Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis
Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis
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DOI：
10.1038/s41388-020-01505-7
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发表时间：
2020-10-13
期刊：
影响因子：
8
通讯作者：
Oike, Yuichi
中科院分区：
文献类型：
--
作者：
Horiguchi, Haruki;Kadomatsu, Tsuyoshi;Oike, Yuichi
先前的研究表明，肿瘤细胞衍生的血管生成素样蛋白2（ANGPTL 2）在某些癌症背景下作为肿瘤促进剂发挥作用。然而，我们最近报道，宿主ANGPTL 2也通过增强小鼠肾癌和小鼠同基因模型中树突状细胞介导的CD 8（+）T细胞抗肿瘤免疫应答显示出肿瘤抑制活性。然而，ANGPTL 2介导的肿瘤抑制的潜在机制是复杂的，并且不是众所周知的。在这里，我们研究了ANGPTL 2在化学诱导的肠道肿瘤发生中的肿瘤抑制功能。在实验性小鼠结肠炎相关结肠癌（CAC）模型中，ANGPTL 2缺陷促进了肠道肿瘤的生长;在肠道肿瘤发生过程中，ANGPTL 2缺陷小鼠不仅表现出CD 8（+）T细胞应答的降低，而且表现出CD 4（+）T细胞应答的降低。此外，我们表明基质来源的ANGPTL 2可以激活骨髓免疫应答。值得注意的是，ANGPTL 2通过NF-κ B途径驱动免疫刺激性巨噬细胞的产生，加速CD 4（+）T辅助1（Th 1）细胞活化。这些发现总体上为ANGPTL 2在癌症病理学中的抗肿瘤功能的复杂机制提供了新的见解。
Previous studies show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. However, we recently reported that host ANGPTL2 also shows tumor suppressive activity by enhancing dendritic cell-mediated CD8(+)T cell anti-tumor immune responses in mouse kidney cancer and murine syngeneic models. However, mechanisms underlying ANGPTL2-mediated tumor suppression are complex and not well known. Here, we investigated ANGPTL2 tumor suppressive function in chemically-induced intestinal tumorigenesis. ANGPTL2 deficiency enhanced intestinal tumor growth in an experimental mouse colitis-associated colon cancer (CAC) model.Angptl2-deficient mice also showed a decrease not only in CD8(+)T cell responses but in CD4(+)T cell responses during intestinal tumorigenesis. Furthermore, we show that stroma-derived ANGPTL2 can activate the myeloid immune response. Notably, ANGPTL2 drove generation of immunostimulatory macrophages via the NF-kappa B pathway, accelerating CD4(+)T helper 1 (Th1) cell activation. These findings overall provide novel insight into the complex mechanisms underlying ANGPTL2 anti-tumor function in cancer pathology.