The Amino-Terminal Oligomerization Domain of Angiopoietin-2 Affects Vascular Remodeling, Mammary Gland Tumor Growth, and Lung Metastasis in Mice
| Autor: | Lloyd W. Ruddock, Ilkka Miinalainen, Mohammadhassan Ansarizadeh, Anna Laitakari, Mika Kaakinen, Emmi Kapiainen, Qin Zhang, Gong-Hong Wei, Veli-Pekka Ronkainen, Hongmin Tu, Taina Pihlajaniemi, Raman Devarajan, Harri Elamaa, Lauri Eklund, Riikka Pietila, Anne Heikkinen, Minna Kihlström |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Stromal cell Angiogenesis Vascular Remodeling Metastasis Angiopoietin-2 Mice 03 medical and health sciences 0302 clinical medicine Genetic model Angiopoietin-1 medicine Animals Melanoma Integrin binding Neovascularization Pathologic biology Chemistry medicine.disease Angiopoietin receptor Primary tumor 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Angiopoietins Blood vessel remodeling |
| Zdroj: | Cancer Research. 81:129-143 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-19-1904 |
| Popis: | 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. 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. See related commentary by Kamiyama and Augustin, p. 35 |
| Databáze: | OpenAIRE |
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