STAT1 gene deficient mice develop accelerated breast cancer growth and metastasis which is reduced by IL-17 blockade.
STAT1 gene deficient mice develop accelerated breast cancer growth and metastasis which is reduced by IL-17 blockade.
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DOI：
10.1080/2162402x.2017.1361088
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Satoskar AR
中科院分区：
文献类型：
--
作者：
Varikuti S;Oghumu S;Elbaz M;Volpedo G;Ahirwar DK;Alarcon PC;Sperling RH;Moretti E;Pioso MS;Kimble J;Nasser MW;Ganju RK;Terrazas C;Satoskar AR
信号转导和转录激活因子1（STAT 1）介导干扰素γ信号传导，其激活与凋亡、炎症、细胞周期和血管生成相关的各种基因的表达。一些实验和临床研究已经研究了STAT 1在乳腺癌原发性肿瘤生长中的作用;然而，其在肿瘤转移中的作用仍有待确定。为了确定STAT 1在乳腺癌转移中的作用，我们分析了原位植入转移性4T1.2细胞的WT或STAT 1 −/−小鼠的生长和转移。STAT 1 −/−小鼠的原发性肿瘤发展更快，与WT小鼠相比，这些小鼠的原发性肿瘤明显更大，并显示出更多的肺转移。与WT小鼠相比，STAT 1 −/−小鼠的原发性肿瘤和脾脏中Ly 6 G + CD 11b+粒细胞MDSC浸润增加，同时肿瘤中Mmp 9和Cxcl 1表达上调。在原发性荷瘤STAT 1 −/−小鼠中阻断IL-17 A可抑制Ly 6 G + CD 11b+细胞的积累，并显著减少肺转移。这些数据表明，STAT 1是原发性乳腺肿瘤生长和转移的重要抑制因子。重要的是，我们发现抗IL-17治疗可以拯救STAT 1缺陷动物免于发展恶化的肺转移，这对于免疫功能低下的乳腺癌患者的免疫治疗可能是重要的。
Signal transducer and activator of transcription 1 (STAT1) mediates interferon gamma signaling which activates the expression of various genes related to apoptosis, inflammation, cell cycle and angiogenesis. Several experimental and clinical studies have investigated the role of STAT1 in primary tumor growth in breast cancer; however, its role in tumor metastasis remains to be determined. To determine the role of STAT1 in breast cancer metastasis, we analyzed growth and metastasis in WT or STAT1−/− mice orthotopically implanted with metastatic 4T1.2 cells. Primary tumor development was faster in STAT1−/− mice and these mice developed significantly bigger primary tumors and displayed more lung metastasis compared with WT counterparts. STAT1−/− mice showed elevated Ly6G+CD11b+ granulocytic MDSC infiltration in their primary tumors and spleens with concomitant upregulation of Mmp9 and Cxcl1 expression in tumors compared with WT counterparts. Blockade of IL-17A in primary tumor-bearing STAT1−/− mice suppressed accumulation of Ly6G+CD11b+ cells and markedly reduced lung metastasis. These data show that STAT1 is an important suppressor of primary breast tumor growth and metastasis. Importantly, we found anti-IL-17 treatment can rescue STAT1 deficient animals from developing exacerbated metastasis to the lungs which could be important for immunotherapies for immunocompromised breast cancer patients.