8 research outputs found
Primary tumorâderived systemic nANGPTL4 inhibits metastasis
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
Preclinical validation of a novel metastasisâinhibiting Tie1 functionâblocking antibody
Abstract The angiopoietin (Ang)âTie pathway has been intensely pursued as candidate secondâgeneration antiâangiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2âtargeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelialâspecific genetic deletion has previously been shown to result in a strong reduction in metastatic growth. Here, we report a novel Tie1 functionâblocking antibody (ABâTie1â39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of ABâTie1â39 strongly impeded systemic metastasis. Furthermore, the administration of ABâTie1â39 in a perioperative therapeutic window led to a significant survival advantage as compared to controlâIgGâtreated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that ABâTie1â39 treatment suppressed tumor cell extravasation at secondary sites. Taken together, the data phenocopy previous genetic work in endothelial Tie1 KO mice and thereby validate ABâTie1â39 as a Tie1 functionâblocking antibody. The study establishes Tie1 as a therapeutic target for metastasis in a perioperative or neoadjuvant setting