癌细胞自主的TRAIL-R信号传导促进KRAS驱动的癌症进展、侵袭和转移。
Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis.
作者信息
von Karstedt Silvia, Conti Annalisa, Nobis Max, Montinaro Antonella, Hartwig Torsten, Lemke Johannes, Legler Karen, Annewanter Franka, Campbell Andrew D, Taraborrelli Lucia, Grosse-Wilde Anne, Coy Johannes F, El-Bahrawy Mona A, Bergmann Frank, Koschny Ronald, Werner Jens, Ganten Tom M, Schweiger Thomas, Hoetzenecker Konrad, Kenessey Istvan, Hegedüs Balazs, Bergmann Michael, Hauser Charlotte, Egberts Jan-Hendrik, Becker Thomas, Röcken Christoph, Kalthoff Holger, Trauzold Anna, Anderson Kurt I, Sansom Owen J, Walczak Henning
机构信息
Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK; Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
出版信息
Cancer Cell. 2015 Apr 13;27(4):561-73. doi: 10.1016/j.ccell.2015.02.014. Epub 2015 Apr 2.
Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.
许多癌症都存在KRAS的致癌突变。目前，对于介导KRAS突变型癌症进展、侵袭和转移的效应分子，人们的了解还不全面。在此，我们鉴定出癌细胞表达的小鼠TRAIL-R，其目前已知的主要功能是诱导细胞凋亡，它是KRAS驱动的癌症进展、侵袭和转移以及体内Rac-1激活的关键介质。在非小细胞肺癌（NSCLC）和胰腺导管腺癌（PDAC）的KRAS驱动的原位模型中，对小鼠TRAIL-R进行癌细胞特异性基因敲除，可通过抑制癌细胞自主迁移、增殖和侵袭来减少肿瘤生长、抑制转移并延长生存期。与此一致的是，TRAIL-R2高表达与人类PDAC侵犯淋巴管以及KRAS突变型结直肠癌患者无转移生存期缩短相关。
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