{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:50:58Z","timestamp":1782449458639,"version":"3.54.5"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005888","name":"Uniwersytet Medyczny w Lodzi","doi-asserted-by":"publisher","award":["503\/1-002-01\/503-11-001"],"award-info":[{"award-number":["503\/1-002-01\/503-11-001"]}],"id":[{"id":"10.13039\/501100005888","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a rising global incidence. Differentiating PDAC from non-malignant pancreatic conditions, particularly chronic pancreatitis (CP), remains challenging due to overlapping clinical and radiological features, highlighting the need for new biomarkers. The best-validated serum biomarker, carbohydrate antigen 19-9 (CA19-9), has limited clinical utility due to its suboptimal sensitivity and specificity. This study aimed to evaluate the diagnostic performance of serum macrophage inhibitory cytokine 1 (GDF15), syncollin (SYCN), and thrombospondin-2 (TSP-2), both alone and in multi-marker panels, for differentiating PDAC from CP and healthy controls (HCs). The selection of these markers was based on prior evidence linking GDF15 to PDAC diagnosis and prognosis, SYCN to pancreatic tissue damage, and TSP-2 to tumor microenvironment remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study included 188 individuals: 78 diagnosed with PDAC, 79 with CP and 31 HCs. PDAC and CP were diagnosed based on clinical, imaging, histopathological, and laboratory findings, and classified according to the 8th TNM classification and the updated Cambridge system, respectively. Serum GDF15, SYCN, and TSP-2 levels were quantified using ELISA. Statistical analyses included group comparisons, correlation testing, and receiver operating characteristic (ROC) curve analysis with assessment of the area under the curve (AUC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>GDF15 and SYCN were significantly elevated in PDAC compared with both CP and HCs, whereas TSP-2 did not differ significantly between those groups. For PDAC vs HCs, GDF15 provided the strongest overall discrimination (AUC\u00a0=\u00a00.86; sensitivity 97%, specificity 71%), while SYCN showed a lower AUC (0.77) but very high specificity (94%). The combined GDF15 + SYCN panel increased AUC to 0.89. For PDAC vs CP, GDF15 achieved moderate diagnostic performance (AUC\u00a0=\u00a00.73), SYCN performed less well (AUC\u00a0=\u00a00.65), and TSP-2 performed near chance (AUC\u00a0=\u00a00.52). Incorporating age and bilirubin in the model improved discrimination between PDAC and CP, yielding a maximum AUC of 0.88. Additionally, positive correlations were observed between SYCN and diabetes, as well as between GDF15 and hyperbilirubinemia, in patients with PDAC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results suggest that GDF15 and SYCN are promising serum biomarkers for PDAC, whereas TSP-2 appears to have limited diagnostic utility.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1866001","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:34:55Z","timestamp":1782448495000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage inhibitory cytokine 1, syncollin and thrombospondin-2 in pancreatic ductal adenocarcinoma and chronic pancreatitis differentiation"],"prefix":"10.3389","volume":"16","author":[{"given":"Michalina","family":"Wieczorek","sequence":"first","affiliation":[{"name":"Department of Digestive Tract Diseases, Medical University of Lodz","place":["Lodz, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz","family":"Wieczorek","sequence":"additional","affiliation":[{"name":"Institute of Information Technology, Lodz University of Technology","place":["Lodz, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Borkowska","sequence":"additional","affiliation":[{"name":"Department of Digestive Tract Diseases, Medical University of Lodz","place":["Lodz, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Malecka-Wojciesko","sequence":"additional","affiliation":[{"name":"Department of Digestive Tract Diseases, Medical University of Lodz","place":["Lodz, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.5114\/ms.2021.112385","article-title":"Pancreatic cancer in Poland: an analysis of incidence, mortality and years of life lost over a period of 22 years","volume":"37","author":"Orlewska","year":"2021","journal-title":"Med Studies\/Studia Medyczne"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/ccr3.2412","article-title":"Bone metastasis as primary presentation of pancreatic ductal adenocarcinoma: a case report and literature review","volume":"7","author":"Argentiero","year":"2019","journal-title":"Clin Case Rep"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1148\/rg.2019190011","article-title":"Chronic pancreatitis or pancreatic tumor? a problem-solving approach","volume":"39","author":"Wolske","year":"2019","journal-title":"Radiographics"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v27.i23.3148","article-title":"Pancreatitis and pancreatic cancer: a case of the chicken or the egg","volume":"27","author":"Umans","year":"2021","journal-title":"World J Gastroenterol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/S2468-1253(19)30416-9","article-title":"Early detection of pancreatic cancer","volume":"5","author":"Pereira","year":"2020","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0000000000001297","article-title":"Serum levels of insulin-like growth factor 1 and insulin-like growth factor-binding protein 2 as a novel biomarker in the detection of pancreatic adenocarcinoma","volume":"54","author":"Wlodarczyk","year":"2020","journal-title":"J Clin Gastroenterol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1159\/000546584","article-title":"Biomarkers for early detection of pancreatic cancer","volume":"41","author":"Bengtsson","year":"2025","journal-title":"Visc Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15235577","article-title":"Gaps and opportunities in the diagnosis and treatment of pancreatic cancer","volume":"15","author":"Caban","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/biom14030364","article-title":"A quest for survival: a review of the early biomarkers of pancreatic cancer and the most effective approaches at present","volume":"14","author":"Bestari","year":"2024","journal-title":"Biomolecules"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10225463","article-title":"Simple serum pancreatic ductal adenocarcinoma (PDAC) protein biomarkers-is there anything in sight","volume":"10","author":"Kapszewicz","year":"2021","journal-title":"J Clin Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2020.188409","article-title":"Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter","volume":"1875","author":"Luo","year":"2021","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.5306\/wjco.v13.i7.630","article-title":"Clinical characteristics and outcomes in carbohydrate antigen 19-9 negative pancreatic cancer","volume":"13","author":"Balaban","year":"2022","journal-title":"World J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2008.12.094","article-title":"How do we interpret an elevated carbohydrate antigen 19-9 level in asymptomatic subjects","volume":"41","author":"Kim","year":"2009","journal-title":"Dig Liver Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3978\/j.issn.2078-6891.2011.021","article-title":"The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal","volume":"3","author":"Ballehaninna","year":"2012","journal-title":"J Gastrointest Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.5114\/pg.2019.83422","article-title":"Diagnostic and therapeutic recommendations in pancreatic ductal adenocarcinoma. Recommendations of the Working Group of the Polish Pancreatic Club","volume":"14","author":"Winter","year":"2019","journal-title":"Gastroenterol Rev"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25137313","article-title":"Macrophages as a source and target of GDF-15","volume":"25","author":"Silva-Bermudez","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-011-6379-0","article-title":"Growth-differentiation factor-15 and functional outcome after acute ischemic stroke","volume":"259","author":"Gr\u00f6schel","year":"2012","journal-title":"J Neurol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2016.255174","article-title":"Growth differentiation factor 15 as a biomarker in cardiovascular disease","volume":"63","author":"Wollert","year":"2017","journal-title":"Clin Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-09-1066","article-title":"Macrophage inhibitory cytokine-1 is increased in individuals before type 2 diabetes diagnosis but is not an independent predictor of type 2 diabetes: the Whitehall II study","volume":"162","author":"Carstensen","year":"2010","journal-title":"Eur J Endocrinol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127518","article-title":"Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma","volume":"10","author":"Liu","year":"2015","journal-title":"PloS One"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M909580199","article-title":"Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression","volume":"275","author":"Li","year":"2000","journal-title":"J Biol Chem"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-578","article-title":"Macrophage inhibitory cytokine 1 (MIC-1\/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma","volume":"14","author":"Wang","year":"2014","journal-title":"BMC Cancer"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80340-2","article-title":"The secretory granule protein syncollin binds to syntaxin in a Ca2(+)-sensitive manner","volume":"90","author":"Edwardson","year":"1997","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.15.11306","article-title":"Analysis of the association of syncollin with the membrane of the pancreatic zymogen granule","volume":"275","author":"An","year":"2000","journal-title":"J Biol Chem"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.5.1545-1554.2002","article-title":"Loss of the zymogen granule protein syncollin affects pancreatic protein synthesis and transport but not secretion","volume":"22","author":"Antonin","year":"2002","journal-title":"Mol Cell Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20041064","article-title":"Syncollin is required for efficient zymogen granule exocytosis","volume":"385","author":"W\u00e4sle","year":"2005","journal-title":"Biochem J"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1021\/pr0499085","article-title":"Comprehensive proteomic analysis of human pancreatic juice","volume":"3","author":"Gr\u00f8nborg","year":"2004","journal-title":"J Proteome Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-13-404","article-title":"Validation of four candidate pancreatic cancer serological biomarkers that improve the performance of CA19.9","volume":"13","author":"Makawita","year":"2013","journal-title":"BMC Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.008599","article-title":"Integrated proteomic profiling of cell line conditioned media and pancreatic juice for the identification of pancreatic cancer biomarkers","volume":"10","author":"Makawita","year":"2011","journal-title":"Mol Cell Proteomics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb09526.x","article-title":"Acinar-ductal-carcinoma sequence in transforming growth factor-alpha transgenic mice","volume":"880","author":"Schmid","year":"1999","journal-title":"Ann N Y Acad Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.15.5401-5408.2003","article-title":"Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling","volume":"23","author":"Lopes","year":"2003","journal-title":"Mol Cell Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7486-z","article-title":"Thrombospondins in cancer","volume":"65","author":"Kazerounian","year":"2008","journal-title":"Cell Mol Life Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.11.2631","article-title":"Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism","volume":"20","author":"Hawighorst","year":"2001","journal-title":"EMBO J"},{"key":"B34","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1186\/s12935-022-02622-x","article-title":"Thrombospondin-2 acts as a bridge between tumor extracellular matrix and immune infiltration in pancreatic and stomach adenocarcinomas: an integrative pan-cancer analysis","volume":"22","author":"Liao","year":"2022","journal-title":"Cancer Cell Int"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21388","article-title":"The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more \"personalized\" approach to cancer staging","volume":"67","author":"Amin","year":"2017","journal-title":"CA Cancer J Clin"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1136\/gut.25.7.756","article-title":"Classification of pancreatitis","volume":"25","author":"Sarner","year":"1984","journal-title":"Gut"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-006-1945-4","article-title":"The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease","volume":"42","author":"Schneider","year":"2007","journal-title":"J Gastroenterol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1385005","article-title":"S3 guideline for chronic pancreatitis - diagnosis, classification and therapy for the radiologist","volume":"186","author":"Schreyer","year":"2014","journal-title":"Rofo"},{"key":"B39","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s12885-019-5385-y","article-title":"Appraising growth differentiation factor 15 as a promising biomarker in digestive system tumors: a meta-analysis","volume":"19","author":"Wang","year":"2019","journal-title":"BMC Cancer"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/5162541","article-title":"Association between circulating growth differentiation factor 15 and cirrhotic primary biliary cholangitis","volume":"2020","author":"Li","year":"2020","journal-title":"BioMed Res Int"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1053\/ejso.1999.0925","article-title":"Elevated tumour marker CA19-9: clinical interpretation and influence of obstructive jaundice","volume":"26","author":"Mann","year":"2000","journal-title":"Eur J Surg Oncol"},{"key":"B42","article-title":"Elevated serum level of carbohydrate antigen 19-9 in benign biliary stricture diseases can reduce its value as a tumor marker","volume":"7","author":"Lin","year":"2014","journal-title":"Int J Clin Exp Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1186\/s12885-021-08204-w","article-title":"Dynamic change of serum CA19-9 levels in benign and Malignant patients with obstructive jaundice after biliary drainage and new correction formulas","volume":"21","author":"Zhao","year":"2021","journal-title":"BMC Cancer"},{"key":"B44","article-title":"Adjusted carbohydrate antigen 19-9. Correlation with histological grade in pancreatic adenocarcinoma","volume":"25","author":"Ortiz-Gonz\u00e1lez","year":"2005","journal-title":"Anticancer Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2174\/138620705774962535","article-title":"Peptidomics biomarker discovery in mouse models of obesity and type 2 diabetes","volume":"8","author":"Budde","year":"2005","journal-title":"Comb Chem High Throughput Screen"},{"key":"B46","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1677\/joe.1.05934","article-title":"Intragranular targeting of syncollin, but not a syncollinGFP chimera, inhibits regulated insulin exocytosis in pancreatic beta-cells","volume":"185","author":"Hays","year":"2005","journal-title":"J Endocrinol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010386","article-title":"Consistent DNA hypomethylations in prostate cancer","volume":"24","author":"Ara\u00fazo-Bravo","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B48","doi-asserted-by":"publisher","first-page":"S","DOI":"10.1016\/S0016-5085(25)02537-5","article-title":"Su1177: macrophage inhibitory cytokine-1 and syncollin may be useful in pancreatic adenocarcinoma (PDAC) differentiation from chronic pancreatitis (CP)","volume":"169","author":"Wieczorek","year":"2025","journal-title":"Gastroenterology"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215693","article-title":"SULF2 enhances GDF15-SMAD axis to facilitate the initiation and progression of pancreatic cancer","volume":"538","author":"He","year":"2022","journal-title":"Cancer Lett"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1038\/s41598-018-19392-0","article-title":"Pancreatic gene expression during recovery after pancreatitis reveals unique transcriptome profiles","volume":"8","author":"Boggs","year":"2018","journal-title":"Sci Rep"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aah5583","article-title":"Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers","volume":"9","author":"Kim","year":"2017","journal-title":"Sci Transl Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-018-07109-6","article-title":"Thrombospondin-2 is a highly specific diagnostic marker and is associated with prognosis in pancreatic cancer","volume":"26","author":"Peng","year":"2019","journal-title":"Ann Surg Oncol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2005.08.008","article-title":"Induced thrombospondin expression in the mouse pancreas during pancreatic injury","volume":"38","author":"Neuschwander-Tetri","year":"2006","journal-title":"Int J Biochem Cell Biol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17111891","article-title":"Changes connected to early chronic pancreatitis and early pancreatic cancer in endoscopic ultrasonography (EUS): Clinical implications","volume":"17","author":"Pawelec","year":"2025","journal-title":"Cancers (Basel)"},{"key":"B55","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1053\/j.gastro.2018.05.023","article-title":"Model to determine risk of pancreatic cancer in patients with new-onset diabetes","volume":"155","author":"Sharma","year":"2018","journal-title":"Gastroenterology"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaf319","article-title":"Pancreatic cancer screening in new-onset and deteriorating diabetes: Preliminary results from the PANDOME study","volume":"111","author":"Frank","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252212159","article-title":"Select endocrine disorders and exosomes in early PDAC diagnosis","volume":"25","author":"Wlodarczyk","year":"2024","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1866001\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:35:01Z","timestamp":1782448501000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1866001\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":57,"alternative-id":["10.3389\/fonc.2026.1866001"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1866001","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]},"article-number":"1866001"}}