University of Oulu

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.

The amino-terminal oligomerization domain of angiopoietin-2 affects vascular remodeling, mammary for gland tumor growth, and lung metastasis in mice

Saved in:
Author: Kapiainen, Emmi1,2,3; Kihlström, Minna K.1,2,3; Pietilä, Riikka1,2,3;
Organizations: 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
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 12.1 MB)
Persistent link:
Language: English
Published: American Association for Cancer Research, 2021
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.

see all

Series: Cancer research
ISSN: 0008-5472
ISSN-E: 1538-7445
ISSN-L: 0008-5472
Volume: 81
Issue: 1
Pages: 129 - 143
DOI: 10.1158/0008-5472.CAN-19-1904
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
1182 Biochemistry, cell and molecular biology
Funding: This research was supported by the Academy of Finland grants (to L. Eklund; 251314, 136880, and 310986).
Academy of Finland Grant Number: 251314
Detailed Information: 251314 (Academy of Finland Funding decision)
136880 (Academy of Finland Funding decision)
310986 (Academy of Finland Funding decision)
Copyright information: © 2020 American Association for Cancer Research.