Department of Surgery, University of Regensburg Medical Center, Regensburg, Germany.
Neoplasia. 2012 Oct;14(10):915-25. doi: 10.1593/neo.12878.
The prognosis of patients suffering from pancreatic cancer is still poor and novel therapeutic options are urgently needed. Recently, the transcription factor signal transducer and activator of transcription 5b (STAT5b) was associated with tumor progression in human solid cancer. Hence, we assessed whether STAT5b might serve as an anticancer target in ductal pancreatic adenocarcinoma (DPAC). We found that nuclear expression of STAT5b can be detected in approximately 50% of DPAC. Blockade of STAT5b by stable shRNA-mediated knockdown showed no effects on tumor cell growth in vitro. However, inhibition of tumor cell motility was found even in response to stimulation with epidermal growth factor or interleukin-6. These findings were paralleled by a reduction of prometastatic and proangiogenic factors in vitro. Subsequent in vivo experiments revealed a strong growth inhibition on STAT5b blockade in subcutaneous and orthotopic models. These findings were paralleled by impaired tumor angiogenesis in vivo. In contrast to the subcutaneous model, the orthotopic model revealed a strong reduction of tumor cell proliferation that emphasizes the meaning of assessing targets in an appropriate microenvironment. Taken together, our results suggest that STAT5b might be a potential novel target for human DPAC.
胰腺癌患者的预后仍然较差，迫切需要新的治疗选择。最近，转录因子信号转导子和转录激活子 5b（STAT5b）与人类实体瘤的肿瘤进展有关。因此，我们评估了 STAT5b 是否可以作为导管腺癌（DPAC）的抗癌靶点。我们发现，大约 50%的 DPAC 中可以检测到 STAT5b 的核表达。通过稳定的 shRNA 介导的敲低阻断 STAT5b 对肿瘤细胞的体外生长没有影响。然而，即使在表皮生长因子或白细胞介素-6 的刺激下，也发现肿瘤细胞的迁移能力受到抑制。这些发现与体外促转移和促血管生成因子的减少相平行。随后的体内实验显示，STAT5b 阻断在皮下和原位模型中具有强烈的生长抑制作用。这些发现与体内肿瘤血管生成的受损相平行。与皮下模型相比，原位模型显示肿瘤细胞增殖明显减少，这强调了在适当的微环境中评估靶点的意义。总之，我们的研究结果表明，STAT5b 可能是人类 DPAC 的一个潜在的新靶点。
