Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα+ fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8+ T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B-NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.

中文翻译：

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血管生成素样蛋白2信号传导在肿瘤进展和抗肿瘤免疫中的双重功能。

血管生成素样蛋白2（ANGPTL2）是一种与血管生成素同源的分泌糖蛋白。先前的研究表明，肿瘤细胞来源的ANGPTL2具有促进肿瘤的功能。在这里，我们进行了机理分析，比较了在黑色素瘤小鼠同基因模型和易位肾细胞癌（tRCC）小鼠模型中ANGPTL2在癌症进展中的功能。肿瘤细胞中的ANGPTL2缺陷减慢了tRCC进程，支持了促进肿瘤的作用。然而，ANGPTL2的全身消融加速了tRCC进程，支持了肿瘤抑制作用。该同基因模型还证明了ANGPTL2在宿主肿瘤微环境细胞中的肿瘤抑制作用。此外，同基因模型表明，肿瘤微环境中的PDGFRα+成纤维细胞表达丰富的ANGPTL2，并有助于抑制肿瘤。此外，宿主ANGPTL2促进CD8 + T细胞交叉启动并增强抗肿瘤免疫应答。重要的是，ANGPTL2通过PIR-B-NOTCH信号激活树突状细胞，并增强了肿瘤疫苗的功效。我们的研究提供了有力的证据，表明ANGPTL2可以在肿瘤的促进或抑制中发挥作用，这取决于它所表达的细胞类型。