Targeted inhibition of the JAK/STAT3 pathway inhibits ovarian carcinoma growth. Mus musculus

Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. Overall design: 8 female C57BL/6JTgMISIIR-TAg mice with ovarian tumors of ~500 mm3 were used. 4 vehicle-treated mice (0.5% hypermellose/0.1%Tween 80);4 drug-treated mice (30 mg/kg AZD1480 in 0.5% hypermellose/0.1%Tween 80).

卵巢癌（Ovarian carcinoma, OC）是美国女性第五大致死性恶性肿瘤。信号转导与转录激活因子3（signal transducer and activator of transcription, STAT3）的持续活化在卵巢癌中极为常见。STAT3可通过细胞因子受体、生长因子受体及非生长因子受体型酪氨酸激酶，由贾纳斯家族激酶（Janus family kinases, JAK）介导激活。STAT3活化可介导肿瘤细胞增殖、存活、运动、侵袭及血管生成；近期研究证实，STAT3活化还可抑制抗肿瘤免疫应答，并促进促肿瘤炎症反应。本研究假设，靶向JAK/STAT3通路的治疗手段可通过直接作用于卵巢癌细胞，以及抑制肿瘤微环境（tumor microenvironment, TME）内的细胞，从而抑制肿瘤生长。为验证该假设，本研究首先在体外实验中评估了小分子JAK抑制剂AZD1480对卵巢癌细胞存活率、凋亡、增殖、迁移及黏附能力的影响；随后在卵巢癌转基因小鼠模型中，评估了AZD1480对体内肿瘤生长与进展、基因表达、肿瘤相关基质金属蛋白酶（matrix metalloproteinase, MMP）活性以及免疫细胞群的影响。实验结果显示，AZD1480处理可抑制培养卵巢癌细胞的STAT3磷酸化水平与DNA结合能力，同时降低其迁移及黏附能力，并可减缓小鼠卵巢肿瘤的生长速率、缩小瘤体体积、减少腹水生成量。此外，与对照组小鼠相比，给药处理可改变荷瘤小鼠腹膜肿瘤微环境内的基因表达谱，降低肿瘤相关MMP活性，并减少抑制性T细胞的数量。综上，本研究结果表明，通过药理学手段抑制JAK2/STAT3通路，可破坏卵巢肿瘤生长与进展所必需的核心生物学功能，该策略因此有望成为极具前景的卵巢癌治疗方案。实验设计：本研究共纳入8只携带约500 mm³卵巢肿瘤的雌性C57BL/6JTgMISIIR-TAg小鼠，分为两组：对照组4只，给予0.5%羟丙基甲基纤维素/0.1%吐温80溶剂处理；给药组4只，给予30 mg/kg AZD1480（溶于0.5%羟丙基甲基纤维素/0.1%吐温80）处理。