The Amino-Terminal Oligomerization Domain Of Angiopoietin-2 Affects Vascular Remodeling, Mammary For Gland Tumor Growth, And Lung Metastasis In Mice

Angiopoietin-2 (ANGPT2) is a context-dependent TIE2 agonistic or antagonistic ligand that induces diverse responses in cancer. Blocking ANGPT2 provides a promising strategy for inhibiting tumor growth and metastasis, yet variable effects of targeting ANGPT2 have complicated drug development. ANGPT2(443) is a naturally occurring, lower oligoineric protein isoform whose expression is increased in cancer. Here, we use a knock-in mouse line (mice expressing Angpt2(443)), a genetic model for breast cancer and metastasis (MMTV-PyMT), a syngeneic melanoma lung colonization model (B16F10), and orthotopic injection of E0771 breast cancer cells to show that alternative forms increase the diversity of Angpt2 function. In a mouse retina model of angiogenesis, expression of Angpt2(443) caused impaired venous development, suggesting enhanced function as a competitive antagonist for Tie2. In mammary gland tumor models, Angpt2(443) differentially affected primary tumor growth and vascularization; these varying effects were associated with Angpt2 protein localization in the endothelium or in the Aroma' extracellular matrix as well as the frequency of Tie2-positive tumor blood vessels. In the presence of metastatic cells, Angpt2(443) promoted destabilization of pulmonary vasculature and lung metastasis. In vitro, ANGPT2(443) was susceptible to proteolytical cleavage, resulting in a monomeric ligand (ANGPT2(DAP)) that inhibited ANGPTI- or ANGPT4-induced TIE2 activation but did not bind to alternative ANGPT2 receptor alpha 5 beta 1 integrin. Collectively, these data reveal novel roles for the ANGPT2 N-terminal domain in blood vessel remodeling, tumor growth, metastasis, integrin binding, and proteolytic regulation.Significance: This study identifies the role of the N-terminal oligomerization domain of angiopoietin-2 in vascular remodeling and lung metastasis and provides new insights into mechanisms underlying the versatile functions of angiopoietin-2 in cancer.