Schulz P, Scholz A, Rexin A, Hauff P, Schirner M, Wiedenmann B, Detjen K
Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin 13353, Germany.
Br J Cancer. 2008 Jul 8;99(1):110-7. doi: 10.1038/sj.bjc.6604457. Epub 2008 Jun 24.
Functional inactivation of the tumour suppressor protein p16(INK4a) constitutes a key event in the multistep process of pancreatic ductal cell transformation. However, the significance of p16 inactivation for complex and tissue-specific aspects of pancreatic cancer progression, such as angiogenesis and metastasis, is less understood. Here, we inducibly re-expressed p16 in vivo in an orthotopic model of pancreatic cancer and examined the impact on these clinically relevant aspects of pancreatic cancer tumour biology. Consistent with previous work in subcutaneous xenograft models, we found p16 capable of reducing primary tumour growth. In addition, p16 restitution resulted in a marked reduction of tumour angiogenesis, largely accounted for by a p16-dependent inhibition of lymphangiogenesis. In excellent agreement with the antilymphangiogenic effect, re-expression of p16 almost completely prevented lymph node metastases of MiaPaca-2 pancreatic tumours. To our knowledge, this is the first report that experimentally links the tumour suppressor p16 to the process of lymphangiogenesis.
肿瘤抑制蛋白p16(INK4a)的功能失活是胰腺导管细胞转化多步骤过程中的关键事件。然而，p16失活对于胰腺癌进展的复杂和组织特异性方面，如血管生成和转移的意义，人们了解较少。在此，我们在胰腺癌原位模型中体内诱导性重新表达p16，并研究其对胰腺癌肿瘤生物学这些临床相关方面的影响。与先前在皮下异种移植模型中的工作一致，我们发现p16能够减少原发性肿瘤生长。此外，p16恢复导致肿瘤血管生成显著减少，这在很大程度上是由p16依赖性抑制淋巴管生成所导致的。与抗淋巴管生成作用高度一致，p16的重新表达几乎完全阻止了MiaPaca-2胰腺肿瘤的淋巴结转移。据我们所知，这是第一份通过实验将肿瘤抑制因子p16与淋巴管生成过程联系起来的报告。
