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
The amino-terminal oligomerization domain of angiopoietin-2 affects vascular remodeling, mammary for gland tumor growth, and lung metastasis in mice
|Author:||Kapiainen, Emmi1,2,3; Kihlström, Minna K.1,2,3; Pietilä, Riikka1,2,3;|
1Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 12.1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022022420723
American Association for Cancer Research,
|Publish Date:|| 2021-10-09
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.
|Pages:||129 - 143|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This research was supported by the Academy of Finland grants (to L. Eklund; 251314, 136880, and 310986).
|Academy of Finland Grant Number:||
251314 (Academy of Finland Funding decision)
136880 (Academy of Finland Funding decision)
310986 (Academy of Finland Funding decision)
© 2020 American Association for Cancer Research.