Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth.
Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth.
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DOI：
10.1038/s41388-018-0523-6
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Buckanovich RJ
中科院分区：
文献类型：
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作者：
McLean K;Tan L;Bolland DE;Coffman LG;Peterson LF;Talpaz M;Neamati N;Buckanovich RJ
卵巢癌相关间充质干细胞（CA-MSC）不仅产生高水平的IL 6，而且还产生相关的细胞因子白血病抑制因子（LIF）。白细胞介素6（IL 6）介导的STAT 3活化被认为是癌症治疗的关键治疗靶点。对LIF的作用知之甚少，LIF可以类似地激活STAT 3，在卵巢癌中。因此，我们试图评估CA-MSC旁分泌LIF信号传导的致瘤作用以及IL 6和LIF在激活卵巢癌STAT 3介导的癌症生长中的冗余。正如预期的那样，我们发现IL 6和LIF都诱导肿瘤细胞中的STAT 3磷酸化。此外，IL 6和LIF均增加ALDH+卵巢癌干细胞样细胞（CSC）的百分比。通过两种细胞因子支持功能冗余，CA-MSC诱导STAT 3磷酸化并增加癌细胞的“干性”。这种作用不被单独的LIF或IL 6阻断抗体抑制，但被双重IL 6/LIF阻断或JAK 2抑制所阻止。类似地，小发夹RNA（shRNA）介导的CA-MSC中IL 6或LIF的减少部分降低但不能完全消除CA-MSC诱导STAT 3磷酸化和干性的能力。重要的是，CA-MSC的体内促肿瘤发生作用通过JAK 2抑制剂鲁索替尼的双重阻断而被消除，其程度比单独用抗IL 6或抗LIF抗体治疗大得多。Ruxolitinib治疗还改善了具有ID 8肿瘤细胞加MSC的免疫活性卵巢癌小鼠模型系统的存活率。在免疫功能低下和免疫活性动物模型中，鲁索替尼治疗的肿瘤均显示磷酸化-STAT 3降低，表明靶向活性。总之，CA-MSC通过IL 6和LIF激活卵巢癌细胞STAT 3信号传导，并增加肿瘤发生癌症的干性。这种功能冗余表明，单一细胞因子的治疗靶向可能不如双重抑制剂治疗或靶向JAK/STAT途径的共享下游因子等策略有效。
Ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) produce not only high levels of IL6 but also the related cytokine leukemia inhibitory factor (LIF). Interleukin 6 (IL6) mediated activation of STAT3 is implicated as a critical therapeutic target for cancer therapy. Less is known about the role of LIF, which can similarly activate STAT3, in ovarian cancer. We therefore sought to evaluate the tumorigenic effects of CA-MSC paracrine LIF signaling and the redundancy of IL6 and LIF in activating ovarian cancer STAT3 mediated cancer growth. As expected, we found that both IL6 and LIF induce STAT3 phosphorylation in tumor cells. In addition, both IL6 and LIF increased the percentage of ALDH+ ovarian cancer stem-like cells (CSC). Supporting redundancy of function by the two cytokines, CA-MSC induced STAT3 phosphorylation and increased cancer cell ‘stemness’. This effect was not inhibited by LIF or IL6 blocking antibodies alone, but was prevented by dual IL6/LIF blockade or JAK2 inhibition. Similarly, small hairpin RNA (shRNA)-mediated reduction of IL6 or LIF in CA-MSC partially decreased but could not completely abrograte the ability of CA-MSC to induce STAT3 phosphorylation and stemness. Importantly, the in vivo pro-tumorigenic effect of CA-MSC is abrogated by dual blockade with the JAK2 inhibitor ruxolitinib to a much greater extent than treatment with anti-IL6 or anti-LIF antibody alone. Ruxolitinib treatment also improves survival in the immunocompetent ovarian cancer mouse model system with ID8 tumor cells plus MSC. Ruxolitinib-treated tumors in both the immunocompromised and immunocompetent animal models demonstrate decreased phospho-STAT3, indicating on-target activity. In conclusion, CA-MSC activate ovarian cancer cell STAT3 signaling via IL6 and LIF and increase tumorigenesis cancer stemness. This functional redundancy suggests that therapeutic targeting of a single cytokine may be less effective than strategies such as dual inhibitor therapy or targeting shared downstream factors of the JAK/STAT pathway.
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影响因子：
11.2
作者：
Burgos-Ojeda D;McLean K;Bai S;Pulaski H;Gong Y;Silva I;Skorecki K;Tzukerman M;Buckanovich RJ
通讯作者：
Buckanovich RJ
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
针对JAK/STAT3信号传导的靶向封锁抑制了卵巢癌的生长。
影响因子：
5.7
作者：
Gritsina G;Xiao F;O'Brien SW;Gabbasov R;Maglaty MA;Xu RH;Thapa RJ;Zhou Y;Nicolas E;Litwin S;Balachandran S;Sigal LJ;Huszar D;Connolly DC
通讯作者：
Connolly DC
影响因子：
8
作者：
Saini U;Naidu S;ElNaggar AC;Bid HK;Wallbillich JJ;Bixel K;Bolyard C;Suarez AA;Kaur B;Kuppusamy P;Hays J;Goodfellow PJ;Cohn DE;Selvendiran K
通讯作者：
Selvendiran K
影响因子：
82.9
作者：
通讯作者：
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