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- Michael Timaner
- 1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
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- Nitzan Letko-Khait
- 2The Laboratory for Cancer Drug Delivery & Cell Based Technologies, Faculty of Biotechnology and Food Engineering, Technion – Israel Institute of Technology, Haifa, Israel.
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- Ruslana Kotsofruk
- 1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
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- Madeleine Benguigui
- 1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
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- Ofrat Beyar-Katz
- 1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
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- Chen Rachman-Tzemah
- 1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
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- Ziv Raviv
- 1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
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- Tomer Bronshtein
- 2The Laboratory for Cancer Drug Delivery & Cell Based Technologies, Faculty of Biotechnology and Food Engineering, Technion – Israel Institute of Technology, Haifa, Israel.
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- Marcelle Machluf
- 2The Laboratory for Cancer Drug Delivery & Cell Based Technologies, Faculty of Biotechnology and Food Engineering, Technion – Israel Institute of Technology, Haifa, Israel.
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- Yuval Shaked
- 1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.
説明
<jats:title>Abstract</jats:title> <jats:p>Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo. These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10–CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.</jats:p> <jats:p>Significance: These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge. Cancer Res; 78(5); 1253–65. ©2018 AACR.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 78 (5), 1253-1265, 2018-02-28
American Association for Cancer Research (AACR)