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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, and reliable prognostic biomarkers are urgently needed to guide risk stratification and treatment. CD74 has been implicated in tumor progression, invasion, and pro-inflammatory signaling in various cancers. This systematic review and meta-analysis aimed to evaluate the association between CD74 expression and key clinicopathological features and survival outcomes in patients with PDAC. A systematic literature search was conducted in PubMed, Web of Science, and Scopus to identify eligible studies reporting on CD74 expression in PDAC tissues (PROSPERO: CRD420261402709). Studies were selected following the PRISMA 2020 guidelines. The methodological quality of the included studies was assessed using the QUIPS tool. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the associations between CD74 expression and perineural invasion (PNI), lymphatic invasion, lymph node metastasis (pN), vascular permeation, pTNM stage, and overall survival. Statistical analyses were performed using Review Manager v5.4. DerSimonian\u2013Laird random-effects models were applied as sensitivity analysis for every outcome, with Mantel\u2013Haenszel fixed-effects models as the primary analysis according to the level of heterogeneity, which was quantified using the I2 statistic. A total of 83 records were initially identified, of which five studies met the inclusion criteria and were included in the quantitative synthesis. CD74-positive expression was significantly associated with an increased risk of perineural invasion (four cohorts, 351 patients; OR = 3.69; 95% CI: 2.27\u20135.99; p &lt; 0.00001; I2 = 0%), lymphatic invasion (four cohorts, 351 patients; OR = 2.05; 95% CI: 1.21\u20133.46; p = 0.007; I2 = 0%), and lymph node metastasis (four cohorts, 462 patients; OR = 1.94; 95% CI: 1.27\u20132.96; p = 0.002; I2 = 0%). A non-significant trend toward increased vascular permeation (three cohorts, 181 patients; OR = 1.99; 95% CI: 0.84\u20134.68; p = 0.12; I2 = 0%) and advanced pTNM stage (three cohorts, 284 patients; OR = 1.62; 95% CI: 0.93\u20132.82; p = 0.09; I2 = 0%) was also observed. Importantly, CD74 positivity was significantly associated with worse overall survival (three cohorts, 293 patients; HR = 2.04, 95% CI: 1.45\u20132.88; p &lt; 0.00001; I2 = 0%). This analysis was structured into two subgroups: HR = 2.21 (95% CI: 1.50\u20133.25) in the two cohorts contributing multivariable-adjusted, immunohistochemistry-based estimates, and HR = 1.52 (95% CI: 0.72\u20133.21) in the single cohort contributing a univariable estimate reconstructed from transcript-level data, with no significant difference between the subgroups (p = 0.38). Because the estimated between-study variance was zero for every outcome, random-effects estimates were almost identical to the fixed-effects estimates throughout. As the pooled survival estimate combines adjusted with unadjusted estimates, it describes a prognostic association rather than established independent prognostic value. This meta-analysis demonstrates that elevated CD74 expression in PDAC is significantly associated with perineural invasion, lymphatic invasion, lymph node metastasis, and poorer overall survival, supporting an association with an adverse prognostic. Because the evidence base comprises few retrospective cohorts that used different, non-standardized thresholds to define CD74 positivity and different definitions of several outcomes, these findings should be regarded as hypothesis-generating: they identify CD74 as a candidate for prospective validation and mechanistic investigation rather than as an established biomarker for risk stratification or therapeutic decision-making. Further large-scale prospective studies are warranted to validate these results and explore the clinical utility of CD74-targeted strategies.<\/jats:p>","DOI":"10.3390\/ijms27198488","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:09:08Z","timestamp":1790161748000},"page":"8488","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic and Clinicopathological Significance of CD74 Expression in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"27","author":[{"given":"Ioan Alexandru","family":"Vacariu","sequence":"first","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Mihaela","family":"Ilie","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Georges Francois Leclerc Cancer Center, 21079 Dijon, France"},{"name":"Cancer Biology Transfer Platform, Georges Francois Leclerc Cancer Center, 21079 Dijon, France"},{"name":"INSERM UMR 1231, Center for Translational and Molecular Medicine (CTM), University of Burgundy Europe, 21079 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristin Constantin","family":"Vere","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1374-276X","authenticated-orcid":false,"given":"Adina","family":"Turcu-Stiolica","sequence":"additional","affiliation":[{"name":"Biostatistics Department, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"},{"name":"Health Economics and Outcomes Research Department, Faculty of Medicine, \u201cIuliu Ha\u0163ieganu\u201d University of Medicine and Pharmacy Cluj-Napoca, Victor Babes Street No. 8, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Manthopoulou","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, General Hospital of Nea Ionia \u201cKonstantopouleio-Patision\u201d, 3\u20135 Theodorou Konstantopoulou Street, Nea Ionia, 14233 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-4294","authenticated-orcid":false,"given":"Mihai Radu","family":"Pahomeanu","sequence":"additional","affiliation":[{"name":"Internal Medicine and Gastroenterology Department, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Internal Medicine and Gastroenterology Department, University Emergency Hospital of Bucharest, 050098 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugen","family":"Tcaciuc","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nicolae Testemitanu State University of Medicine and Pharmacy, MD-2004 Chisinau, Moldova"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian Constantin","family":"Toma","sequence":"additional","affiliation":[{"name":"General Surgery Department, Dr. Constantin Andreoiu, Ploiesti County Emergency Hospital, 100097 Ploiesti, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1984-791X","authenticated-orcid":false,"given":"Bogdan Silviu","family":"Ungureanu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Juthani, R., and Manne, A. (2025). Blood-based biomarkers in pancreatic ductal adenocarcinoma: Developments over the last decade and what holds for the future\u2014A review. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1555963"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sun, Y., Jiang, W., Liao, X., and Wang, D. (2024). Hallmarks of perineural invasion in pancreatic ductal adenocarcinoma: New biological dimensions. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1421067"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s12032-024-02564-6","article-title":"Exploring the role of antigen-presenting cancer-associated fibroblasts and CD74 on the pancreatic ductal adenocarcinoma tumor microenvironment","volume":"42","author":"Thomas","year":"2024","journal-title":"Med. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e15122","DOI":"10.1111\/exd.15122","article-title":"The role of macrophage migration inhibitory factor family and CD74 in the pathogenesis of melanoma","volume":"33","author":"Tanese","year":"2024","journal-title":"Exp. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18632\/oncotarget.28341","article-title":"Targeting CD74 in B-cell non-Hodgkin lymphoma with the antibody\u2013drug conjugate STRO-001","volume":"14","author":"Li","year":"2023","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hong, W.C., Lee, D.E., Kang, H.W., Kim, M.J., Kim, M., Kim, J.H., Fang, S., Kim, H.J., and Park, J.S. (2023). CD74 promotes a pro-inflammatory tumor microenvironment by inducing S100A8 and S100A9 secretion in pancreatic cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612993"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014A web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1745-6215-8-16","article-title":"Practical methods for incorporating summary time-to-event data into meta-analysis","volume":"8","author":"Tierney","year":"2007","journal-title":"Trials"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"280","DOI":"10.7326\/0003-4819-158-4-201302190-00009","article-title":"Assessing bias in studies of prognostic factors","volume":"158","author":"Hayden","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1158\/1078-0432.CCR-05-1852","article-title":"Establishment of perineural invasion models and analysis of gene expression revealed an invariant chain (CD74) as a possible molecule involved in perineural invasion in pancreatic cancer","volume":"12","author":"Koide","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1245\/s10434-009-0532-3","article-title":"CD74 is a novel prognostic factor for patients with pancreatic cancer receiving multimodal therapy","volume":"16","author":"Nagata","year":"2009","journal-title":"Ann. Surg. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S1499-3872(14)60011-4","article-title":"Effect of CD74 on the prognosis of patients with resectable pancreatic cancer","volume":"13","author":"Zhang","year":"2014","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.canlet.2021.03.016","article-title":"CD74 promotes perineural invasion of cancer cells and mediates neuroplasticity via the AKT\/EGR-1\/GDNF axis in pancreatic ductal adenocarcinoma","volume":"508","author":"Zhang","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.bbamcr.2016.03.026","article-title":"The multifaceted roles of the invariant chain CD74\u2014More than just a chaperone","volume":"1863","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wen, Y., Cai, W., Yang, J., Fu, X., Putha, L., Xia, Q., Windsor, J.A., Phillips, A.R., Tyndall, J.D.A., and Du, D. (2021). Targeting macrophage migration inhibitory factor in acute pancreatitis and pancreatic cancer. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.638950"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1084\/jem.20030286","article-title":"MIF signal transduction initiated by binding to CD74","volume":"197","author":"Leng","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.immuni.2006.08.020","article-title":"CD44 is the signaling component of the macrophage migration inhibitory factor\u2013CD74 receptor complex","volume":"25","author":"Shi","year":"2006","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Farr, L., Ghosh, S., and Moonah, S. (2020). Role of MIF cytokine\/CD74 receptor pathway in protecting against injury and promoting repair. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01273"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12957-016-0797-5","article-title":"Macrophage migration inhibitory factor regulates the expression of VEGF-C through MAPK signal pathways in breast cancer MCF-7 cells","volume":"14","author":"Zhang","year":"2016","journal-title":"World J. Surg. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.3892\/ol.2013.1261","article-title":"Effect of CCR7, CXCR4 and VEGF-C on the lymph node metastasis of human pancreatic ductal adenocarcinoma","volume":"5","author":"Guo","year":"2013","journal-title":"Oncol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E403","DOI":"10.1210\/jc.2010-0417","article-title":"Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways","volume":"95","author":"Veillat","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1517\/13543780903463854","article-title":"Milatuzumab\u2014A promising new immunotherapeutic agent","volume":"19","author":"Berkova","year":"2010","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4155\/fmc.10.281","article-title":"MIF as a disease target: ISO-1 as a proof-of-concept therapeutic","volume":"3","author":"VanPatten","year":"2011","journal-title":"Future Med. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8488\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:25:14Z","timestamp":1790310314000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":24,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198488"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198488","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]}}}