Jang Jae-Hwi, Baerts Lesley, Waumans Yannick, De Meester Ingrid, Yamada Yoshito, Limani Perparim, Gil-Bazo Ignacio, Weder Walter, Jungraithmayr Wolfgang
Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
Department of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.
Clin Exp Metastasis. 2015 Oct;32(7):677-87. doi: 10.1007/s10585-015-9736-z. Epub 2015 Aug 2.
Metastases rather than primary cancers determine nowadays the survival of patients. One of the most common primary malignancies is colorectal cancer and this type of tumor is characterized by a high tendency to spread metastases to the lung and liver. CD26/DPP4 is a transmembrane molecule with enzymatic functions which cleaves biologically active peptides. Recently, CD26/DPP4 has become the focus of cancer research and it was shown that CD26/DPP4-positive cancer cells display increased metastatic activity. Here, we tested if the CD26/DPP4-inhibitor Vildagliptin suppresses the development and growth of mouse colorectal lung metastases. This inhibitor of CD26/DPP4 was employed on mouse (C57BL/6) colorectal lung metastases, established by intravenous injection of the syngeneic cell line MC38. For mechanistic analysis, a subcutaneous tumor model was used. The treatment with Vildagliptin significantly suppressed both, the incidence and growth of lung metastases. Autophagy markers (LC3, p62, and ATF4) decreased, apoptosis increased (TUNEL, pH3/Ki-76), and the cell cycle regulator pCDC2 was inhibited. In conclusion, we here showed an anti-tumor effect of Vildagliptin via downregulation of autophagy resulting in increased apoptosis and modulation of the cell cycle. We therefore propose Vildagliptin for the evaluation as a new therapeutic approach for the treatment of colorectal cancer lung metastases.
如今，决定患者生存的是转移瘤而非原发性癌症。最常见的原发性恶性肿瘤之一是结直肠癌，这类肿瘤的特点是极易向肺和肝转移。CD26/DPP4是一种具有酶功能的跨膜分子，可裂解生物活性肽。最近，CD26/DPP4已成为癌症研究的焦点，研究表明CD26/DPP4阳性癌细胞的转移活性增强。在此，我们测试了CD26/DPP4抑制剂维格列汀是否能抑制小鼠结直肠癌肺转移的发生和生长。该CD26/DPP4抑制剂用于通过静脉注射同基因细胞系MC38建立的小鼠（C57BL/6）结直肠癌肺转移模型。为进行机制分析，使用了皮下肿瘤模型。维格列汀治疗显著抑制了肺转移的发生率和生长。自噬标志物（LC3、p62和ATF4）减少，细胞凋亡增加（TUNEL、pH3/Ki-76），细胞周期调节因子pCDC2受到抑制。总之，我们在此表明维格列汀通过下调自噬产生抗肿瘤作用，从而导致细胞凋亡增加并调节细胞周期。因此，我们建议对维格列汀进行评估，作为治疗结直肠癌肺转移的一种新的治疗方法。
