Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Cancer Res. 2021 Jan 1;81(1):129-143. doi: 10.1158/0008-5472.CAN-19-1904. Epub 2020 Oct 9.
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 is a naturally occurring, lower oligomeric protein isoform whose expression is increased in cancer. Here, we use a knock-in mouse line (mice expressing Angpt2), a genetic model for breast cancer and metastasis (MMTV-), 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 caused impaired venous development, suggesting enhanced function as a competitive antagonist for Tie2. In mammary gland tumor models, Angpt2 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, Angpt2 promoted destabilization of pulmonary vasculature and lung metastasis. , ANGPT2 was susceptible to proteolytical cleavage, resulting in a monomeric ligand (ANGPT2) 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..
血管生成素-2（ANGPT2）是一种依赖于上下文的 TIE2 激动剂或拮抗剂配体，它在癌症中诱导多种反应。阻断 ANGPT2 为抑制肿瘤生长和转移提供了一种有前途的策略，但靶向 ANGPT2 的效果各不相同，这使得药物开发变得复杂。ANGPT2 是一种天然存在的低聚蛋白同工型，其表达在癌症中增加。在这里，我们使用一种敲入小鼠系（表达 Angpt2 的小鼠）、一种乳腺癌和转移的遗传模型（MMTV-）、一种同源黑色素瘤肺定植模型（B16F10）和 E0771 乳腺癌细胞的原位注射来表明替代形式增加了 Angpt2 功能的多样性。在小鼠视网膜血管生成模型中，ANGPT2 的表达导致静脉发育受损，表明其作为 Tie2 竞争性拮抗剂的功能增强。在乳腺肿瘤模型中，Angpt2 对原发性肿瘤生长和血管生成的影响不同；这些不同的影响与 Angpt2 蛋白在血管内皮或基质细胞外基质中的定位以及 Tie2 阳性肿瘤血管的频率有关。在存在转移细胞的情况下，Angpt2 促进了肺血管的不稳定和肺转移。此外，ANGPT2 易受蛋白水解切割，产生一种单体配体（ANGPT2），它抑制了 ANGPT1 或 ANGPT4 诱导的 TIE2 激活，但不与替代的 ANGPT2 受体α5β1 整联蛋白结合。总之，这些数据揭示了血管生成素-2 N 端结构域在血管重塑、肿瘤生长、转移、整联蛋白结合和蛋白水解调节中的新作用。意义：本研究确定了血管生成素-2 N 端寡聚结构域在血管重塑和肺转移中的作用，并为血管生成素-2 在癌症中的多功能作用的机制提供了新的见解。
