Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer D'Costa Z, Jones K, Azad A, van Stiphout R, Lim SY, Gomes AL, Kinchesh P, Smart SC, Gillies McKenna W, Buffa FM, Sansom OJ, Muschel RJ, O'Neill E & Fokas E Cancer Res. 77, 5952-5962 (2017) Speaker: Jia-Wen Chen (陳佳文) Time: 14:00~15:00, Mar. 14, 2018 Commentator: Dr. Cheung, Chun Hei Antonio (張雋曦老師) Place: Room 601 Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis for overall survival. Gemcitabine (2′, 2′-difluorodeoxycytidine), a fluorinated nucleoside analog, can inhibit cellular DNA synthesis and is widely used in the treatment of many solid tumors including PDAC, but patients often show poor response. Previous studies showed that gemcitabine caused DNA damage induces acute cytokine release, which may contribute to resistance during the course of treatment as well as to treatment failure.1 However, the underlying mechanism to gemcitabine resistance of the PDAC remains largely unexplored. In this study, the authors using cytokine array identified a potential secretory biomarker of gemcitabine resistance in the KPC mouse model of PDAC. They found that treatment of PDAC with gemcitabine led to upregulation of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1). TIMP1 is an inhibitor of the matrix metalloproteinases (MMPs), which are involved in degradation of the extracellular matrix and affect cancer cell metastasis. Differently, TIMP1 can induce cancer cell proliferation, apoptosis, and metastasis.2 Here, TIMP1 was upregulated in the patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions compared to the normal pancreatic tissue. The authors demonstrated the oncogenic role of the TIMP1 in primary pancreatic tumors and metastases both in vitro and in vivo. In addition, they identified the potential pathways downstream of TIMP1 by microarray. Gene annotation reveals enriched gene expression profiles of inflammation, cell adhesion, and chemotaxis in PANC1 TIMP1 knockdown cells. Furthermore, TIMP1 suppression associated with decreased vascular density in the tumor xenografts and liver metastasis, and reduced liver infiltration by immunosuppressive cell populations, followed by reduction of liver metastasis. In summary, the authors reveal that TIMP1 upregulation arise is a resistance mechanism to gemcitabine treatment of pancreatic patients. Combine therapy of TIMP1-specific inhibitors with the conventional chemo/radiotherapy may be considered for PDAC patient treatment. References: 1 Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355-366 (2010). 2 Stetler-Stevenson, W. G. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Science signaling 1, re6-re6 (2008).