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| Status |
Public on Aug 08, 2017 |
| Title |
Gemcitabine induced TIMP-1 attenuates therapy response and promotes tumour growth and liver metastasis in pancreatic cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC) but patients often show poor or complete lack of response to this agent. Molecular markers downstream of Gemcitabine treatment in pre-clinical models may provide an insight into resistance mechanisms. We identified potential secretory biomarkers of Gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC using cytokine arrays. We validated the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) in primary pancreatic tumours and metastasis using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP-1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increases inflammatory cytokines including TIMP-1 in the KPC mouse model. TIMP-1 is upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. Additionally, we demonstrate that TIMP-1 plays a role in tumour proliferation and angiogenesis, while inhibition resensitises to gemcitabine and radiotherapy. Strikingly, serum TIMP-1 levels support the formation of liver metastasis through the recruitment of immunosuppressive cell populations, such as CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs to the hepatic microenvironment. Gemcitabine treatment results in upregulation of the pro-tumourigenic/pro-metastatic cytokine TIMP-1, which partially explains the therapeutic resistance and poor responses to this therapy in PDAC. Our study provides a rationale for the development and testing of TIMP-1 specific inhibitors in addition to chemo/radiotherapy.
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| Overall design |
Wild-type and TIMP1 knock down PANC1cell lines are compared with in each group six replicates. Wild-type (N=6): PANC1 with a lentiviral integration of the pLKO.1 puro vector. TIMP1 knock down (N=6): PANC1 with a lentiviral integration of pLKO.1 vector containing shRNA against human TIMP1.
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| Contributor(s) |
D'Costa Z, van Stiphout R, O'Neill E, Fokas E |
| Citation(s) |
28765154 |
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| Submission date |
Feb 14, 2017 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Ruud van Stiphout |
| Organization name |
University of Oxford
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| Street address |
Old Road Campus Research Building
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| City |
Oxford |
| ZIP/Postal code |
OX3 7DQ |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA374729 |
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