Pancreatic Cancer Diagnosis and Management: Has the Time Come to Prick the Bubble?

Pancreatic cancer (PC) is associated with poor prognosis and very dismal survival rates. The most effective possibility of cure is tumor resection, which is only possible in about 15% of patients diagnosed at early stages of disease progression. Recent whole-genome sequencing studies pointed genetic alterations in 12 core signaling pathways in PC. These observations hint at the possibility that the initial mutation in PC might appear nearly 20 years before any symptoms occur, suggesting that a large window of opportunity may exist for early detection. Biomarkers with the potential to identify pre-neoplastic disease or very early stages of cancer are of great promise to improve patient survival. The concept of liquid biopsy refers to a minimally invasive sampling and analysis of liquid biomarkers that can be isolated from body fluids, primarily blood, urine and saliva. A myriad of circulating molecules may be useful as tumor markers, including cell-free DNA (cfDNA), cell-free RNA (cfRNA), circulating tumor cells (CTC), circulating tumor proteins, and extracellular vesicles, more specifically exosomes. In this review, we discuss with more detail the potential role of exosomes in several aspects related to PC, from initiation to tumor progression and its applicability in early detection and treatment. Exosomes are small circulating extracellular vesicles of 50–150 nm in diameter released from the plasma membrane by almost all cells and exhibit some advantages over other biomarkers. Exosomes are central players of intercellular communication and they have been implicated in a series of biological process, including tumorigenesis, migration and metastasis. Several exosomal microRNAs and proteins have been observed to distinguish PC from benign pancreatic diseases and healthy controls. Besides their possible role in diagnosis, understanding exosomes functions in cancer has clarified the importance of microenvironment in PC progression as well as its influence in proliferation, metastasis and resistance to chemotherapy. Increasing knowledge on cancer exosomes provides valuable insights on new therapeutic targets and can potentially open new strategies to treat this disease. Continuous research is needed to ascertain the reliability of using exosomes and their content as potential biomarkers, so that, hopefully, in the near future, they will provide the opportunity for early diagnosis, treatment intervention and increase survival of PC patients.

[1]  P. Kuhn,et al.  Circulating Tumor Cells: Fluid Surrogates of Solid Tumors. , 2017, Annual review of pathology.

[2]  J. Redzic,et al.  Examination of the specificity of tumor cell derived exosomes with tumor cells in vitro. , 2014, Biochimica et biophysica acta.

[3]  S. Batra,et al.  Early diagnosis of pancreatic cancer: challenges and new developments. , 2012, Biomarkers in medicine.

[4]  Stefania Raimondo,et al.  Interleukin 3- receptor targeted exosomes inhibit in vitro and in vivo Chronic Myelogenous Leukemia cell growth , 2017, Theranostics.

[5]  M. Falconi,et al.  Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas. , 2014, World journal of gastroenterology.

[6]  C. Chelala,et al.  Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays , 2008, Oncogene.

[7]  J. Weitz,et al.  Exosomes: novel implications in diagnosis and treatment of gastrointestinal cancer , 2016, Langenbeck's Archives of Surgery.

[8]  Xianjun Yu,et al.  Circulating biomarkers for early diagnosis of pancreatic cancer: facts and hopes. , 2018, American journal of cancer research.

[9]  F. Colina-Ruizdelgado,et al.  Pathological features and diagnosis of intraductal papillary mucinous neoplasm of the pancreas. , 2014, World journal of gastrointestinal oncology.

[10]  American gastroenterological association medical position statement: epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. , 1999, Gastroenterology.

[11]  T. Thundat,et al.  Nanomechanical sandwich assay for multiple cancer biomarkers in breast cancer cell-derived exosomes. , 2016, Nanoscale.

[12]  Avner Friedman,et al.  The Role of Exosomes in Pancreatic Cancer Microenvironment , 2017, Bulletin of Mathematical Biology.

[13]  Arlene M Correa,et al.  Endoscopic Ultrasound-Guided Fine Needle Aspiration and Multidetector Spiral CT in the Diagnosis of Pancreatic Cancer , 2004, American Journal of Gastroenterology.

[14]  G. Macedo,et al.  Glypican-1 circulating exosomes: a promising clue to individualize surveillance of pancreatic cysts? , 2018, European Radiology.

[15]  W. Brugge Pancreatic cyst surveillance: Threat or opportunity? , 2016, Gastrointestinal Endoscopy.

[16]  A. Goel,et al.  Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers , 2017, Clinical Cancer Research.

[17]  G. Macedo,et al.  Pancreatic cancer screening: Still a delusion? , 2017, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[18]  X. Tan,et al.  The role of pancreatic cancer-derived exosomes in cancer progress and their potential application as biomarkers , 2017, Clinical and Translational Oncology.

[19]  M. Fukayama,et al.  Clonality and K-ras mutation analyses of epithelia in intraductal papillary mucinous tumor and mucinous cystic tumor of the pancreas , 2002, Virchows Archiv.

[20]  T. Pawlik,et al.  Exosomes in Pancreatic Cancer: from Early Detection to Treatment , 2018, Journal of Gastrointestinal Surgery.

[21]  Benjamin D. Smith,et al.  Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. , 2014, Cancer research.

[22]  S. Melo,et al.  The Biology of Cancer Exosomes: Insights and New Perspectives. , 2017, Cancer research.

[23]  S. Melo,et al.  Non-coding RNAs in Exosomes: New Players in Cancer Biology , 2015, Current genomics.

[24]  J. Rasko,et al.  Circulating tumour cells and circulating free nucleic acid as prognostic and predictive biomarkers in colorectal cancer. , 2014, Cancer letters.

[25]  R. Pozzi Mucelli,et al.  CEUS of the pancreas: Still research or the standard of care. , 2015, European journal of radiology.

[26]  M. Büchler,et al.  Combined evaluation of a panel of protein and miRNA serum‐exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity , 2015, International journal of cancer.

[27]  C. Verbeke,et al.  Proteomic Mucin Profiling for the Identification of Cystic Precursors of Pancreatic Cancer , 2014, Journal of the National Cancer Institute.

[28]  F. Nicolantonio,et al.  Liquid biopsy: monitoring cancer-genetics in the blood , 2013, Nature Reviews Clinical Oncology.

[29]  Xiaohang Zhao,et al.  Elevated glypican‐1 expression is associated with an unfavorable prognosis in pancreatic ductal adenocarcinoma , 2017, Cancer medicine.

[30]  F. Bazzoli,et al.  The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. , 2013, Gastrointestinal endoscopy.

[31]  Carlo C. Maley,et al.  Clonal evolution in cancer , 2012, Nature.

[32]  B. Bao,et al.  Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review , 2013, Cancer and Metastasis Reviews.

[33]  Zhiqiang Gao,et al.  Progress in Exosome Isolation Techniques , 2017, Theranostics.

[34]  L. Tanoue Cancer Statistics, 2011: The Impact of Eliminating Socioeconomic and Racial Disparities on Premature Cancer Deaths , 2012 .

[35]  R. Hruban,et al.  Dpc4 Protein in Mucinous Cystic Neoplasms of the Pancreas: Frequent Loss of Expression in Invasive Carcinomas Suggests a Role in Genetic Progression , 2000, The American journal of surgical pathology.

[36]  Long R. Jiao,et al.  Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden , 2018, Oncotarget.

[37]  F. Gao,et al.  Pancreatic cancer and associated exosomes. , 2017, Cancer biomarkers : section A of Disease markers.

[38]  Lei Wang,et al.  The clinical significance of circulating GPC1 positive exosomes and its regulative miRNAs in colon cancer patients , 2017, Oncotarget.

[39]  P. Robbins,et al.  Regulation of immune responses by extracellular vesicles , 2014, Nature Reviews Immunology.

[40]  Jiong Wu,et al.  Identification of serum biomarkers for pancreatic adenocarcinoma by proteomic analysis , 2009, Cancer science.

[41]  Gary K. Schwartz,et al.  Tumour exosome integrins determine organotropic metastasis , 2015, Nature.

[42]  D. Sahani,et al.  Radiology of pancreatic adenocarcinoma: Current status of imaging , 2007, Journal of gastroenterology and hepatology.

[43]  J. Salk Clonal evolution in cancer , 2010 .

[44]  Xingjun Guo,et al.  MicroRNA-138-5p regulates pancreatic cancer cell growth through targeting FOXC1 , 2015, Cellular Oncology.

[45]  Kristie L. Rose,et al.  Proteomics characterization of exosome cargo. , 2015, Methods.

[46]  D. Lyden,et al.  Cancer Exosomes as Mediators of Drug Resistance. , 2016, Methods in molecular biology.

[47]  T. Okumura,et al.  An elevated expression of serum exosomal microRNA-191, − 21, −451a of pancreatic neoplasm is considered to be efficient diagnostic marker , 2018, BMC Cancer.

[48]  F. Campbell,et al.  Cystic neoplasms of the exocrine pancreas , 2008, Histopathology.

[49]  Non-coding RNAs in pancreatic cancer: challenges and opportunities for clinical application , 2016, Cellular Oncology.

[50]  Linda S. Lee,et al.  A microRNA-based test improves endoscopic ultrasound-guided cytologic diagnosis of pancreatic cancer. , 2014, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[51]  L. Broemeling,et al.  Detection of small pancreatic tumors with multiphasic helical CT. , 2004, AJR. American journal of roentgenology.

[52]  L. Wood,et al.  Pancreatic cancer , 2016, The Lancet.

[53]  Andrew Menzies,et al.  The patterns and dynamics of genomic instability in metastatic pancreatic cancer , 2010, Nature.

[54]  Michael A. Hollingsworth,et al.  Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver , 2015, Nature Cell Biology.

[55]  M. Korc,et al.  Label-Free Nanoplasmonic-Based Short Noncoding RNA Sensing at Attomolar Concentrations Allows for Quantitative and Highly Specific Assay of MicroRNA-10b in Biological Fluids and Circulating Exosomes , 2015, ACS nano.

[56]  R. Emerson,et al.  Endoscopic ultrasound‐guided fine‐needle aspiration cytology diagnosis of intraductal papillary mucinous neoplasm of the pancreas is highly predictive of pancreatic neoplasia , 2006, Diagnostic cytopathology.

[57]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[58]  Yongxin Yang,et al.  Prognostic value of glypican-1 for patients with advanced pancreatic cancer following regional intra-arterial chemotherapy. , 2018, Oncology letters.

[59]  Michael Goggins,et al.  Update on familial pancreatic cancer. , 2010, Advances in surgery.

[60]  T. Liang,et al.  Liquid biopsy in pancreatic cancer: the beginning of a new era , 2018, Oncotarget.

[61]  Hakho Lee,et al.  Multiparametric plasma EV profiling facilitates diagnosis of pancreatic malignancy , 2017, Science Translational Medicine.

[62]  M. Mino‐Kenudson,et al.  Mucinous Cystic Neoplasm of the Pancreas is Not an Aggressive Entity: Lessons From 163 Resected Patients , 2008, Annals of surgery.

[63]  You Zhou,et al.  Diagnostic Efficacy of Cell Block Immunohistochemistry, Smear Cytology, and Liquid-Based Cytology in Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Pancreatic Lesions: A Single-Institution Experience , 2014, PloS one.

[64]  Paul Fockens,et al.  International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer , 2012, Gut.

[65]  Cheng Qian,et al.  Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer , 2016, Oncotarget.

[66]  R. Hruban,et al.  Increased Prevalence of Precursor Lesions in Familial Pancreatic Cancer Patients , 2009, Clinical Cancer Research.

[67]  L. Ming,et al.  Role of exosomes in pancreatic cancer , 2018, Oncology letters.

[68]  Shadan Ali,et al.  Differential Expression of MicroRNAs in Tissues and Plasma Co-exists as a Biomarker for Pancreatic Cancer. , 2015, Journal of cancer science & therapy.

[69]  Lei Wang,et al.  GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer , 2017, Journal of cellular and molecular medicine.

[70]  M. Farnell,et al.  Pancreatic mucinous cystic neoplasm defined by ovarian stroma: demographics, clinical features, and prevalence of cancer. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[71]  R. DePinho,et al.  Genetics and biology of pancreatic ductal adenocarcinoma , 2006, Genes & development.

[72]  M. Goggins Identifying molecular markers for the early detection of pancreatic neoplasia. , 2007, Seminars in oncology.

[73]  H. Pitt Curative treatment for pancreatic neoplasms. Standard resection. , 1995, The Surgical clinics of North America.

[74]  Douglas B. Evans,et al.  Current staging systems for pancreatic cancer. , 2012, Cancer journal.

[75]  R. Lamerz Role of tumour markers, cytogenetics. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[76]  Wei Zhu,et al.  Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: A miRNA expression analysis. , 2018, Gene.

[77]  C. Rosty,et al.  Early detection of pancreatic carcinoma. , 2002, Hematology/oncology clinics of North America.

[78]  A. Scarpa,et al.  Clinical implications of biological markers in Pancreatic Ductal Adenocarcinoma. , 2012, Surgical oncology.

[79]  Michael J Heller,et al.  Integrated Analysis of Exosomal Protein Biomarkers on Alternating Current Electrokinetic Chips Enables Rapid Detection of Pancreatic Cancer in Patient Blood. , 2018, ACS nano.

[80]  M. Giovannini Endoscopic Ultrasound Elastography , 2011, Pancreatology.

[81]  R H Hruban,et al.  Pancreatic Intraepithelial Neoplasia: A New Nomenclature and Classification System for Pancreatic Duct Lesions , 2001, The American journal of surgical pathology.

[82]  E. Nakakura,et al.  Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. , 2017, Journal of the National Comprehensive Cancer Network : JNCCN.

[83]  George A Calin,et al.  Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. , 2014, Cancer cell.

[84]  C. Fernández‐del Castillo,et al.  Preoperative evaluation and management of the pancreatic head mass , 2013, Journal of surgical oncology.

[85]  M. Giovannini,et al.  Endoscopic ultrasound elastography for evaluation of lymph nodes and pancreatic masses: a multicenter study. , 2009, World journal of gastroenterology.

[86]  H. Risch,et al.  Exosomes: potential for early detection in pancreatic cancer. , 2016, Future oncology.

[87]  M. Zöller,et al.  Exosomal tumor microRNA modulates premetastatic organ cells. , 2013, Neoplasia.

[88]  S. Kourembanas Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. , 2015, Annual review of physiology.

[89]  S. Melo,et al.  Exosomes in cancer: Use them or target them? , 2017, Seminars in cell & developmental biology.

[90]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[91]  M. Zali,et al.  Diagnostic potency of EUS-guided FNA for the evaluation of pancreatic mass lesions , 2016, Endoscopic ultrasound.

[92]  A. Molinari,et al.  Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells* , 2009, The Journal of Biological Chemistry.

[93]  C. Coch,et al.  Exosomes as nucleic acid nanocarriers. , 2013, Advanced drug delivery reviews.

[94]  N. Machado,et al.  Intraductal Papillary Mucinous Neoplasm of Pancreas , 2015, North American journal of medical sciences.

[95]  S. Melo,et al.  Quantitative Analysis of Precursors MicroRNAs and Their Respective Mature MicroRNAs in Cancer Exosomes Overtime. , 2018, Methods in molecular biology.

[96]  Vikesh K. Singh,et al.  Advances in Biomedical Imaging, Bioengineering, and Related Technologies for the Development of Biomarkers of Pancreatic Disease: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Biomedical Imaging and Bioengineering Workshop , 2015, Pancreas.

[97]  A. Masamune,et al.  Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. , 2018, Biochemical and biophysical research communications.

[98]  G. Karmazanovsky,et al.  Pancreatic head cancer: accuracy of CT in determination of resectability , 2005, Abdominal Imaging.

[99]  M. Kimmey,et al.  Early Diagnosis and Treatment of Pancreatic Dysplasia in Patients with a Family History of Pancreatic Cancer , 1999, Annals of Internal Medicine.

[100]  S. Hanash,et al.  High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[101]  Christine A Iacobuzio-Donahue,et al.  Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays. , 2006, Cancer research.

[102]  Giovanni Parmigiani,et al.  PancPRO: risk assessment for individuals with a family history of pancreatic cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[103]  G. Rice,et al.  Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression , 2016, Oncotarget.

[104]  W. Schlosser,et al.  Ca 19-9 serum course and prognosis of pancreatic cancer , 1996, International journal of pancreatology : official journal of the International Association of Pancreatology.

[105]  E. O’Reilly,et al.  Biomarker-Based Therapy in Pancreatic Ductal Adenocarcinoma: An Emerging Reality? , 2017, Clinical Cancer Research.

[106]  V. LeBleu,et al.  Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer , 2017, Cancer biology & therapy.

[107]  L. Wood,et al.  Pathology and Molecular Genetics of Pancreatic Neoplasms , 2012, Cancer journal.

[108]  E. Dimagno,et al.  Clinical and pathologic correlation of 84 mucinous cystic neoplasms of the pancreas: can one reliably differentiate benign from malignant (or premalignant) neoplasms? , 2000, Annals of surgery.

[109]  M. Takigawa,et al.  Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes , 2014, Journal of Cell Communication and Signaling.

[110]  R. Edwards,et al.  Elevated tumour marker CA19-9: clinical interpretation and influence of obstructive jaundice. , 2000, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[111]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[112]  Christian Pilarsky,et al.  Glypican-1 identifies cancer exosomes and detects early pancreatic cancer , 2015, Nature.

[113]  Lianfang Zheng,et al.  Extracellular vesicles as mediators of the progression and chemoresistance of pancreatic cancer and their potential clinical applications , 2018, Molecular Cancer.

[114]  A. Jemal,et al.  Cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

[115]  J. Habermann,et al.  Serum biomarkers for improved diagnostic of pancreatic cancer: a current overview , 2011, Journal of Cancer Research and Clinical Oncology.

[116]  P. Spellman,et al.  Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy , 2011, Nature Medicine.

[117]  Y. Takeda,et al.  MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma , 2017, Scientific Reports.

[118]  Xi Chen,et al.  Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts , 2015, Cancer science.

[119]  J. Barkin,et al.  Should Patients With a Strong Family History of Pancreatic Cancer Be Screened on a Periodic Basis for Cancer of the Pancreas? , 2009, Pancreas.

[120]  Thomas Howard,et al.  Comparison of Endoscopic Ultrasonography and Multidetector Computed Tomography for Detecting and Staging Pancreatic Cancer , 2004, Annals of Internal Medicine.

[121]  D. Aust,et al.  Precursor Lesions for Sporadic Pancreatic Cancer: PanIN, IPMN, and MCN , 2014, BioMed research international.

[122]  Wing Hung Wong,et al.  Inferring Loss-of-Heterozygosity from Unpaired Tumors Using High-Density Oligonucleotide SNP Arrays , 2006, PLoS Comput. Biol..

[123]  J. L. Noia Últimos avances sobre los tumores pancreáticos , 2011 .

[124]  Jen Jen Yeh,et al.  Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma , 2015, Nature Genetics.

[125]  A. Kallioniemi,et al.  Pancreatic adenocarcinoma—Genetic portrait from chromosomes to microarrays , 2006, Genes, chromosomes & cancer.

[126]  Junfeng Shi,et al.  A signal-amplifiable biochip quantifies extracellular vesicle-associated RNAs for early cancer detection , 2017, Nature Communications.

[127]  M. Eloubeidi,et al.  Pancreatico-biliary endoscopic ultrasound: a systematic review of the levels of evidence, performance and outcomes. , 2012, World journal of gastroenterology.

[128]  C. Iacobuzio-Donahue,et al.  Pancreatic cancer biology and genetics from an evolutionary perspective , 2016, Nature Reviews Cancer.

[129]  J. Kench,et al.  Whole genomes redefine the mutational landscape of pancreatic cancer , 2015, Nature.

[130]  M. Goggins,et al.  Pancreatic cancer: Classifying pancreatic cancer using gene expression profiling , 2015, Nature Reviews Gastroenterology &Hepatology.

[131]  M. Zöller Pancreatic cancer diagnosis by free and exosomal miRNA. , 2013, World journal of gastrointestinal pathophysiology.

[132]  D. Brenner,et al.  Computed tomography--an increasing source of radiation exposure. , 2007, The New England journal of medicine.

[133]  S. Agelaki,et al.  What's new on circulating tumor cells? A meeting report , 2010, Breast Cancer Research.

[134]  Raghu Kalluri,et al.  Exosomes Facilitate Therapeutic Targeting of Oncogenic Kras in Pancreatic Cancer , 2017, Nature.

[135]  S Hanash,et al.  Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[136]  Xingjun Guo,et al.  miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1 , 2016, Oncotarget.

[137]  Zhe Zhang,et al.  Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. , 2012, Gastroenterology.

[138]  G. Raposo,et al.  Extracellular vesicles shuffling intercellular messages: for good or for bad. , 2015, Current opinion in cell biology.

[139]  Damon H. May,et al.  Protein alterations associated with pancreatic cancer and chronic pancreatitis found in human plasma using global quantitative proteomics profiling. , 2011, Journal of proteome research.

[140]  H. Pitt,et al.  CA 19-9 in pancreatic cancer. , 1998, Surgical oncology clinics of North America.

[141]  Ri-sheng Que,et al.  Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma , 2013, World Journal of Surgical Oncology.

[142]  H. Mulcahy,et al.  Detection of Circulating Tumour DNA in the Blood (Plasma/Serum) of Cancer Patients , 2004, Cancer and Metastasis Reviews.

[143]  M. Hidalgo Pancreatic cancer. , 2010, The New England journal of medicine.

[144]  Bin Zhou,et al.  Early detection of pancreatic cancer: Where are we now and where are we going? , 2017, International journal of cancer.

[145]  R. Gibbs,et al.  Genomic analyses identify molecular subtypes of pancreatic cancer , 2016, Nature.

[146]  D. Mukhopadhyay,et al.  Pancreatic Cancer–Derived Exosomes Cause Paraneoplastic β-cell Dysfunction , 2014, Clinical Cancer Research.

[147]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[148]  W. Perman,et al.  Diffusion-Weighted Magnetic Resonance Imaging of the Pancreas , 2009, Topics in magnetic resonance imaging : TMRI.

[149]  L. Diaz,et al.  Liquid biopsies: genotyping circulating tumor DNA. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[150]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[151]  Christine A Iacobuzio-Donahue,et al.  Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project , 2011, Gut.

[152]  M. Canto Screening and surveillance approaches in familial pancreatic cancer. , 2008, Gastrointestinal endoscopy clinics of North America.

[153]  Eun Sun Lee,et al.  Imaging diagnosis of pancreatic cancer: a state-of-the-art review. , 2014, World journal of gastroenterology.

[154]  C. Robles-Medranda Confocal endomicroscopy: Is it time to move on? , 2016, World journal of gastrointestinal endoscopy.

[155]  J. Solassol,et al.  Circulating Cell Free Tumor DNA Detection as a Routine Tool for Lung Cancer Patient Management , 2017, International journal of molecular sciences.

[156]  S. Melo,et al.  Exosomes and Immune Response in Cancer: Friends or Foes? , 2018, Front. Immunol..

[157]  R. Setterquist,et al.  Methods for the extraction and RNA profiling of exosomes. , 2013, World journal of methodology.