Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target.
Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target.
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DOI：
10.1038/onc.2016.197
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发表时间：
2017-01-12
期刊：
影响因子：
8
通讯作者：
Selvendiran K
中科院分区：
文献类型：
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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
尽管STAT3通路的激活与多种癌症类型（包括卵巢癌）的肿瘤进展有关，但STAT3在卵巢癌中侵袭和转移的确切机制尚未完全阐明。我们发现pSTAT3 Tyr705在患者腹水和腹水衍生卵巢癌细胞（ADOCCs）中构成性激活，并且STAT3的表达范围可以非常高到低。将pSTAT3高表达的ADOCCs体内移植到小鼠卵巢囊中，可导致大的原发肿瘤和广泛的腹膜及肝脏转移。相比之下，低STAT3表达的ADOCCs或STAT3表达下调的ADOCCs在体内导致肿瘤生长减少和无转移。来自ADOCC培养基的细胞因子激活STAT3敲除（Ko）细胞中的IL-6/STAT通路，补偿细胞中固有STAT3的缺失。HO-3867（一种新的STAT3抑制剂，在原位小鼠模型中浓度为100 ppm）通过靶向STAT3及其下游蛋白显著抑制卵巢肿瘤生长、血管生成和转移。HO-3867被发现在新鲜采集的人类卵巢癌的体外培养物中具有细胞毒性作用，包括那些对铂基化疗具有耐药性的卵巢癌。我们的研究结果表明，STAT3是卵巢肿瘤进展/转移所必需的，并强调了HO-3867靶向STAT3作为卵巢癌治疗策略的潜力。
Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases as well liver. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knocked down led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the IL-6/STAT pathway in the STAT3 knockout (Ko) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 ppm in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis, and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex-vivo cultures of freshly-collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.