Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation
CCAAT/enhancer-binding protein delta (C/EBPδ) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C/EBPδ in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/11/8/1079 |
| _version_ | 1827685827804659712 |
|---|---|
| author | JanWillem Duitman Leonie Hartl Joris J. T. H. Roelofs Maarten F. Bijlsma C. Arnold Spek |
| author_facet | JanWillem Duitman Leonie Hartl Joris J. T. H. Roelofs Maarten F. Bijlsma C. Arnold Spek |
| author_sort | JanWillem Duitman |
| collection | DOAJ |
| description | CCAAT/enhancer-binding protein delta (C/EBPδ) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C/EBPδ in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties in vitro. Interestingly however, next to C/EBPδ expression in tumor cells, C/EBPδ is also expressed by cells constituting the tumor microenvironment and by cells comprising the organs and parenchyma. However, the functional relevance of systemic C/EBPδ in carcinogenesis remains elusive. Here, we consequently assessed the potential importance of C/EBPδ in somatic tissues by utilizing an orthotopic pancreatic cancer model. In doing so, we show that genetic ablation of C/EBPδ 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/EBPδ<sup>-/-</sup> mice. In line with reduced metastasis formation in C/EBPδ<sup>-/-</sup> mice, C/EBPδ-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/EBPδ<sup>-/-</sup> mice. Overall, we show that systemic C/EBPδ facilitates pancreatic cancer metastasis, and we suggest this is due to C/EBPδ-PAFR-dependent tumor cell extravasation. |
| first_indexed | 2024-03-10T08:59:57Z |
| format | Article |
| id | doaj.art-fbc593a762624215b2689b7d8cd45af3 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T08:59:57Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-fbc593a762624215b2689b7d8cd45af32023-11-22T06:54:28ZengMDPI AGBiomolecules2218-273X2021-07-01118107910.3390/biom11081079Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis FormationJanWillem Duitman0Leonie Hartl1Joris J. T. H. Roelofs2Maarten F. Bijlsma3C. Arnold Spek4Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The NetherlandsLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The NetherlandsDepartment of Pathology, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The NetherlandsLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The NetherlandsLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1012 VT Amsterdam, The NetherlandsCCAAT/enhancer-binding protein delta (C/EBPδ) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C/EBPδ in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties in vitro. Interestingly however, next to C/EBPδ expression in tumor cells, C/EBPδ is also expressed by cells constituting the tumor microenvironment and by cells comprising the organs and parenchyma. However, the functional relevance of systemic C/EBPδ in carcinogenesis remains elusive. Here, we consequently assessed the potential importance of C/EBPδ in somatic tissues by utilizing an orthotopic pancreatic cancer model. In doing so, we show that genetic ablation of C/EBPδ 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/EBPδ<sup>-/-</sup> mice. In line with reduced metastasis formation in C/EBPδ<sup>-/-</sup> mice, C/EBPδ-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/EBPδ<sup>-/-</sup> mice. Overall, we show that systemic C/EBPδ facilitates pancreatic cancer metastasis, and we suggest this is due to C/EBPδ-PAFR-dependent tumor cell extravasation.https://www.mdpi.com/2218-273X/11/8/1079CCAAT/enhancer-binding protein deltaCEBPDpancreatic cancerPDACextravasationmetastasis |
| spellingShingle | JanWillem Duitman Leonie Hartl Joris J. T. H. Roelofs Maarten F. Bijlsma C. Arnold Spek Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation Biomolecules CCAAT/enhancer-binding protein delta CEBPD pancreatic cancer PDAC extravasation metastasis |
| title | Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation |
| title_full | Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation |
| title_fullStr | Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation |
| title_full_unstemmed | Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation |
| title_short | Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation |
| title_sort | non tumor ccaat enhancer binding protein delta potentiates tumor cell extravasation and pancreatic cancer metastasis formation |
| topic | CCAAT/enhancer-binding protein delta CEBPD pancreatic cancer PDAC extravasation metastasis |
| url | https://www.mdpi.com/2218-273X/11/8/1079 |
| work_keys_str_mv | AT janwillemduitman nontumorccaatenhancerbindingproteindeltapotentiatestumorcellextravasationandpancreaticcancermetastasisformation AT leoniehartl nontumorccaatenhancerbindingproteindeltapotentiatestumorcellextravasationandpancreaticcancermetastasisformation AT jorisjthroelofs nontumorccaatenhancerbindingproteindeltapotentiatestumorcellextravasationandpancreaticcancermetastasisformation AT maartenfbijlsma nontumorccaatenhancerbindingproteindeltapotentiatestumorcellextravasationandpancreaticcancermetastasisformation AT carnoldspek nontumorccaatenhancerbindingproteindeltapotentiatestumorcellextravasationandpancreaticcancermetastasisformation |