The Amino-Terminal Oligomerization Domain of Angiopoietin-2 Affects Vascular Remodeling, Mammary Gland Tumor Growth, and Lung Metastasis in Mice

Abstract Angiopoietin-2 (ANGPT2) is a context-dependent TIE2 agonistic or antagonistic ligand that induces diverse responses in cancer. Blocking ANGPT2 provides promising strategy for inhibiting tumor growth and metastasis, yet variable effects of targeting have complicated drug development. ANGPT2443 naturally occurring, lower oligomeric protein isoform whose expression increased Here, we use knock-in mouse line (mice expressing Angpt2443), genetic model breast cancer metastasis (MMTV-PyMT), syngeneic melanoma lung colonization (B16F10), orthotopic injection E0771 cells to show alternative forms increase the diversity Angpt2 function. In retina angiogenesis, Angpt2443 caused impaired venous development, suggesting enhanced function as competitive antagonist Tie2. mammary gland models, differentially affected primary vascularization; these varying were associated with localization endothelium stromal extracellular matrix well frequency Tie2-positive blood vessels. presence metastatic cells, promoted destabilization pulmonary vasculature metastasis. vitro, was susceptible proteolytical cleavage, resulting monomeric (ANGPT2DAP) inhibited ANGPT1- ANGPT4-induced activation but did not bind receptor α5β1 integrin. Collectively, data reveal novel roles N-terminal domain vessel remodeling, growth, integrin binding, proteolytic regulation. Significance: This study identifies role oligomerization angiopoietin-2 vascular remodeling new insights into mechanisms underlying versatile functions See related commentary by Kamiyama Augustin, p. 35