Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer.
Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer.
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DOI：
10.3390/cancers12123631
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发表时间：
2020-12-04
期刊：
影响因子：
5.2
通讯作者：
Ghansah T
中科院分区：
文献类型：
--
作者：
Villalobos-Ayala K;Ortiz Rivera I;Alvarez C;Husain K;DeLoach D;Krystal G;Hibbs ML;Jiang K;Ghansah T
Src Homology 2 （SH2）结构域的肌醇5′-磷酸酶-1 （SHIP-1）是骨髓细胞发育和影响肿瘤免疫功能的必需蛋白和主要调节因子。我们之前发表过SHIP-1调节免疫抑制性骨髓细胞的扩张和功能，这与小鼠胰腺癌的进展有关。本研究表明，在不同的胰腺癌模型中，生物类黄酮芹菜素恢复了SHIP-1的表达，显著增加了杀瘤性肿瘤相关巨噬细胞（TAM），同时显著降低了免疫抑制TAM的百分比，并改善了肿瘤微环境中的抗肿瘤免疫反应。我们的研究结果表明，SHIP-1可能是一个潜在的新的治疗靶点，可以促进肿瘤杀伤TAM的发展，从而帮助治疗胰腺癌。胰腺癌（PC）预后极差，因为炎性肿瘤微环境（TME）中免疫抑制性髓源性抑制细胞（MDSC）和肿瘤相关巨噬细胞（TAM）的扩张，使效应免疫细胞的募集停止，使免疫治疗无效。因此，鉴定可以调节免疫抑制TME的新分子靶标对于PC干预是有必要的。Src同源-2 （SH2）结构域肌醇5′-磷酸酶-1 （SHIP-1）是一种脂质信号蛋白，是髓细胞发育和功能的调节因子。在此，我们使用生物类黄酮芹菜素（API）来减轻不同PC模型的炎症。异位或正位PC野生型小鼠经API处理后，可诱导SHIP-1表达，降低炎性肿瘤源性因子（TDF），增加杀瘤巨噬细胞比例，增强抗肿瘤免疫反应，使肿瘤负荷较载药PC小鼠减轻。相反，ship -1缺陷小鼠表现出肿瘤负荷增加和促肿瘤巨噬细胞比例增加。这些结果进一步支持了SHIP-1表达在胰腺TME中促进促肿瘤巨噬细胞发育的重要性。我们的研究结果表明，增加SHIP-1表达的药物可能为治疗PC提供新的治疗选择。
Src Homology 2 (SH2) domain-containing Inositol 5’-Phosphatase-1 (SHIP-1) is an essential protein and the master regulator of myeloid cell development and function that impacts tumor immunity. We previously published that SHIP-1 regulates the expansion and function of immunosuppressive myeloid cells, which correlated with pancreatic cancer progression in mice. Here, we show that the bioflavonoid Apigenin restored SHIP-1 expression, significantly increased tumoricidal Tumor-Associated Macrophages (TAM) while significantly decreased immunosuppressive TAM percentages and improved anti-tumor immune responses in the tumor microenvironment using different pancreatic cancer models. Our research findings suggest that SHIP-1 may be a potential novel therapeutic target to promote the development of tumoricidal TAM that can assist in the treatment of pancreatic cancer. Pancreatic cancer (PC) has an extremely poor prognosis due to the expansion of immunosuppressive myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the inflammatory tumor microenvironment (TME), which halts the recruitment of effector immune cells and renders immunotherapy ineffective. Thus, the identification of new molecular targets that can modulate the immunosuppressive TME is warranted for PC intervention. Src Homology-2 (SH2) domain-containing Inositol 5′-Phosphatase-1 (SHIP-1) is a lipid signaling protein and a regulator of myeloid cell development and function. Herein, we used the bioflavonoid apigenin (API) to reduce inflammation in different PC models. Wild type mice harboring heterotopic or orthotopic PC were treated with API, which induced SHIP-1 expression, reduced inflammatory tumor-derived factors (TDF), increased the proportion of tumoricidal macrophages and enhanced anti-tumor immune responses, resulting in a reduction in tumor burden compared to vehicle-treated PC mice. In contrast, SHIP-1-deficient mice exhibited an increased tumor burden and displayed augmented proportions of pro-tumor macrophages. These results provide further support for the importance of SHIP-1 expression in promoting pro-tumor macrophage development in the pancreatic TME. Our findings suggest that agents augmenting SHIP-1 expression may provide novel therapeutic options for the treatment of PC.
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影响因子：
10.1
作者：
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通讯作者：
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影响因子：
5.2
作者：
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作者：
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作者：
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