The amino-terminal oligomerization domain of angiopoietin-2 affects vascular remodeling, mammary for gland tumor growth, and lung metastasis in mice
Kapiainen, Emmi; Kihlström, Minna K.; Pietilä, Riikka; Kaakinen, Mika; Ronkainen, Veli-Pekka; Tu, Hongmin; Heikkinen, Anne; Devarajan, Raman; Miinalainen, Ilkka; Laitakari, Anna; Ansarizadeh, Mohammadhassan; Zhang, Qin; Wei, Gong-Hong; Ruddock, Lloyd; Pihlajaniemi, Taina; Elamaa, Harri; Eklund, Lauri (2020-10-09)
Emmi Kapiainen, Minna K. Kihlström, Riikka Pietilä, Mika Kaakinen, Veli-Pekka Ronkainen, Hongmin Tu, Anne Heikkinen, Raman Devarajan, Ilkka Miinalainen, Anna Laitakari, Mohammadhassan Ansarizadeh, Qin Zhang, Gong-Hong Wei, Lloyd Ruddock, Taina Pihlajaniemi, Harri Elamaa, Lauri Eklund; The Amino-Terminal Oligomerization Domain of Angiopoietin-2 Affects Vascular Remodeling, Mammary Gland Tumor Growth, and Lung Metastasis in Mice. Cancer Res 1 January 2021; 81 (1): 129–143. https://doi.org/10.1158/0008-5472.CAN-19-1904
© 2020 American Association for Cancer Research.
https://rightsstatements.org/vocab/InC/1.0/
https://urn.fi/URN:NBN:fi-fe2022022420723
Tiivistelmä
Abstract
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. ANGPT2₄₄₃ is a naturally occurring, lower oligomeric protein isoform whose expression is increased in cancer. Here, we use a knock-in mouse line (mice expressing Angpt2₄₄₃), 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 Angpt2₄₄₃ caused impaired venous development, suggesting enhanced function as a competitive antagonist for Tie2. In mammary gland tumor models, Angpt2₄₄₃ differentially affected primary tumor growth and vascularization; these varying effects were associated with Angpt2 protein localization in the endothelium or in the stromal extracellular matrix as well as the frequency of Tie2-positive tumor blood vessels. In the presence of metastatic cells, Angpt2₄₄₃ promoted destabilization of pulmonary vasculature and lung metastasis. In vitro, ANGPT2₄₄₃ was susceptible to proteolytical cleavage, resulting in a monomeric ligand (ANGPT2DAP) that inhibited ANGPT1- or ANGPT4-induced TIE2 activation but did not bind to alternative ANGPT2 receptor α5β1 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.
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