Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-26T21:02:35.816Z Has data issue: false hasContentIssue false
  • English
  • Français

Review of clinical and emerging biomarkers for early diagnosis and treatment management of pancreatic cancer: towards personalised medicine

Published online by Cambridge University Press:  06 April 2021

Ernest Osei Open the ORCID record for Ernest Osei [Opens in a new window] ,
Christabel Oghinan ,
Akua Asare ,
Hillary Ho  and
Solomon Manful
Ernest Osei*
Affiliation:
Department of Medical Physics, Grand River Regional Cancer Centre, Kitchener, ON, Canada Department of Physics and Astronomy, University of Waterloo, Waterloo, ON, Canada Department of Systems Design Engineering, University of Waterloo, Waterloo, ON, Canada Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ONCanada
Christabel Oghinan
Affiliation:
Department of Applied Health Sciences, Brock University, St. Catherine, ON, Canada
Akua Asare
Affiliation:
Department of General Science, Brock University, St. Catherine, ON, Canada
Hillary Ho
Affiliation:
Department of Physics and Astronomy, University of Waterloo, Waterloo, ON, Canada
Solomon Manful
Affiliation:
Department of Applied Health Sciences, Brock University, St. Catherine, ON, Canada
*
Author for correspondence: Ernest Osei, Department of Medical Physics, Grand River Regional Cancer Centre, Kitchener, ON, Canada. Tel: (519) 749-4300. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Background:

Pancreatic cancer is the 12th most commonly diagnosed cancer and the 3rd leading cause of cancer mortality and accounts for approximately 2·7% of all newly diagnosed cancer cases and 6·4% of all cancer mortalities in Canada. It has a very poor survival rate mainly due to the difficulty of detecting the disease at an early stage. Consequently, in the advancement of disease management towards the concept of precision medicine that takes individual patient variabilities into account, several investigators have focused on the identification of effective clinical biomarkers with high specificity and sensitivity, capable of early diagnosis of symptomatic patients and early detection of the disease in asymptomatic individuals at high risk for developing pancreatic cancer.

Materials and methods:

We searched several databases from August to December 2020 for relevant studies published in English between 2000 and 2020 and reporting on biomarkers for the management of pancreatic cancer. In this narrative review paper, we describe 13 clinical and emerging biomarkers for pancreatic cancers used in screening for early detection and diagnosis, to identify patients’ risk for metastatic disease and subsequent relapse, to monitor patient response to specific treatment and to provide clinicians the possibility of prospectively identifying groups of patients who will benefit from a particular treatment.

Conclusions:

Current and emerging biomarkers for pancreatic cancer with high specificity and sensitivity has the potential to account for individual patient variabilities, for early detection of disease before the onset of metastasis to improve treatment outcome and patients’ survival, help screen high-risk populations, predict prognosis, provide accurate information of patient response to specific treatment and improve patients monitoring during treatment. Thus, the future holds promise for the use of effective clinical biomarkers or a panel of biomarkers for personalised patient-specific targeted medicine for pancreatic cancer.

Keywords

biomarkerspancreatic cancerpersonalised treatmentserumtargeted medicine
Type
Literature Review
Information
Journal of Radiotherapy in Practice , Volume 21 , Issue 3 , September 2022 , pp. 421 - 433
Check for updates
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Canadian Cancer Statistics Advisory Committee. Canadian Cancer Statistics 2019. 2019; Available at: cancer.ca/Canadian-Cancer-Statistics-2019-EN. Accessed on 11th August 2020.Google Scholar
Brenner, D R, Weir, H K, Demers, A A et al. Projected estimates of cancer in Canada in 2020. Canad Med Assoc J (CMAJ) 2020; 192 (9): E199–E205.CrossRefGoogle ScholarPubMed
Haeberle, L, Esposito, I. Pathology of pancreatic cancer. Transl Gastroenterol Hepatol 2019; 4: 50.CrossRefGoogle ScholarPubMed
Takayama, R, Nakagawa, H, Sawaki, A et al. Serum tumor antigen REG4 as a diagnostic biomarker in pancreatic ductal adenocarcinoma. J Gastroenterol 2010; 45 (1): 52–59.CrossRefGoogle ScholarPubMed
Rückert, F, Pilarsky, C, Grützmann, R. Serum Tumor Markers in Pancreatic Cancer—Recent Discoveries. Cancers 2010; 2 (2): 1107–1124.CrossRefGoogle ScholarPubMed
Bergquist, J R, Puig, C A, Shubert, C R et al. Carbohydrate Antigen 19–9 Elevation in Anatomically Resectable, Early-Stage Pancreatic Cancer Is Independently Associated with Decreased Overall Survival and an Indication for Neoadjuvant Therapy: A National Cancer Database Study. J Am Coll Surg 2016; 223 (1): 52–65.CrossRefGoogle Scholar
Mohamed, A, Saad, Y, Saleh, D et al. Can Serum ICAM 1 distinguish pancreatic cancer from chronic pancreatitis? Asian Pac J Cancer Prev 2016; 17 (10): 4671–4675.Google ScholarPubMed
Tempia-Caliera, A A, Horvath, L Z, Zimmermann, A et al. Adhesion molecules in human pancreatic cancer. J Surg Oncol 2002; 79 (2): 93–100.CrossRefGoogle ScholarPubMed
Bausch, D, Thomas, S, Mino-Kenudson, M et al. Plectin-1 as a novel biomarker for pancreatic cancer. Clin Cancer Res 2011; 17 (2): 302–309.CrossRefGoogle ScholarPubMed
Takehara, A, Eguchi, H, Ohigashi, H et al. Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4. Cancer Sci 2006; 97 (11): 1191–1197.CrossRefGoogle ScholarPubMed
Deshwar, A B, Sugar, E, Torto, D et al. Diagnostic intervals and pancreatic ductal adenocarcinoma (PDAC) resectability: a single-center retrospective analysis. Ann Pancreat Cancer 2018; 1: 13. doi: 10.21037/apc.2018.02.01. Epub 2018 Feb 27. PMID: 29683142; PMCID: PMC5909699…CrossRefGoogle ScholarPubMed
Lukács, G, Kovács, Á, Csanádi, M et al. Benefits of timely care in pancreatic cancer: a systematic review to navigate through the contradictory evidence. Cancer Manag Res 2019; 11: 9849–9861. doi: 10.2147/CMAR.S221427. PMID: 31819622; PMCID: PMC6875504.CrossRefGoogle ScholarPubMed
Poruk, K E, Firpo, M A, Adler, D G, Mulvihill, S J. Screening for pancreatic cancer: why, how, and who? Ann Surg 2013; 257 (1): 17–26. doi: 10.1097/SLA.0b013e31825ffbfb. PMID: 22895395; PMCID: PMC4113008.…CrossRefGoogle ScholarPubMed
Gobbi, P G, Bergonzi, M, Comelli, M et al. The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer. Cancer Epidemiol 2013; 37 (2): 186–190. doi: 10.1016/j.canep.2012.12.002. Epub 2013 Jan 29. PMID: 23369450 CrossRefGoogle ScholarPubMed
Ballehaninna, U K, Chamberlain, R S. Serum CA 19–9 as a Biomarker for Pancreatic Cancer—A Comprehensive Review. Indian J Surg Oncol 2011; 2 (2): 88–100.CrossRefGoogle ScholarPubMed
Kim, J, Lee, K T, Lee, J K, Paik, S W, Rhee, J C, Choi, K W. Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population. J Gastroenterol Hepatol 2004; 19 (2): 182–186 CrossRefGoogle Scholar
Bauer, T M, El-Rayes, B F, Li, X et al. Carbohydrate antigen 19–9 is a prognostic and predictive biomarker in patients with advanced pancreatic cancer who receive gemcitabine-containing chemotherapy: a pooled analysis of 6 prospective trials. Cancer 2013; 119 (2): 285–292.CrossRefGoogle ScholarPubMed
Ballehaninna, U K, Chamberlain, R S. The clinical utility of serum CA 19–9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol 2012; 3 (2): 105–119.Google Scholar
Roland, C L, Harken, A H, Sarr, M G, Barnett, C C. ICAM-1 expression determines malignant potential of cancer. Surgery 2007; 141 (6): 705–707.CrossRefGoogle ScholarPubMed
Long, E O. Intercellular Adhesion Molecule 1 (ICAM-1): getting a grip on leukocyte adhesion. J Immunol 2011; 186 (9): 5021–5023.CrossRefGoogle ScholarPubMed
Khaled, Y S, Ammori, B J, Elkord, E. Increased levels of granulocytic myeloid-derived suppressor cells in peripheral blood and tumour tissue of pancreatic cancer patients. J Immunol Res 2014; 2014: 879897–9.CrossRefGoogle ScholarPubMed
Thyagarajan, A, Alshehri, M S A, Miller, K L R, Sherwin, C M, Travers, J B, Sahu, R P. Myeloid-derived suppressor cells and pancreatic cancer: implications in novel therapeutic approaches. Cancers 2019; 11 (11): 1627.CrossRefGoogle ScholarPubMed
Lv, M, Wang, K, Huang, X. Myeloid-derived suppressor cells in hematological malignancies: friends or foes. J Hematol Oncol 2019; 12 (1): 105.CrossRefGoogle ScholarPubMed
Gabrilovich, D I. Myeloid-derived suppressor cells. Cancer Immunol Res 2017; 5 (1): 3–8.CrossRefGoogle ScholarPubMed
Siret, C, Collignon, A, Silvy, F et al. Deciphering the crosstalk between myeloid-derived suppressor cells and regulatory T cells in pancreatic ductal adenocarcinoma. Front Immunol 2020; 10:3070.CrossRefGoogle ScholarPubMed
Markowitz, J, Brooks, T R, Duggan, M C et al. Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease. Cancer Immunol Immunother 2015; 64 (2): 149–159.CrossRefGoogle ScholarPubMed
Gabrilovich, D I, Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9 (3): 162–174.CrossRefGoogle ScholarPubMed
Trovato, R, Fiore, A, Sartori, S et al. Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3. J Immunother Cancer 2019;7 (1): 255.CrossRefGoogle ScholarPubMed
Rajabinejad, M, Salari, F, Gorgin Karaji, A, Rezaiemanesh, A. The role of myeloid-derived suppressor cells in the pathogenesis of rheumatoid arthritis; anti- or pro-inflammatory cells? Artif Cells Nanomed Biotechnol 2019; 47 (1): 4149–4158.CrossRefGoogle ScholarPubMed
Porembka, M R, Mitchem, J B, Belt, B A et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 2012; 61 (9): 1373–1385.CrossRefGoogle ScholarPubMed
Domogatskaya, A, Rodin, S, Tryggvason, K. Functional diversity of laminins. Ann Rev Cell Dev Biol 2012; 28 (1): 523–553.CrossRefGoogle ScholarPubMed
Katayama, M, Sanzen, N, Funakoshi, A, Sekiguchi, K. Laminin gamma 2-chain fragment in the circulation: a prognostic indicator of epithelial tumor invasion. Cancer Res (Chicago, Ill.) 2003; 63 (1): 222–229.Google Scholar
O’Leary, N A, Wright, M W, Brister, J R et al. Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res 2016; 44 (D1): D733–D745.CrossRefGoogle ScholarPubMed
Chan, A, Prassas, I, Dimitromanolakis, A et al. Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer. Clin Cancer Res 2014; 20 (22): 5787–5795.CrossRefGoogle ScholarPubMed
Katayama, M, Funakoshi, A, Sumii, T, Sanzen, N, Sekiguchi, K. Laminin gamma2-chain fragment circulating level increases in patients with metastatic pancreatic ductal cell adenocarcinomas. Cancer Lett 2005; 225 (1): 167.CrossRefGoogle ScholarPubMed
Garg, M, Braunstein, G, Koeffler, H P. LAMC2 as a therapeutic target for cancers. Expert Opin Ther Targets 2014; 18 (9): 979–982.CrossRefGoogle ScholarPubMed
Wang, H, Cai, J, Du, S, Wei, W, Shen, X. LAMC2 modulates the acidity of microenvironments to promote invasion and migration of pancreatic cancer cells via regulating AKT-dependent NHE1 activity. Exp Cell Res 2020; 391 (1): 111984.CrossRefGoogle ScholarPubMed
Takahashi, S, Hasebe, T, Oda, T et al. Cytoplasmic expression of laminin γ2 chain correlates with postoperative hepatic metastasis and poor prognosis in patients with pancreatic ductal adenocarcinoma. Cancer 2002; 94 (6): 1894–1901.CrossRefGoogle ScholarPubMed
Kosanam, H, Prassas, I, Chrystoja, C C et al. Laminin, gamma 2 (LAMC2): a promising new putative pancreatic cancer biomarker identified by proteomic analysis of pancreatic adenocarcinoma tissues. Mol Cell Proteomics 2013; 12 (10): 2820–2832.CrossRefGoogle ScholarPubMed
Uhlen, M, Zhang, C, Lee, S et al. A pathology atlas of the human cancer transcriptome. Science (American Association for the Advancement of Science) 2017; 357 (6352): eaan2507. doi: 10.1126/science.aan2507.Google ScholarPubMed
Lee, J H, Lee, S. The roles of carcinoembryonic antigen in liver metastasis and therapeutic approaches. Gastroenterol Res Pract 2017; 2017: 1–11.Google ScholarPubMed
Meng, Q, Shi, S, Liang, C et al. Diagnostic and prognostic value of carcinoembryonic antigen in pancreatic cancer: a systematic review and meta-analysis. OncoTargets Ther 2017; 10: 4591–4598.CrossRefGoogle ScholarPubMed
Gan, N, Jia, L, Zheng, L. A sandwich electrochemical immunosensor using magnetic DNA nanoprobes for carcinoembryonic antigen. Int J Mol Sci 2011; 12 (11): 7410–7423.CrossRefGoogle ScholarPubMed
Imaoka, H, Mizuno, N, Hara, K et al. Prognostic impact of carcinoembryonic antigen (CEA) on patients with metastatic pancreatic cancer: a retrospective cohort study. Pancreatology 2016; 16 (5): 859–864.CrossRefGoogle ScholarPubMed
Hu, C J, Kaushal, S, Cao, H S T et al. Half-antibody functionalized lipid−polymer hybrid nanoparticles for targeted drug delivery to carcinoembryonic antigen presenting pancreatic cancer cells. Mol Pharm 2010; 7 (3): 914–920.CrossRefGoogle ScholarPubMed
Futakawa, N, Kimura, W, Yamagata, S et al. Significance of K-ras mutation and CEA level in pancreatic juice in the diagnosis of pancreatic cancer. J Hep Bil Pancr Surg 2000; 7 (1): 63–71.Google Scholar
Lee, K J, Yi, S W, Chung, M J et al. Serum CA 19–9 and CEA levels as a prognostic factor in pancreatic adenocarcinoma. Yonsei Med J 2013; 54 (3): 643–649.CrossRefGoogle ScholarPubMed
Poruk, K E, Gay, D Z, Brown, K et al. The clinical utility of CA 19–9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med 2013; 13 (3): 340–351.Google ScholarPubMed
Arpino, V, Brock, M, Gill, S E. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol 2015; 44–46: 247–254.CrossRefGoogle ScholarPubMed
Brew, K, Nagase, H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochimica et biophysica acta. Molecular cell research 2010; 1803 (1): 55–71.CrossRefGoogle ScholarPubMed
Stocum, D L. Mechanisms of urodele limb regeneration. Regeneration 2017; 4 (4): 159–200.CrossRefGoogle ScholarPubMed
Crawford, J M, Bioulac-Sage, P, Hytiroglou, P. 1 - Structure, Function, and Responses to Injury. MacSween’s Pathology of the Liver. Seventh Edition ed.: Elsevier Ltd; 2018:1–87.Google Scholar
Poruk, K E, Firpo, M A, Scaife, C L et al. Serum osteopontin and tissue inhibitor of metalloproteinase 1 as diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. Pancreas 2013; 42 (2): 193–197.CrossRefGoogle ScholarPubMed
Prokopchuk, O, Grünwald, B, Nitsche, U et al. Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer. BMC Cancer 2018; 18 (1): 128.CrossRefGoogle ScholarPubMed
D’Costa, Z, Jones, K, Azad, A et al. Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer. Cancer Research 2017; 77 (21): 5952–5962.CrossRefGoogle ScholarPubMed
Kufe, D W. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 2009; 9 (12): 874–885.CrossRefGoogle Scholar
Haridas, D, Ponnusamy, M P, Chugh, S, Lakshmanan, I, Seshacharyulu, P, Batra, S K. MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB J 2014; 28 (10): 4183–4199.CrossRefGoogle ScholarPubMed
Chen, S, Dallas, M R, Balzer, E M, Konstantopoulos, K. Mucin 16 is a functional selectin ligand on pancreatic cancer cells. FASEB J 2012; 26 (3): 1349–1359.CrossRefGoogle ScholarPubMed
Chen, S, Hung, W, Wang, P, Paul, C, Konstantopoulos, K. Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Sci Rep 2013; 3 (1): 1870.CrossRefGoogle ScholarPubMed
Kaur, S, Kumar, S, Momi, N, Sasson, A R, Batra, S K. Mucins in pancreatic cancer and its microenvironment. Nat Rev Gastroenterol Hepatol 2013a; 10 (10): 607–620.CrossRefGoogle ScholarPubMed
Haridas, D, Chakraborty, S, Ponnusamy, M P et al. Pathobiological implications of MUC16 expression in pancreatic cancer. PloS one 2011; 6 (10): e26839. doi: 10.1371/journal.pone.0026839.CrossRefGoogle ScholarPubMed
Diamandis, E P, Bast, J, Robert, C, Gold, P, Chu, T M, Magnani, J L. Reflection on the discovery of carcinoembryonic antigen, prostate-specific antigen, and cancer antigens CA125 and CA19–9. Clin Chem (Baltimore, Md.) 2013; 59 (1): 22–31.Google ScholarPubMed
Das, S, Batra, S K. Understanding the Unique Attributes of MUC16 (CA125): potential Implications in Targeted Therapy. Cancer Res (Chicago, Ill.) 2015; 75 (22): 4669–4674.CrossRefGoogle ScholarPubMed
Aithal, A, Rauth, S, Kshirsagar, P et al. MUC16 as a novel target for cancer therapy. Expert Opin Ther Targets 2018; 22 (8): 675–686.CrossRefGoogle ScholarPubMed
Einama, T, Kamachi, H, Nishihara, H et al. Co-expression of mesothelin and CA125 correlates with Unfavorable patient outcome in pancreatic ductal adenocarcinoma. Pancreas 2011; 40 (8): 1276–1282.CrossRefGoogle ScholarPubMed
Castañón, M J, Walko, G, Winter, L, Wiche, G. Plectin–intermediate filament partnership in skin, skeletal muscle, and peripheral nerve. Histochem Cell Biol 2013; 140 (1): 33–53.CrossRefGoogle ScholarPubMed
Konkalmatt, P R, Deng, D, Thomas, S et al. Plectin-1 targeted AAV vector for the molecular imaging of pancreatic cancer. Front Oncol 2013; 3:84.CrossRefGoogle ScholarPubMed
Liu, C G, Maercker, C, Castanon, M J, Hauptmann, R, Wiche, G. Human plectin: organization of the gene, sequence analysis, and chromosome localization (8q24). Proc Natl Acad Sci 1996; 93 (9): 4278–4283.CrossRefGoogle Scholar
Kelly, K A, Bardeesy, N, Anbazhagan, R et al. Targeted Nanoparticles for imaging incipient pancreatic ductal adenocarcinoma. PLoS Med 2008; 5 (4): e85.CrossRefGoogle Scholar
Bausch, D, Mino-Kenudson, M, Fernández-del Castillo, C, Warshaw, A L, Kelly, K A, Thayer, S P. Plectin-1 is a biomarker of malignant pancreatic intraductal papillary mucinous neoplasms. J Gastrointest Surg 2009; 13 (11): 1948–1954.CrossRefGoogle Scholar
Chen, X, Zhou, H, Li, X et al. Plectin-1 targeted dual-modality nanoparticles for pancreatic cancer imaging. EBioMedicine 2018; 30: 129–137.CrossRefGoogle ScholarPubMed
Parikh, A, Stephan, A, Tzanakakis, E S. Regenerating proteins and their expression, regulation, and signaling. BioMol Concepts 2012; 3 (1): 57–70.CrossRefGoogle Scholar
Ma, X, Wu, D, Zhous, S, Wan, F, Lui, H, Xu, X, et al. The pancreatic cancer secreted REG4 promotes macrophage polarization to M2 through EGFR/AKT/CREB pathway. Oncol Rep 2015; 35 (1): 189–196.CrossRefGoogle ScholarPubMed
Legoffic, A, Calvo, E, Cano, C et al. The reg4 gene, amplified in the early stages of pancreatic cancer development, is a promising therapeutic target. PloS one 2009; 4 (10): e7495.CrossRefGoogle ScholarPubMed
Wang, S, Qiu, Y, Bai, B. The expression, regulation, and biomarker potential of glypican-1 in cancer. Front Oncol 2019; 9: 614.CrossRefGoogle ScholarPubMed
Lu, H, Niu, F, Liu, F, Gao, J, Sun, Y, Zhao, X. Elevated glypican-1 expression is associated with an unfavorable prognosis in pancreatic ductal adenocarcinoma. Cancer Med (Malden, MA) 2017; 6 (6): 1181–1191.CrossRefGoogle ScholarPubMed
Qian, J, Tan, Y, Zhang, Y, Yang, Y, Li, X. Prognostic value of glypican-1 for patients with advanced pancreatic cancer following regional intra-arterial chemotherapy. Oncol Lett 2018; 16 (1): 1253–1258.Google ScholarPubMed
Hasan, S, Jacob, R, Manne, U, Paluri, R. Advances in pancreatic cancer biomarkers. Oncol Rev 2019; 13 (1): 410.CrossRefGoogle ScholarPubMed
Melo, S A, Luecke, L B, Kahlert, C et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature (London) 2015; 523 (7559): 177–182.CrossRefGoogle ScholarPubMed
Herreros-Villanueva, M, Bujanda, L. Glypican-1 in exosomes as biomarker for early detection of pancreatic cancer. Ann Transl Med 2016; 4 (4): 64.Google ScholarPubMed
Frampton, A E, Prado, M M, López-Jiménez, E et al. Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden. Oncotarget 2018; 9 (27): 19006–19013.CrossRefGoogle ScholarPubMed
Kleeff, J, Ishiwata, T, Kumbasar, A et al. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J Clin Invest 1998; 102 (9): 1662–1673.CrossRefGoogle ScholarPubMed
Wang, X, Li, Y, Tian, H et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma. BMC Cancer 2014; 14 (1): 578.CrossRefGoogle ScholarPubMed
Koopmann, J, Buckhaults, P, Brown, D A et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res 2004; 10 (7): 2386–2392.CrossRefGoogle ScholarPubMed
Koopmann, J, Rosenzweig, C N W, Zhang, Z et al. Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19–9. Clin Cancer Res 2006; 12 (2): 442–446.CrossRefGoogle ScholarPubMed
Kaur, S, Baine, M J, Guha, S et al. NGAL, MIC-1 and CA19–9 in pancreatic juice: pathobiological implications in diagnosing benign and malignant disease of the pancreas. Pancreas 2013; 42 (3): 494–501.CrossRefGoogle Scholar
Chen, Y, Liu, D, Zhao, Y, Wang, H, Gao, Y, Chen, Y. Diagnostic performance of serum macrophage inhibitory cytokine-1 in pancreatic cancer: a meta-analysis and meta-regression analysis. DNA Cell Biol 2014; 33 (6): 370–377.CrossRefGoogle ScholarPubMed
Bauskin, A R, Brown, D A, Kuffner, T et al. Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. Cancer res 2006; 66 (10): 4983–4986.CrossRefGoogle ScholarPubMed
Kunovsky, L, Tesarikova, P, Kala, Z et al. The use of biomarkers in early diagnostics of pancreatic cancer. Canad J Gastroenterol Hepatol 2018; 2018: 1–10.CrossRefGoogle ScholarPubMed
Agarwal, M K, Hastak, K, Jackson, M W, Breit, S N, Stark, G R, Agarwal, M L. Macrophage inhibitory cytokine 1 mediates a P53-dependent protective arrest in S phase in response to starvation for DNA precursors. Proc Nat Acad Sci 2006; 103 (44): 16278–16283.CrossRefGoogle Scholar
Lambert, J R, Kelly, J A, Shim, M et al. Prostate derived factor in human prostate cancer cells: gene induction by vitamin D via a p53-dependent mechanism and inhibition of prostate cancer cell growth. J Cell Physiol 2006; 208 (3): 566–574.CrossRefGoogle Scholar
Pérez-Torras, S, García-Manteiga, J, Mercadé, E et al. Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (hENT1) enhances gemcitabine response in human pancreatic cancer. Biochem Pharmacol 2008; 76 (3): 322–329.CrossRefGoogle ScholarPubMed
Farrell, J J, Elsaleh, H, Garcia, M et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology (New York, N.Y. 1943) 2009; 136 (1): 187–195.Google ScholarPubMed
Mohelnikova-Duchonova, B, Melichar, B. Human equilibrative nucleoside transporter 1 (hENT1): do we really have a new predictive biomarker of chemotherapy outcome in pancreatic cancer patients? Pancreatology 2013; 13 (6): 558–563.CrossRefGoogle ScholarPubMed
Bird, N T E, Elmasry, M, Jones, R et al. Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy. Br J Surg 2017; 104 (4): 328–336.CrossRefGoogle ScholarPubMed
Morinaga, S, Morinaga, S, Nakamura, Y et al. Immunohistochemical Analysis of Human Equilibrative Nucleoside Transporter-1 (hENT1) predicts survival in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy. Ann Surg Oncol 2012; 19 (S3): 558–564.CrossRefGoogle ScholarPubMed
Spratlin, J L, Mackey, J R. Human Equilibrative Nucleoside Transporter 1 (hENT1) in pancreatic adenocarcinoma: towards individualized treatment decisions. Cancers 2010; 2 (4): 2044–2054.CrossRefGoogle ScholarPubMed
Raffenne, J, Nicolle, R, Puleo, F et al. hENT1 testing in pancreatic ductal adenocarcinoma: are we ready? A multimodal evaluation of hENT1 status. Cancers 2019; 11 (11): 1808.CrossRefGoogle Scholar
Nordh, S, Ansari, D, Andersson, R. hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: a systematic review. World J Gastroenterol 2014; 20 (26): 8482–8490.CrossRefGoogle ScholarPubMed
Greenhalf, W, Ghaneh, P, Neoptolemos, J P et al. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J Nat Cancer Inst 2014; 106 (1): djt347.CrossRefGoogle ScholarPubMed
Pop, V, Seicean, A, Lupan, I, Samasca, G, Burz, C. IL-6 roles – Molecular pathway and clinical implication in pancreatic cancer – A systemic review. Immunol Lett 2017; 181:45–50.CrossRefGoogle ScholarPubMed
Kang, S, Tanaka, T, Narazaki, M, Kishimoto, T. Targeting interleukin-6 signaling in clinic. Immunity (Cambridge, Mass.) 2019; 50 (4): 1007–1023.Google ScholarPubMed
Talar-Wojnarowska, R, Gasiorowska, A, Smolarz, B, Romanowicz-Makowska, H, Kulig, A, Malecka-Panas, E. Clinical Significance of Interleukin-6 (Il-6) gene polymorphism and Il-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig Dis Sci 2009; 54 (3): 683–689.CrossRefGoogle ScholarPubMed
Mroczko, B, Groblewska, M, Gryko, M, Kędra, B, Szmitkowski, M. Diagnostic usefulness of serum interleukin 6 (IL-6) and C-reactive protein (CRP) in the differentiation between pancreatic cancer and chronic pancreatitis. J Clin Lab Anal 2010; 24 (4): 256–261.CrossRefGoogle ScholarPubMed
Goumas, F A, Holmer, R, Egberts, J et al. Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. Int J Cancer 2015; 137 (5): 1035–1046.CrossRefGoogle ScholarPubMed
Błogowski, W, Deskur, A, Budkowska, M et al. Selected cytokines in patients with pancreatic cancer: a preliminary report. PloS one 2014; 9 (5): e97613.CrossRefGoogle ScholarPubMed
Miura, T, Mitsunaga, S, Shimizu, S et al. Characterization of patient with high serum level of IL-6 in advanced pancreatic cancer. Ann Oncol 2013; 24: ix33.CrossRefGoogle Scholar
Mace, TA, Shakya, R, Pitarresi, J R et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 2018; 67 (2): 320–332.CrossRefGoogle ScholarPubMed
Zhang, Y, Yan, W, Collins, M A et al. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res (Chicago, Ill.) 2013; 73 (20): 6359–6374.CrossRefGoogle ScholarPubMed