family of glycan-binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies.
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17
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Dobiasch S, Szanyi S, Kjaev A, Werner J, Strauss A, Weis C, Grenacher L, Kapilov-Buchman K, Israel LL, Lellouche JP, Locatelli E, Franchini MC, Vandooren J, Opdenakker G, Felix K. Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer. J Nanobiotechnology 2016; 14:81. [PMID: 27993133 PMCID: PMC5168863 DOI: 10.1186/s12951-016-0236-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 12/03/2016] [Indexed: 11/24/2022] Open
Abstract
Background Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues. Results Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t-PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over-expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN-Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA-vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs. Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections. Conclusions The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising.
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Affiliation(s)
- Sophie Dobiasch
- Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.,Department of Radiation Oncology, Technische Universität München, Munich, Germany
| | - Szilard Szanyi
- Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Aleko Kjaev
- Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Jens Werner
- Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.,Department of General-, Visceral-, Transplantations-, Vascular- and Thorax-Surgery LMU Munich, München, Germany
| | - Albert Strauss
- Department of Radiology, University of Heidelberg, Heidelberg, Germany
| | - Christian Weis
- Department of Radiology, University of Heidelberg, Heidelberg, Germany
| | - Lars Grenacher
- Department of Radiology, University of Heidelberg, Heidelberg, Germany.,Diagnostik München, Diagnostic Imaging and Prevention Center, Munich, Germany
| | - Katya Kapilov-Buchman
- Nanomaterials Research Center, Institute for Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel
| | - Liron-Limor Israel
- Nanomaterials Research Center, Institute for Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel
| | - Jean-Paul Lellouche
- Nanomaterials Research Center, Institute for Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel
| | - Erica Locatelli
- Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, Italy
| | - Mauro Comes Franchini
- Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, Italy
| | - Jennifer Vandooren
- Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Ghislain Opdenakker
- Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Klaus Felix
- Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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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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Stromal Fibrosis and Expression of Matricellular Proteins Correlate With Histological Grade of Intraductal Papillary Mucinous Neoplasm of the Pancreas. Pancreas 2016; 45:1145-52. [PMID: 26967452 PMCID: PMC4993122 DOI: 10.1097/mpa.0000000000000617] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE The aim of the study was to clarify the correlation between the microenvironmental factors and histological grade in intraductal papillary mucinous neoplasm (IPMN). METHODS We investigated 65 IPMNs resected at Yamagata University Hospital between 2000 and 2011, and all cases were categorized to low-inter (including low- and intermediate-grade dysplasia) and high-inv (including high-grade dysplasia and IPMN with an associated invasive carcinoma) groups. We compared between the 2 groups pathologically with regard to fibrosis and the expression of alpha-smooth muscle actin (α-SMA), periostin, and galectin-1 in the periductal stroma of IPMN. RESULTS There were 41 low-inter and 24 high-inv. The subtype was categorized as 22 main duct type (MD-IPMN) and 43 branch duct type (BD-IPMN). The degree of fibrosis and the expression of α-SMA, periostin, and galectin-1 were significantly higher in high-inv than in low-inter within BD-IPMNs. Multivariate logistic regression analysis indicated that high expression of α-SMA (odds ratio, 13.802; 95% confidence interval, 1.108-171.893; P = 0.0414) was a significant independent related factor of high-inv in BD-IPMN. CONCLUSIONS Stromal fibrosis and expression of α-SMA, periostin, and galectin-1 are more marked in high-inv than in low-inter within BD-IPMNs, and they could become new markers for determining the indications for surgery in BD-IPMN.
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20
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TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors. Cell Rep 2016; 16:1762-1773. [PMID: 27477282 DOI: 10.1016/j.celrep.2016.06.086] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 05/31/2016] [Accepted: 06/22/2016] [Indexed: 12/13/2022] Open
Abstract
Deregulated cathepsin proteolysis occurs across numerous cancers, but in vivo substrates mediating tumorigenesis remain ill-defined. Applying 8-plex iTRAQ terminal amine isotopic labeling of substrates (TAILS), a systems-level N-terminome degradomics approach, we identified cathepsin B, H, L, S, and Z in vivo substrates and cleavage sites with the use of six different cathepsin knockout genotypes in the Rip1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis. Among 1,935 proteins and 1,114 N termini identified by TAILS, stable proteolytic products were identified in wild-type tumors compared with one or more different cathepsin knockouts (17%-44% of 139 cleavages). This suggests a lack of compensation at the substrate level by other cathepsins. The majority of neo-N termini (56%-83%) for all cathepsins was consistent with protein degradation. We validated substrates, including the glycolytic enzyme pyruvate kinase M2 associated with the Warburg effect, the ER chaperone GRP78, and the oncoprotein prothymosin-alpha. Thus, the identification of cathepsin substrates in tumorigenesis improves the understanding of cathepsin functions in normal physiology and cancer.
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21
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Hendley AM, Wang YJ, Polireddy K, Alsina J, Ahmed I, Lafaro KJ, Zhang H, Roy N, Savidge SG, Cao Y, Hebrok M, Maitra A, Reynolds AB, Goggins M, Younes M, Iacobuzio-Donahue CA, Leach SD, Bailey JM. p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia. Cancer Res 2016; 76:3351-63. [PMID: 27032419 DOI: 10.1158/0008-5472.can-15-2268] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 03/14/2016] [Indexed: 01/01/2023]
Abstract
Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351-63. ©2016 AACR.
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Affiliation(s)
- Audrey M Hendley
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Yue J Wang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kishore Polireddy
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Janivette Alsina
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ishrat Ahmed
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kelly J Lafaro
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Hao Zhang
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Nilotpal Roy
- Diabetes Center, University of California, San Francisco, San Francisco, California
| | - Samuel G Savidge
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yanna Cao
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Matthias Hebrok
- Diabetes Center, University of California, San Francisco, San Francisco, California
| | - Anirban Maitra
- Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Albert B Reynolds
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Michael Goggins
- Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mamoun Younes
- Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston, Texas
| | - Christine A Iacobuzio-Donahue
- The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Steven D Leach
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Jennifer M Bailey
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas.
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22
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Pancreatic preneoplastic lesions plasma signatures and biomarkers based on proteome profiling of mouse models. Br J Cancer 2015; 113:1590-8. [PMID: 26512875 PMCID: PMC4705884 DOI: 10.1038/bjc.2015.370] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 08/28/2015] [Accepted: 09/30/2015] [Indexed: 12/27/2022] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a mortality that is almost identical to incidence. Because early detected PDAC is potentially curable, blood-based biomarkers that could detect currently developing neoplasia would improve patient survival and management. PDAC develops from pancreatic intraepithelial neoplasia (PanIN) lesions, graded from low grade (PanIN1) to high grade (PanIN3). We made the hypothesis that specific proteomic signatures from each precancerous stage exist and are detectable in plasma. Methods: We explored the peptide profiles of microdissected PanIN cells and of plasma samples corresponding to the different PanIN grade from genetically engineered mouse models of PDAC using capillary electrophoresis coupled to mass spectrometry (CE-MS) and Chip-MS/MS. Results: We successfully characterised differential peptides profiles from PanIN microdissected cells. We found that plasma from tumor-bearing mice and age-matched controls exhibit discriminative peptide signatures. We also determined plasma peptide signatures corresponding to low- and high-grade precancerous step present in the mice pancreas using the two mass spectrometry technologies. Importantly, we identified biomarkers specific of PanIN3. Conclusions: We demonstrate that benign and advanced PanIN lesions display distinct plasma peptide patterns. This strongly supports the perspectives of developing a non-invasive screening test for prediction and early detection of PDAC.
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23
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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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Rosenberger I, Strauss A, Dobiasch S, Weis C, Szanyi S, Gil-Iceta L, Alonso E, González Esparza M, Gómez-Vallejo V, Szczupak B, Plaza-García S, Mirzaei S, Israel LL, Bianchessi S, Scanziani E, Lellouche JP, Knoll P, Werner J, Felix K, Grenacher L, Reese T, Kreuter J, Jiménez-González M. Targeted diagnostic magnetic nanoparticles for medical imaging of pancreatic cancer. J Control Release 2015; 214:76-84. [PMID: 26192099 DOI: 10.1016/j.jconrel.2015.07.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 07/14/2015] [Accepted: 07/15/2015] [Indexed: 01/15/2023]
Abstract
Highly aggressive cancer types such as pancreatic cancer possess a mortality rate of up to 80% within the first 6months after diagnosis. To reduce this high mortality rate, more sensitive diagnostic tools allowing an early stage medical imaging of even very small tumours are needed. For this purpose, magnetic, biodegradable nanoparticles prepared using recombinant human serum albumin (rHSA) and incorporated iron oxide (maghemite, γ-Fe2O3) nanoparticles were developed. Galectin-1 has been chosen as target receptor as this protein is upregulated in pancreatic cancer and its precursor lesions but not in healthy pancreatic tissue nor in pancreatitis. Tissue plasminogen activator derived peptides (t-PA-ligands), that have a high affinity to galectin-1 have been chosen as target moieties and were covalently attached onto the nanoparticle surface. Improved targeting and imaging properties were shown in mice using single photon emission computed tomography-computer tomography (SPECT-CT), a handheld gamma camera, and magnetic resonance imaging (MRI).
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Affiliation(s)
- I Rosenberger
- Institute of Pharmaceutical Technology, Biocenter Niederursel, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany; Wilhelimnenspital, Institute of Nuclear Medicine, Montleartstr. 37, 1160 Wien, Austria
| | - A Strauss
- Department of Diagnostic Radiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - S Dobiasch
- Department of General and Visceral Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - C Weis
- Department of Diagnostic Radiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - S Szanyi
- Department of General and Visceral Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - L Gil-Iceta
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
| | - E Alonso
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
| | - M González Esparza
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
| | - V Gómez-Vallejo
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
| | - B Szczupak
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
| | - S Plaza-García
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
| | - S Mirzaei
- Wilhelimnenspital, Institute of Nuclear Medicine, Montleartstr. 37, 1160 Wien, Austria
| | - L L Israel
- Department of Chemistry & Institute of Nanotechnology & Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - S Bianchessi
- Fondazione Filarete, Viale Ortles 22/4, 20139 Milano, Italy
| | - E Scanziani
- Fondazione Filarete, Viale Ortles 22/4, 20139 Milano, Italy
| | - J-P Lellouche
- Department of Chemistry & Institute of Nanotechnology & Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - P Knoll
- Wilhelimnenspital, Institute of Nuclear Medicine, Montleartstr. 37, 1160 Wien, Austria
| | - J Werner
- Department of General and Visceral Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany; Department of General-, Visceral-, Transplantation-, Vascular- and Thorax-Surgery LMU Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - K Felix
- Department of General and Visceral Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - L Grenacher
- Department of Diagnostic Radiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - T Reese
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
| | - J Kreuter
- Institute of Pharmaceutical Technology, Biocenter Niederursel, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
| | - M Jiménez-González
- CIC biomaGUNE, Molecular Imaging Unit, Paseo Miramón No 182, Parque Tecnológico de San Sebastián, 20009 San Sebastián, Guipúzcoa, Spain
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Thijssen VL, Heusschen R, Caers J, Griffioen AW. Galectin expression in cancer diagnosis and prognosis: A systematic review. Biochim Biophys Acta Rev Cancer 2015; 1855:235-47. [PMID: 25819524 DOI: 10.1016/j.bbcan.2015.03.003] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 03/14/2015] [Accepted: 03/16/2015] [Indexed: 02/07/2023]
Abstract
Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients.
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Affiliation(s)
- Victor L Thijssen
- Angiogenesis Laboratory, Department Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands; Angiogenesis Laboratory, Department of Radiation Oncology, VU University Medical Center, Amsterdam, the Netherlands.
| | - Roy Heusschen
- Laboratory of Hematology, GIGA-Research, University of Liege, Liege, Belgium
| | - Jo Caers
- Laboratory of Hematology, GIGA-Research, University of Liege, Liege, Belgium
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands
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Chen R, Dawson DW, Pan S, Ottenhof NA, de Wilde RF, Wolfgang CL, May DH, Crispin DA, Lai LA, Lay AR, Waghray M, Wang S, McIntosh MW, Simeone DM, Maitra A, Brentnall TA. Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma. J Transl Med 2015; 95:43-55. [PMID: 25347153 PMCID: PMC4281293 DOI: 10.1038/labinvest.2014.128] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 08/06/2014] [Accepted: 08/30/2014] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFβ-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.
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Affiliation(s)
- Ru Chen
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - David W Dawson
- 1] Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA [2] Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Sheng Pan
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Niki A Ottenhof
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Roeland F de Wilde
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Christopher L Wolfgang
- Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Damon H May
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, WA, USA
| | - David A Crispin
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Lisa A Lai
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Anna R Lay
- Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA
| | - Meghna Waghray
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Shouli Wang
- Department of Pathology, Soochow University School of Medicine, Suzhou, China
| | - Martin W McIntosh
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, WA, USA
| | - Diane M Simeone
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Anirban Maitra
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Biphasic Alterations in Expression and Subcellular Localization of MUC1 in Pancreatic Ductal Carcinogenesis in Syrian Hamsters. Pancreas 2015; 44:76-86. [PMID: 25036908 DOI: 10.1097/mpa.0000000000000178] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The aim of the present study was to characterize molecular targets for the prevention/diagnosis of pancreatic cancer using a chemically induced hamster pancreatic carcinogenesis model, in which background injuries to the parenchyma, for example, chronic pancreatitis or acinar atrophy, are limited. METHODS Gene expression profiles in atypical hyperplasias were first investigated using a microarray technique. Immunohistochemical analyses of early lesions and invasive ductal carcinoma (IDC) were then conducted for MUC1, of which mRNA levels were prominent among the up-regulated genes, in contrast with the coexpression of epithelial-mesenchymal transition (EMT)-related proteins. RESULTS Immunohistochemistry for MUC1 cytoplasmic domain (MUC1-CD), which was not detected in normal-like pancreatic ducts, was positive in the apical surfaces of the epithelia of hyperplasias with and without atypia and IDC areas with distinct tubular patterns. In contrast, cytoplasmic/nuclear positivity for MUC1-CD was observed in the invasive front of IDCs. The coexpression of EMT-related proteins, such as slug and vimentin, with cytoplasmic/nuclear MUC1-CD was also detected. CONCLUSIONS Alterations in the expression and subcellular localization of MUC1 represent a biphasic phenomenon, and the latter may be associated with EMT in pancreatic carcinogenesis in hamsters, which indicates that changes in MUC1 are important targets for pancreatic cancer prevention and chemotherapy.
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28
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Xu Z, Pothula SP, Wilson JS, Apte MV. Pancreatic cancer and its stroma: a conspiracy theory. World J Gastroenterol 2014; 20:11216-11229. [PMID: 25170206 PMCID: PMC4145760 DOI: 10.3748/wjg.v20.i32.11216] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 02/18/2014] [Accepted: 04/15/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells (pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biology and the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.
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29
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Martínez-Bosch N, Fernández-Barrena MG, Moreno M, Ortiz-Zapater E, Munné-Collado J, Iglesias M, André S, Gabius HJ, Hwang RF, Poirier F, Navas C, Guerra C, Fernández-Zapico ME, Navarro P. Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation. Cancer Res 2014; 74:3512-24. [PMID: 24812270 PMCID: PMC4332591 DOI: 10.1158/0008-5472.can-13-3013] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy.
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Affiliation(s)
| | - Maite G Fernández-Barrena
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
| | | | | | - Jessica Munné-Collado
- Authors' Affiliations: Cancer Research Program and Department of Pathology, IMIM (Hospital del Mar Medical Research Institute), Barcelona
| | - Mar Iglesias
- Authors' Affiliations: Cancer Research Program and Department of Pathology, IMIM (Hospital del Mar Medical Research Institute), Barcelona
| | - Sabine André
- Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, München, Germany; and
| | - Hans-Joachim Gabius
- Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, München, Germany; and
| | - Rosa F Hwang
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Françoise Poirier
- Institute Jacques Monod, CNRS UMR7592, Université Paris Diderot, Paris, France
| | | | | | - Martin E Fernández-Zapico
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
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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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31
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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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32
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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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Mu Y, Chen Y, Zhang G, Zhan X, Li Y, Liu T, Li G, Li M, Xiao Z, Gong X, Chen Z. Identification of stromal differentially expressed proteins in the colon carcinoma by quantitative proteomics. Electrophoresis 2013; 34:1679-92. [PMID: 23737015 DOI: 10.1002/elps.201200596] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 01/28/2013] [Accepted: 02/07/2013] [Indexed: 12/18/2022]
Abstract
Tumor microenvironment plays very important roles in the carcinogenesis. A variety of stromal cells in the microenvironment have been modified to support the unique needs of the malignant state. This study was to discover stromal differentially expressed proteins (DEPs) that were involved in colon carcinoma carcinogenesis. Laser capture microdissection (LCM) was captured and isolated the stromal cells from colon adenocarcinoma (CAC) and non-neoplastic colon mucosa (NNCM) tissues, respectively. Seventy DEPs were identified between the pooled LCM-enriched CAC and NNCM stroma samples by iTRAQ-based quantitative proteomics. Gene Ontology (GO) relationship analysis revealed that DEPs were hierarchically grouped into 10 clusters, and were involved in multiple biological functions that were altered during carcinogenesis, including extracellular matrix organization, cytoskeleton, transport, metabolism, inflammatory response, protein polymerization, and cell motility. Pathway network analysis revealed 6 networks and 56 network eligible proteins with Ingenuity pathway analysis. Four significant networks functioned in digestive system development and its function, inflammatory disease, and developmental disorder. Eight DEPs (DCN, FN1, PKM2, HSP90B1, S100A9, MYH9, TUBB, and YWHAZ) were validated by Western blotting, and four DEPs (DCN, FN1, PKM2, and HSP90B1) were validated by immunohistochemical analysis. It is the first report of stromal DEPs between CAC and NNCM tissues. It will be helpful to recognize the roles of stromas in the colon carcinoma microenvironment, and improve the understanding of carcinogenesis in colon carcinoma. The present data suggest that DCN, FN1, PKM2, HSP90B1, S100A9, MYH9, TUBB, and YWHAZ might be the potential targets for colon cancer prevention and therapy.
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Affiliation(s)
- Yibing Mu
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, P. R. China
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Twenty-one proteins up-regulated in human H-ras oncogene transgenic rat pancreas cancers are up-regulated in human pancreas cancer. Pancreas 2013; 42:1034-9. [PMID: 23648844 DOI: 10.1097/mpa.0b013e3182883624] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES We have established rat models of pancreatic ductal adenocarcinoma (PDAC) in which expression of a human H-ras(G12V) or K-ras(G12V) oncogene regulated by the Cre/lox system drives pancreatic carcinogenesis. Pancreatic ductal adenocarcinoma which develops in H-ras(G12V) and K-ras(G12V) transgenic rats is cytogenetically and histopathologically similar to human PDAC. The present study was designed to determine the feasibility of using the commercially available H-ras(G12V) transgenic rat to find diagnostic protein biomarkers for human pancreatic cancer. METHODS For an animal model to be useful for searching for protein biomarkers for a disease, it is essential that proteins that are up-regulated in the model are also up-regulated in humans. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to compare H-ras(G12V) transgenic rat PDAC with surrounding normal pancreas tissue. RESULTS We identified 30 up-regulated proteins in the H-ras(G12V) transgenic rat PDAC lesions; importantly, 21 human homologs of these 30 rat proteins are up-regulated in human pancreatic cancer patients. CONCLUSIONS These results indicate that numerous proteins that are up-regulated in H-ras(G12V) transgenic rat PDAC are also up-regulated in human pancreatic cancer; therefore, this rat model can be used to search for diagnostic biomarkers for this disease.
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35
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Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 2013; 144:1210-1219. [PMID: 23622130 PMCID: PMC3729446 DOI: 10.1053/j.gastro.2012.11.037] [Citation(s) in RCA: 364] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Revised: 11/27/2012] [Accepted: 11/28/2012] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. Treatments that target tumor cells have largely failed. This could be because research has focused on cancer cells and the influence of the stroma on tumor progression has been largely ignored. The focus of pancreatic cancer research began to change with the identification of pancreatic stellate cells, which produce the pancreatic tumor stroma. There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. We review the background and recent advances in these areas, along with important areas of future research that could improve therapy.
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Affiliation(s)
- Minoti V. Apte
- Pancreatic Research Groups
- Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales Sydney, New South Wales, Australia
| | - Jeremy S. Wilson
- Pancreatic Research Groups
- Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales Sydney, New South Wales, Australia
| | - Aurelia Lugea
- Pancreatic Research Groups
- Department of Veterans Affairs and University of California, Los Angeles, California
| | - Stephen J. Pandol
- Pancreatic Research Groups
- Department of Veterans Affairs and University of California, Los Angeles, California
- Cedars-Sinai Medical Center, Los Angeles, California
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36
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Crnogorac-Jurcevic T, Chelala C, Barry S, Harada T, Bhakta V, Lattimore S, Jurcevic S, Bronner M, Lemoine NR, Brentnall TA. Molecular analysis of precursor lesions in familial pancreatic cancer. PLoS One 2013; 8:e54830. [PMID: 23372777 PMCID: PMC3553106 DOI: 10.1371/journal.pone.0054830] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 12/17/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND With less than a 5% survival rate pancreatic adenocarcinoma (PDAC) is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical. METHODS AND FINDINGS We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses. CONCLUSIONS Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic pancreatic adenocarcinoma.
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Affiliation(s)
- Tatjana Crnogorac-Jurcevic
- Molecular Oncology Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
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Pan S, Brentnall TA, Kelly K, Chen R. Tissue proteomics in pancreatic cancer study: discovery, emerging technologies, and challenges. Proteomics 2013; 13:710-21. [PMID: 23125171 DOI: 10.1002/pmic.201200319] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 10/01/2012] [Accepted: 10/05/2012] [Indexed: 12/22/2022]
Abstract
Pancreatic cancer is a highly lethal disease that is difficult to diagnose and treat. The advances in proteomics technology, especially quantitative proteomics, have stimulated a great interest in applying this technology for pancreatic cancer study. A variety of tissue proteomics approaches have been applied to investigate pancreatic cancer and the associated diseases. These studies were carried out with various goals, aiming to better understand the molecular mechanisms underlying pancreatic tumorigenesis, to improve therapeutic treatment and to identify cancer associated protein signatures, signaling events as well as interactions between cancer cells and tumor microenvironment. Here, we provide an overview on the tissue proteomics studies of pancreatic cancer reported in the past few years in light of discovery and technology development.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington, Seattle, WA 98195, USA.
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Abstract
Alpha-actinins (ACTNs) were originally identified as cytoskeletal proteins which cross-link filamentous actin to establish cytoskeletal architect that protects cells from mechanical stress and controls cell movement. Notably, unlike other ACTNs, alpha-actinin 4 (ACTN4) displays unique characteristics in signaling transduction, nuclear translocation, and gene expression regulation. Initial reports indicated that ACTN4 is part of the breast cancer cell motile apparatus and is highly expressed in the nucleus. These results imply that ACTN4 plays a role in breast cancer tumorigenesis. While several observations in breast cancer and other cancers support this hypothesis, little direct evidence links the tumorigenic phenotype with ACTN4-mediated pathological mechanisms. Recently, several studies have demonstrated that in addition to its role in coordinating cytoskeleton, ACTN4 interacts with signaling mediators, chromatin remodeling factors, and transcription factors including nuclear receptors. Thus, ACTN4 functions as a versatile promoter for breast cancer tumorigenesis and appears to be an ideal drug target for future therapeutic development.
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Affiliation(s)
- Kuo-Sheng Hsu
- Department of Biochemistry, School of Medicine, Case Western Reserve University-CWRU, The Comprehensive Cancer Center of CWRU, Cleveland, Ohio, USA
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Shukla HD, Vaitiekunas P, Cotter RJ. Advances in membrane proteomics and cancer biomarker discovery: current status and future perspective. Proteomics 2012; 12:3085-104. [PMID: 22890602 DOI: 10.1002/pmic.201100519] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Revised: 07/05/2012] [Accepted: 07/27/2012] [Indexed: 02/06/2023]
Abstract
Membrane proteomic analysis has been proven to be a promising tool for identifying new and specific biomarkers that can be used for prognosis and monitoring of various cancers. Membrane proteins are of great interest particularly those with functional domains exposed to the extracellular environment. Integral membrane proteins represent about one-third of the proteins encoded by the human genome and assume a variety of key biological functions, such as cell-to-cell communication, receptor-mediated signal transduction, selective transport, and pharmacological actions. More than two-thirds of membrane proteins are drug targets, highlighting their immensely important pharmaceutical significance. Most plasma membrane proteins and proteins from other cellular membranes have several PTMs; for example, glycosylation, phosphorylation, and nitrosylation, and moreover, PTMs of proteins are known to play a key role in tumor biology. These modifications often cause change in stoichiometry and microheterogeneity in a protein molecule, which is apparent during electrophoretic separation. Furthermore, the analysis of glyco- and phosphoproteome of cell membrane presents a number of challenges mainly due to their low abundance, their large dynamic range, and the inherent hydrophobicity of membrane proteins. Under pathological conditions, PTMs, such as phosphorylation and glycosylation are frequently altered and have been recognized as a potential source for disease biomarkers. Thus, their accurate differential expression analysis, along with differential PTM analysis is of paramount importance. Here we summarize the current status of membrane-based biomarkers in various cancers, and future perspective of membrane biomarker research.
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Affiliation(s)
- Hem D Shukla
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
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Chen R, Pan S, Ottenhof NA, de Wilde RF, Wolfgang CL, Lane Z, Post J, Bronner MP, Willmann JK, Maitra A, Brentnall TA. Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma. Cancer Biol Ther 2012; 13:899-907. [PMID: 22785208 DOI: 10.4161/cbt.20842] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.
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Affiliation(s)
- Ru Chen
- Department of Medicine, University of Washington, Seattle, WA, USA
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Pan S, Chen R, Brand RE, Hawley S, Tamura Y, Gafken PR, Milless BP, Goodlett DR, Rush J, Brentnall TA. Multiplex targeted proteomic assay for biomarker detection in plasma: a pancreatic cancer biomarker case study. J Proteome Res 2012; 11:1937-48. [PMID: 22316387 DOI: 10.1021/pr201117w] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Biomarkers are most frequently proteins that are measured in the blood. Their development largely relies on antibody creation to test the protein candidate performance in blood samples of diseased versus nondiseased patients. The creation of such antibody assays has been a bottleneck in biomarker progress due to the cost, extensive time, and effort required to complete the task. Targeted proteomics is an emerging technology that is playing an increasingly important role to facilitate disease biomarker development. In this study, we applied a SRM-based targeted proteomics platform to directly detect candidate biomarker proteins in plasma to evaluate their clinical utility for pancreatic cancer detection. The characterization of these protein candidates used a clinically well-characterized cohort that included plasma samples from patients with pancreatic cancer, chronic pancreatitis, and healthy age-matched controls. Three of the five candidate proteins, including gelsolin, lumican, and tissue inhibitor of metalloproteinase 1, demonstrated an AUC value greater than 0.75 in distinguishing pancreatic cancer from the controls. In addition, we provide an analysis of the reproducibility, accuracy, and robustness of the SRM-based proteomics platform. This information addresses important technical issues that could aid in the adoption of the targeted proteomics platform for practical clinical utility.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington , Seattle, Washington 98195, United States.
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Pan S, Chen R, Stevens T, Bronner MP, May D, Tamura Y, McIntosh MW, Brentnall TA. Proteomics portrait of archival lesions of chronic pancreatitis. PLoS One 2011; 6:e27574. [PMID: 22132114 PMCID: PMC3223181 DOI: 10.1371/journal.pone.0027574] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 10/19/2011] [Indexed: 12/11/2022] Open
Abstract
Chronic pancreatitis is a chronic inflammatory disorder of the pancreas. The etiology is multi-fold, but all lead to progressive scarring and loss of pancreatic function. Early diagnosis is difficult; and the understanding of the molecular events that underlie this progressive disease is limited. In this study, we investigated differential proteins associated with mild and severe chronic pancreatitis in comparison with normal pancreas and pancreatic cancer. Paraffin-embedded formalin-fixed tissues from five well-characterized specimens each of normal pancreas (NL), mild chronic pancreatitis (MCP), severe chronic pancreatitis (SCP) and pancreatic ductal adenocarcinoma (PDAC) were subjected to proteomic analysis using a “label-free” comparative approach. Our results show that the numbers of differential proteins increase substantially with the disease severity, from mild to severe chronic pancreatitis, while the number of dysregulated proteins is highest in pancreatic adenocarcinoma. Important functional groups and biological processes associated with chronic pancreatitis and cancer include acinar cell secretory proteins, pancreatic fibrosis/stellate cell activation, glycoproteins, and inflammatory proteins. Three differential proteins were selected for verification by immunohistochemistry, including collagen 14A1, lumican and versican. Further canonical pathway analysis revealed that acute phase response signal, prothrombin activation pathway, and pancreatic fibrosis/pancreatic stellate cell activation pathway were the most significant pathways involved in chronic pancreatitis, while pathways relating to metabolism were the most significant pathways in pancreatic adenocarcinoma. Our study reveals a group of differentially expressed proteins and the related pathways that may shed light on the pathogenesis of chronic pancreatitis and the common molecular events associated with chronic pancreatitis and pancreatic adenocarcinoma.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
- * E-mail: (SP); (TB)
| | - Ru Chen
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Tyler Stevens
- Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Mary P. Bronner
- Department of Anatomic Pathology, University of Utah, Salt Lake City, Utah, United States of America
| | - Damon May
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, Washington, United States of America
| | - Yasuko Tamura
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Martin W. McIntosh
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, Washington, United States of America
| | - Teresa A. Brentnall
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
- * E-mail: (SP); (TB)
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Xue X, Lu Z, Tang D, Yao J, An Y, Wu J, Li Q, Gao W, Xu Z, Qian Z, Dai C, Wei J, Miao Y, Jiang K. Galectin-1 secreted by activated stellate cells in pancreatic ductal adenocarcinoma stroma promotes proliferation and invasion of pancreatic cancer cells: an in vitro study on the microenvironment of pancreatic ductal adenocarcinoma. Pancreas 2011; 40:832-839. [PMID: 21747316 DOI: 10.1097/mpa.0b013e318217945e] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES This study aimed to clarify that the activated pancreatic stellate cells (PaSCs) are the origin of the highly expressed galectin-1 in the stroma of pancreatic ductal adenocarcinoma (PDAC) tissue and to evaluate the effect of the secreted galectin-1 on proliferation and invasion ability of pancreatic cancer cell line CFPAC-1 in vitro. METHODS Different kinds of PaSCs were isolated from the normal or cancerous pancreatic tissues and cultured. Immunohistochemistry study, quantitative polymerase chain reaction, and Western blot were carried out to check the cellular origin of galectin-1 in PDAC tissue. By using modified Boyden chambers, in vitro coculture system of PaSCs was established with the pancreatic cancer cell line CFPAC-1 and based on which we assessed the proliferation and invasion ability of CFPAC-1 with or without galectin-1 antagonists. RESULTS We identified PaSCs as the primary source of the highly expressed galectin-1 in PDAC stroma. Galectin-1 secreted by PaSCs increased CFPAC-1 proliferative rate in the proliferation assay and facilitated CFPAC-1 infiltration in the invasion assay. CONCLUSIONS Under malignant circumstances, PaSCs express and secret galectin-1, which could further promote the proliferation and invasion of cancer cells.
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Affiliation(s)
- Xiaofeng Xue
- Laboratory of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
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Pan S, Chen R, Crispin DA, May D, Stevens T, McIntosh M, Bronner MP, Ziogas A, Anton-Culver H, Brentnall TA. Protein alterations associated with pancreatic cancer and chronic pancreatitis found in human plasma using global quantitative proteomics profiling. J Proteome Res 2011; 10:2359-76. [PMID: 21443201 PMCID: PMC3090497 DOI: 10.1021/pr101148r] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic cancer is a lethal disease that is difficult to diagnose at early stages when curable treatments are effective. Biomarkers that can improve current pancreatic cancer detection would have great value in improving patient management and survival rate. A large scale quantitative proteomics study was performed to search for the plasma protein alterations associated with pancreatic cancer. The enormous complexity of the plasma proteome and the vast dynamic range of protein concentration therein present major challenges for quantitative global profiling of plasma. To address these challenges, multidimensional fractionation at both protein and peptide levels was applied to enhance the depth of proteomics analysis. Employing stringent criteria, more than 1300 proteins total were identified in plasma across 8-orders of magnitude in protein concentration. Differential proteins associated with pancreatic cancer were identified, and their relationship with the proteome of pancreatic tissue and pancreatic juice from our previous studies was discussed. A subgroup of differentially expressed proteins was selected for biomarker testing using an independent cohort of plasma and serum samples from well-diagnosed patients with pancreatic cancer, chronic pancreatitis, and nonpancreatic disease controls. Using ELISA methodology, the performance of each of these protein candidates was benchmarked against CA19-9, the current gold standard for a pancreatic cancer blood test. A composite marker of TIMP1 and ICAM1 demonstrate significantly better performance than CA19-9 in distinguishing pancreatic cancer from the nonpancreatic disease controls and chronic pancreatitis controls. In addition, protein AZGP1 was identified as a biomarker candidate for chronic pancreatitis. The discovery and technical challenges associated with plasma-based quantitative proteomics are discussed and may benefit the development of plasma proteomics technology in general. The protein candidates identified in this study provide a biomarker candidate pool for future investigations.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Ru Chen
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - David A. Crispin
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Damon May
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, WA 98109, USA
| | - Tyler Stevens
- Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Martin McIntosh
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, WA 98109, USA
| | - Mary P. Bronner
- Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Argyrios Ziogas
- Department of Epidemiology, University of California, Irvine, CA 92697, USA
| | - Hoda Anton-Culver
- Department of Epidemiology, University of California, Irvine, CA 92697, USA
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Gutiérrez ML, Sayagués JM, Abad MDM, Bengoechea O, González-González M, Orfao A, Muñoz-Bellvis L. Cytogenetic heterogeneity of pancreatic ductal adenocarcinomas: identification of intratumoral pathways of clonal evolution. Histopathology 2011; 58:486-97. [PMID: 21323969 DOI: 10.1111/j.1365-2559.2011.03771.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Chakraborty S, Baine MJ, Sasson AR, Batra SK. Current status of molecular markers for early detection of sporadic pancreatic cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2011; 1815:44-64. [PMID: 20888394 PMCID: PMC3014374 DOI: 10.1016/j.bbcan.2010.09.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Revised: 09/23/2010] [Accepted: 09/24/2010] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy with near 100% mortality. This is in part due to the fact that most patients present with metastatic or locally advanced disease at the time of diagnosis. Significantly, in nearly 95% of PC patients there is neither an associated family history of PC nor of diseases known to be associated with an increased risk of PC. These groups of patients who comprise the bulk of PC cases are termed as "sporadic PC" in contrast to the familial PC cases that comprise only about 5% of all PCs. Given the insidious onset of the malignancy and its extreme resistance to chemo and radiotherapy, an abundance of research in recent years has focused on identifying biomarkers for the early detection of PC, specifically aiming at the sporadic PC cohort. However, while several studies have established that asymptomatic individuals with a positive family history of PC and those with certain heritable syndromes are candidates for PC screening, the role of screening in identifying sporadic PC is still an unsettled question. The present review attempts to assess this critical question by investigating the recent advances made in molecular markers with potential use in the early diagnosis of sporadic PC - the largest cohort of PC cases worldwide. It also outlines a novel yet simple risk factor based stratification system that could be potentially employed by clinicians to identify those individuals who are at an elevated risk for the development of sporadic PC and therefore candidates for screening.
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Affiliation(s)
- Subhankar Chakraborty
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
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Screening technologies for target identification in pancreatic cancer. Cancers (Basel) 2010; 3:79-90. [PMID: 24212607 PMCID: PMC3756350 DOI: 10.3390/cancers3010079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Revised: 12/21/2010] [Accepted: 12/23/2010] [Indexed: 01/19/2023] Open
Abstract
Pancreatic cancer exhibits an extraordinarily high level of resistance to almost any kind of systemic therapy evaluated in clinical trials so far. Therefore, the identification of novel therapeutic targets is urgently required. High-throughput screens have emerged as an important tool to identify putative targets for diagnosis and therapy in an unbiased manner. More than a decade ago, microarray technology was introduced to identify differentially expressed genes in pancreatic cancer as compared to normal pancreas, chronic pancreatitis and other cancer types located in close proximity to the pancreas. In addition, proteomic screens have facilitated the identification of differentially secreted proteins in body fluids of pancreatic cancer patients, serving as possible biomarkers. Recently, RNA interference-based loss-of-function screens have been used to identify functionally relevant genes, whose knock-down has impact on pancreatic cancer cell viability, thereby representing potential new targets for therapeutic intervention. This review summarizes recent results of transcriptional, proteomic and functional screens in pancreatic cancer and discusses potentials and limitations of the respective technologies as well as their impact on future therapeutic developments.
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McKinney KQ, Lee YY, Choi HS, Groseclose G, Iannitti DA, Martinie JB, Russo MW, Lundgren DH, Han DK, Bonkovsky HL, Hwang SI. Discovery of putative pancreatic cancer biomarkers using subcellular proteomics. J Proteomics 2010; 74:79-88. [PMID: 20807598 DOI: 10.1016/j.jprot.2010.08.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Revised: 07/16/2010] [Accepted: 08/24/2010] [Indexed: 01/07/2023]
Abstract
Pancreatic cancer (PC) is a highly aggressive disease that frequently remains undetected until it has progressed to an advanced, systemic stage. Successful treatment of PC is hindered by the lack of early detection. The application of proteomic analysis to PC combined with subcellular fractionation has introduced new possibilities in the field of biomarker discovery. We utilized matched pairs of pancreas tumor and non-tumor pancreas from patients undergoing tumor resection. The tissues were treated to obtain cellular protein fractions corresponding to cytosol, membrane, nucleus and cytoskeleton. The fractions were then separated by molecular weight and digested with trypsin, followed by liquid chromatography and tandem mass spectrometry. The spectra obtained were searched using Sequest engine and combined into a single analysis file to obtain a semi-quantitative number, spectral count, using Scaffold software. We identified 2393 unique proteins in non-tumor and cancer pancreas. Utilizing PLGEM statistical analysis we determined 104 proteins were significantly changed in cancer. From these, we further validated four secreted proteins that are up-regulated in cancer and have potential for development as minimally-invasive diagnostic markers. We conclude that subcellular fractionation followed by gel electrophoresis and tandem mass spectrometry is a powerful strategy for identification of differentially expressed proteins in pancreatic cancer.
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Affiliation(s)
- Kimberly Q McKinney
- Proteomics Laboratory for Clinical and Translational Research, Carolinas HealthCare System, Charlotte, NC, USA
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Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A 2010; 107:13438-43. [PMID: 20624967 DOI: 10.1073/pnas.1002423107] [Citation(s) in RCA: 162] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in KrasG12D-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial-mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.
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Li YL, Ye F, Cheng XD, Hu Y, Zhou CY, LÜ WG, Xie X. Identification of glia maturation factor beta as an independent prognostic predictor for serous ovarian cancer. Eur J Cancer 2010; 46:2104-18. [DOI: 10.1016/j.ejca.2010.04.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Revised: 04/06/2010] [Accepted: 04/19/2010] [Indexed: 12/15/2022]
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