Bulk Etmar, Hascher Antje, Liersch Ruediger, Mesters Rolf M, Diederichs Sven, Sargin Bülent, Gerke Volker, Hotfilder Marc, Vormoor Josef, Berdel Wolfgang E, Serve Hubert, Müller-Tidow Carsten
Departments of Medicine, Hematology and Oncology, University of Münster, Münster, Germany.
Cancer Res. 2008 Mar 15;68(6):1896-904. doi: 10.1158/0008-5472.CAN-07-2390.
Development of distant metastasis is the major reason for cancer-related deaths worldwide. Adjuvant therapy approaches after local therapies are most effective when specific targets are inhibited. Recently, we identified S100P overexpression as a strong predictor for metastasis development in early-stage non-small cell lung cancer (NSCLC) patients. Here, we show that S100P overexpression increased angiogenesis in and metastasis formation from s.c. xenotransplants of NSCLC cells. Plasmid-derived short hairpin RNAs (shRNA) were developed as specific adjuvant therapy. I.v. injected shRNA against S100P significantly decreased S100P protein expression in xenograft tumors and inhibited tumor angiogenesis in vivo. Metastasis formation 8 weeks after primary tumor resection was significantly reduced. Lung metastases developed in 31% of mice treated with S100P-targeting shRNAs compared with 64% in control shRNA-treated mice (P < 0.05). These findings suggest that RNA interference-based therapy approaches can be highly effective in the adjuvant setting.
远处转移的发生是全球癌症相关死亡的主要原因。当特定靶点被抑制时，局部治疗后的辅助治疗方法最为有效。最近，我们发现S100P过表达是早期非小细胞肺癌（NSCLC）患者转移发生的有力预测指标。在此，我们表明S100P过表达增加了NSCLC细胞皮下异种移植瘤的血管生成和转移形成。质粒衍生的短发夹RNA（shRNA）被开发为特异性辅助治疗。静脉注射针对S100P的shRNA可显著降低异种移植瘤中S100P蛋白表达，并在体内抑制肿瘤血管生成。原发肿瘤切除8周后转移形成明显减少。与对照shRNA处理的小鼠中64%相比，用靶向S100P的shRNAs处理的小鼠中有31%发生了肺转移（P<0.05）。这些发现表明基于RNA干扰的治疗方法在辅助治疗中可能非常有效。
