Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells
Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells
复制标题
DOI：
10.1158/2326-6066.cir-17-0675
复制
发表时间：
2018-06-01
影响因子：
10.1
通讯作者：
Arico, Eleonora
中科院分区：
文献类型：
--
作者：
Castiello, Luciano;Sestili, Paola;Arico, Eleonora
I型干扰素是一类抗病毒免疫调节细胞因子，参与肿瘤发生、发展的多个阶段。干扰素-I直接作用于肿瘤细胞以抑制细胞生长，并间接地通过激活免疫细胞来启动抗肿瘤反应。为了了解内源性干扰素-I在自发的癌基因驱动的癌症发生中的作用，我们研究了HER2/neu转基因(Neut)小鼠的肿瘤，这些小鼠携带Ifni受体(IFNAR1)的非功能性突变。这样的小鼠对这种细胞因子家族没有反应。与亲本neu(+/-)鼠(Neut鼠)相比，IFNAR1(-/-)neu(+/-)鼠(IFNAR-Neut鼠)发病更早，肿瘤多样性增加，血管生成明显。IFNAR-Neut肿瘤表现出乳腺癌患者中具有不良预后价值的基因的去调控，包括乳腺癌干细胞(BCSC)标志物乙醛脱氢酶-1A1(ALDH1A1)。通过ALDH1A1酶活性、克隆形成试验和成瘤能力评估，在IFNAR-Neut肿瘤中观察到BCSCs的数量增加。在体外，Neut(+)乳房和细胞系暴露于干扰素-I抗体导致ALDH(+)细胞的频率增加，这表明干扰素-I控制肿瘤细胞的干性。综上所述，这些结果揭示了干扰素-I通过对BCSCs的内在控制在Neut驱动的自发性癌症发生中的作用。(C)2018年AACR。
Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neu(+/-) mice (neuT mice), IFNAR1(-/-) neu(+/-) mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuT(+) mammospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDH(+) cells, suggesting that IFN-I controls stemness in tumor cells. Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. (C) 2018 AACR.