转移
安格普特4
原发性肿瘤
癌症研究
肿瘤进展
Wnt信号通路
生物
串扰
背景(考古学)
癌症
医学
信号转导
基因
细胞生物学
遗传学
古生物学
物理
光学
作者
Corinne Hübers,Ashik Ahmed Abdul Pari,Denise Grieshober,Martin Petkov,Albrecht Schmidt,Tatjana Messmer,Christian Moritz Heyer,Sebastian Schölch,Stephanie S. Kapel,Nicolas Gengenbacher,Mahak Singhal,Benjamin Schieb,Claudine Fricke,Rainer Will,Kim Remans,Jochen Utikal,Christoph Reissfelder,Matthias Schlesner,Kairbaan Hodivala-Dilke,Sander Kersten,Sergij Goerdt,Hellmut G. Augustin,Moritz Felcht
摘要
Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.
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