{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:10:58Z","timestamp":1790914258630,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["2014-6782"],"award-info":[{"award-number":["2014-6782"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["J. Duitman 016.186.046"],"award-info":[{"award-number":["J. Duitman 016.186.046"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>CCAAT\/enhancer-binding protein delta (C\/EBP\u03b4) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C\/EBP\u03b4 in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties in vitro. Interestingly however, next to C\/EBP\u03b4 expression in tumor cells, C\/EBP\u03b4 is also expressed by cells constituting the tumor microenvironment and by cells comprising the organs and parenchyma. However, the functional relevance of systemic C\/EBP\u03b4 in carcinogenesis remains elusive. Here, we consequently assessed the potential importance of C\/EBP\u03b4 in somatic tissues by utilizing an orthotopic pancreatic cancer model. In doing so, we show that genetic ablation of C\/EBP\u03b4 does not significantly affect primary tumor growth but has a strong impact on metastases; wildtype mice developed metastases at multiple sites, whilst this was not the case in C\/EBP\u03b4-\/- mice. In line with reduced metastasis formation in C\/EBP\u03b4-\/- mice, C\/EBP\u03b4-deficiency also limited tumor cell dissemination in a specific extravasation model. Tumor cell extravasation was dependent on the platelet-activating factor receptor (PAFR) as a PAFR antagonist inhibited tumor cell extravasation in wildtype mice but not in C\/EBP\u03b4-\/- mice. Overall, we show that systemic C\/EBP\u03b4 facilitates pancreatic cancer metastasis, and we suggest this is due to C\/EBP\u03b4-PAFR-dependent tumor cell extravasation.<\/jats:p>","DOI":"10.3390\/biom11081079","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T22:06:48Z","timestamp":1626991608000},"page":"1079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Non-Tumor CCAAT\/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4254-3380","authenticated-orcid":false,"given":"JanWillem","family":"Duitman","sequence":"first","affiliation":[{"name":"Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7285-2155","authenticated-orcid":false,"given":"Leonie","family":"Hartl","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9595-6571","authenticated-orcid":false,"given":"Joris J. T. H.","family":"Roelofs","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6627-3229","authenticated-orcid":false,"given":"Maarten F.","family":"Bijlsma","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"},{"name":"Oncode Institute, 3521 AL Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2149-4068","authenticated-orcid":false,"given":"C. Arnold","family":"Spek","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA. Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14740\/wjon1166","article-title":"Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13014-019-1345-6","article-title":"Pancreatic ductal adenocarcinoma: Biological hallmarks, current status, and future perspectives of combined modality treatment approaches","volume":"14","author":"Orth","year":"2019","journal-title":"Radiat. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"De Vita, F., Ventriglia, J., Febbraro, A., Laterza, M.M., Fabozzi, A., Savastano, B., Petrillo, A., Diana, A., Giordano, G., and Troiani, T. (2016). NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): From clinical trials to clinical practice. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2671-9"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"28545","DOI":"10.1074\/jbc.273.44.28545","article-title":"Biological role of the CCAAT\/enhancer-binding protein family of transcription factors","volume":"273","author":"Xanthopoulos","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1038\/sj.onc.1208393","article-title":"C\/EBP\u03b4 expression in a BCR-ABL-positive cell line induces growth arrest and myeloid differentiation","volume":"24","author":"Gery","year":"2005","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s10911-009-9120-1","article-title":"A mouse mammary gland involution mRNA signature identifies biological pathways potentially associated with breast cancer metastasis","volume":"14","author":"Stein","year":"2009","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4762","DOI":"10.1158\/0008-5472.CAN-03-3619","article-title":"CCAAT\/enhancer-binding protein delta: A molecular target of 1,25-dihydroxyvitamin D3 in androgen-responsive prostate cancer LNCaP cells","volume":"65","author":"Ikezoe","year":"2005","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1002\/jcb.20224","article-title":"CCAAT\/enhancer binding protein \u03b4 (C\/EBP\u03b4) regulation and expression in human mammary epithelial cells: II. Analysis of activating signal transduction pathways, transcriptional, post-transcriptional, and post-translational control","volume":"93","author":"Sivko","year":"2004","journal-title":"J. Cell. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10549-005-9061-3","article-title":"Promoter methylation reduces C\/EBP\u03b4 (CEBPD) gene expression in the SUM-52PE human breast cancer cell line and in primary breast tumors","volume":"95","author":"Tang","year":"2006","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10931","DOI":"10.1073\/pnas.1932980100","article-title":"A neural survival factor is a candidate oncogene in breast cancer","volume":"100","author":"Porter","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3895","DOI":"10.1182\/blood-2006-08-040147","article-title":"The C\/EBP\u03b4 tumor suppressor is silenced by hypermethylation in acute myeloid leukemia","volume":"109","author":"Agrawal","year":"2007","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30919","DOI":"10.1074\/jbc.M804029200","article-title":"Epigenetic silencing of CCAAT\/enhancer-binding protein \u03b4 activity by YY1\/polycomb group\/DNA methyltransferase complex","volume":"283","author":"Ko","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s11060-009-0024-0","article-title":"The cell growth inhibitory transcription factor C\/EBPd is expressed in human meningiomas in association with low histological grade and proliferation index","volume":"97","author":"Barresi","year":"2010","journal-title":"J. Neurooncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.1038\/onc.2016.156","article-title":"The C\/EBP\u03b4 protein is stabilized by estrogen receptor \u03b1 activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer","volume":"35","author":"Balamurugan","year":"2016","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/bjc.2012.308","article-title":"Site-specific CpG methylation in the CCAAT\/enhancer binding protein delta (CEBPD) CpG island in breast cancer is associated with metastatic relapse","volume":"107","author":"Palmieri","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hartl, L., Duitman, J., Aberson, H.L., Chen, K., Dijk, F., Roelofs, J.J.T.H., Dings, M.P.G., Hooijer, G.K.J., Hernanda, P.Y., and Pan, Q. (2020). CCAAT\/Enhancer-Binding Protein Delta (C\/EBP\u03b4): A previously unrecognized tumor suppressor that limits the oncogenic potential of pancreatic ductal adenocarcinoma cells. Cancers, 12.","DOI":"10.3390\/cancers12092546"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BST20110606","article-title":"Novel control of cAMP-regulated transcription in vascular endothelial cells","volume":"40","author":"Milne","year":"2012","journal-title":"Biochem. Soc. Trans."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/BF03402216","article-title":"Transcriptional regulation of the human iNOS gene by IL-1\u03b2 in endothelial cells","volume":"7","author":"Kolyada","year":"2001","journal-title":"Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7212","DOI":"10.4049\/jimmunol.0802971","article-title":"Differential Role for c-Rel and C\/EBP\u03b2\/\u03b4 in TLR-Mediated Induction of Proinflammatory Cytokines","volume":"182","author":"Lu","year":"2009","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chang, L.H., Huang, H.S., Wu, P.T., Jou, I.M., Pan, M.H., Chang, W.C., Wang, D.D.H., and Wang, J.M. (2012). Role of Macrophage CCAAT\/Enhancer Binding Protein Delta in the Pathogenesis of Rheumatoid Arthritis in Collagen-Induced Arthritic Mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045378"},{"key":"ref_22","first-page":"10908","article-title":"Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT\/enhancer binding protein \u03b4","volume":"95","author":"Sterneck","year":"1998","journal-title":"Neurobiology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: Archive for functional genomics data sets\u2014Update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D711","DOI":"10.1093\/nar\/gky964","article-title":"ArrayExpress update\u2014From bulk to single-cell expression data","volume":"47","author":"Athar","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_25","unstructured":"Koster, J. (2021, February 08). R2: Genomics Analysis and Visualization Platform. Available online: http:\/\/r2.amc.nl."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ccell.2017.11.007","article-title":"\u03b22 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer","volume":"33","author":"Renz","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1111\/j.1582-4934.2008.00289.x","article-title":"Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling","volume":"12","author":"Pilarsky","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/path.4411","article-title":"Protease-activated receptor 2 suppresses lymphangiogenesis and subsequent lymph node metastasis in a murine pancreatic cancer model","volume":"234","author":"Shi","year":"2014","journal-title":"J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1002\/ijc.28726","article-title":"Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance","volume":"135","author":"Queiroz","year":"2014","journal-title":"Int. J. Cancer."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ebiom.2019.05.002","article-title":"CCAAT\/enhancer binding protein delta (C\/EBP\u03b4) demonstrates a dichotomous role in tumor initiation and promotion of epithelial carcinoma","volume":"44","author":"Sowamber","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"846387","DOI":"10.1155\/2013\/846387","article-title":"Molecular profiling predicts the existence of two functionally distinct classes of ovarian cancer stroma","volume":"2013","author":"Lili","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s10549-008-9982-8","article-title":"Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer","volume":"114","author":"Casey","year":"2009","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.1182\/blood-2011-03-341222","article-title":"Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain","volume":"118","author":"Horowitz","year":"2011","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1182\/blood-2009-04-217679","article-title":"Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement","volume":"114","author":"Niers","year":"2009","journal-title":"Blood"},{"key":"ref_35","first-page":"2662","article-title":"Augmentation of Tumor Metastasis by Platelet-activating Factor","volume":"56","author":"Im","year":"1996","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9113","DOI":"10.1073\/pnas.1202641109","article-title":"CCAAT\/enhancer-binding protein \u03b4 facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner","volume":"109","author":"Duitman","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1016\/j.ajpath.2012.01.040","article-title":"The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma","volume":"180","author":"Cooper","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"31069","DOI":"10.18632\/oncotarget.5209","article-title":"CEBPD amplification and overexpression in urothelial carcinoma: A driver of tumor metastasis indicating adverse prognosis","volume":"6","author":"Wang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12929-014-0110-2","article-title":"Biological roles of CCAAT\/enhancer-binding protein delta during inflammation","volume":"22","author":"Ko","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"23987","DOI":"10.18632\/oncotarget.4364","article-title":"Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers","volume":"6","author":"Chi","year":"2015","journal-title":"Oncotarget"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e32532","DOI":"10.7554\/eLife.32532","article-title":"C\/EBP\u03b4 drives interactions between human MAIT cells and endothelial cells that are important for extravasation","volume":"7","author":"Lee","year":"2018","journal-title":"Elife"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13046-020-01601-2","article-title":"Liquit biopsy and tumor heterogeneity in metastatic solid tumors: The potentiality of blood samples","volume":"39","author":"Russano","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/978-1-62703-287-2_11","article-title":"Development of orthotopic pancreatic tumor mouse models","volume":"980","author":"Qiu","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1159\/000329413","article-title":"A syngeneic orthotopic murine model of pancreatic adenocarcinoma in the C57\/BL6 mouse using the panc02 and 6606PDA cell lines","volume":"47","author":"Partecke","year":"2011","journal-title":"Eur. Surg. Res."},{"key":"ref_45","first-page":"512","article-title":"Quantitation of Cell Shedding into Efferent Blood of Mammary Adenocarcinoma","volume":"35","author":"Butler","year":"1975","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1158\/1078-0432.CCR-0102-03","article-title":"Clinical Significance of Immunocytochemical Detection of Tumor Cells Using Digital Microscopy in Peripheral Blood and Bone Marrow of Breast Cancer Patients","volume":"10","author":"Pierga","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrc865","article-title":"Dissemination and growth of cancer cells in metastatic sites","volume":"2","author":"Chambers","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhang, F., Liu, L., Zhang, H., and Liu, Z.L. (2018). Effect of Platelet-activating factor on barrier function of ARPE-19 cells. bioRxiv, 398131.","DOI":"10.1101\/398131"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.neuroscience.2018.02.039","article-title":"Effects of Platelet-Activating Factor on Brain Microvascular Endothelial Cells","volume":"377","author":"Brailoiu","year":"2018","journal-title":"Neuroscience"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4137\/CGM.S14501","article-title":"Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis","volume":"7","author":"Hackler","year":"2014","journal-title":"Cancer Growth Metastasis"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/8\/1079\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:33:14Z","timestamp":1760164394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/8\/1079"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,22]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["biom11081079"],"URL":"https:\/\/doi.org\/10.3390\/biom11081079","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,22]]}}}