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000124440 0247_ $$2doi$$a10.1016/j.ccell.2017.05.006
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000124440 1001_ $$0P:(DE-He78)b7267d2eb18316483adbd62e60d9a3ad$$aYuan, Detian$$b0$$eFirst author
000124440 245__ $$aKupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.
000124440 260__ $$aCambridge, Mass.$$bCell Press$$c2017
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000124440 520__ $$aIntrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.
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000124440 7001_ $$0P:(DE-He78)fab123fab286a8dcfd7f622e70598d6a$$aHuang, Shan$$b1
000124440 7001_ $$aBerger, Emanuel$$b2
000124440 7001_ $$aLiu, Lei$$b3
000124440 7001_ $$aGross, Nina$$b4
000124440 7001_ $$aHeinzmann, Florian$$b5
000124440 7001_ $$aRingelhan, Marc$$b6
000124440 7001_ $$0P:(DE-HGF)0$$aConnor, Tracy O$$b7
000124440 7001_ $$0P:(DE-He78)475fbe15f759c77d8668a5031687c5a1$$aStadler, Mira$$b8
000124440 7001_ $$0P:(DE-He78)aa3ff9fc2739d5cb7f822cbd7c1e39c9$$aMeister, Michael$$b9
000124440 7001_ $$aWeber, Julia$$b10
000124440 7001_ $$aÖllinger, Rupert$$b11
000124440 7001_ $$aSimonavicius, Nicole$$b12
000124440 7001_ $$aReisinger, Florian$$b13
000124440 7001_ $$aHartmann, Daniel$$b14
000124440 7001_ $$aMeyer, Rüdiger$$b15
000124440 7001_ $$aReich, Maria$$b16
000124440 7001_ $$aSeehawer, Marco$$b17
000124440 7001_ $$aLeone, Valentina$$b18
000124440 7001_ $$aHöchst, Bastian$$b19
000124440 7001_ $$aWohlleber, Dirk$$b20
000124440 7001_ $$aJörs, Simone$$b21
000124440 7001_ $$aPrinz, Marco$$b22
000124440 7001_ $$aSpalding, Duncan$$b23
000124440 7001_ $$aProtzer, Ulrike$$b24
000124440 7001_ $$aLuedde, Tom$$b25
000124440 7001_ $$aTerracciano, Luigi$$b26
000124440 7001_ $$aMatter, Matthias$$b27
000124440 7001_ $$aLongerich, Thomas$$b28
000124440 7001_ $$aKnolle, Percy$$b29
000124440 7001_ $$aRied, Thomas$$b30
000124440 7001_ $$aKeitel, Verena$$b31
000124440 7001_ $$aGeisler, Fabian$$b32
000124440 7001_ $$aUnger, Kristian$$b33
000124440 7001_ $$aCinnamon, Einat$$b34
000124440 7001_ $$aPikarsky, Eli$$b35
000124440 7001_ $$aHüser, Norbert$$b36
000124440 7001_ $$aDavis, Roger J$$b37
000124440 7001_ $$0P:(DE-He78)ceccc9aed8c6e89c00795bce1f1d83a3$$aTschaharganeh, Darjus Felix$$b38
000124440 7001_ $$aRad, Roland$$b39
000124440 7001_ $$aWeber, Achim$$b40
000124440 7001_ $$0P:(DE-He78)1ba2900406378e069d32db376c7818db$$aZender, Lars$$b41
000124440 7001_ $$aHaller, Dirk$$b42
000124440 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b43$$eLast author
000124440 773__ $$0PERI:(DE-600)2074034-7$$a10.1016/j.ccell.2017.05.006$$gVol. 31, no. 6, p. 771 - 789.e6$$n6$$p771 - 789.e6$$tCancer cell$$v31$$x1535-6108$$y2017
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