Hepatology：揭示癌细胞在肝脏中扩散转移的分子机理

  为了成功入侵机体健康组织，肿瘤细胞会脱离肿瘤母体组织进入血液或者淋巴系统，为了完成这一目的，肿瘤细胞会利用特殊的酶类-蛋白酶类来破碎肿瘤周围环境中的组织，随后就肿瘤细胞就可以畅通无阻地进入血液或者淋巴系统中；为了抑制这种特殊蛋白酶的产生，机体会产生抑制剂，比如蛋白质TIMP-1，其可以有效阻断蛋白酶类的功能。
  在肿瘤发生转移期间，机体抑制剂的控制功能非但没有起到正向作用，其反而会促进肿瘤细胞发生转移，对许多癌症患者进行研究发现，血液中高水平的TIMP-1抑制蛋白并不会减缓癌症的扩散；相反地其会促进癌症的恶化，这项研究由慕尼黑工业大学的科学家们开展，相关研究刊登于国际杂志Hepatology上。
  文章中，研究者高浓度的抑制蛋白TIMP-1可以诱导肝脏组织局部炎症的发生，此时中性白细胞会迁移至肝脏中；循环在机体血液中的肿瘤循环细胞就会利用这些细胞和分子改变在肝脏中“定居”并且快速转移；研究者Kruger解释道，TIMP-1可以在肝脏中产生一种癌细胞比较“喜欢”的区域，一旦该区域形成就会开启原发性肿瘤的扩散和转移。
  在科学家们发现促癌细胞转移效应的TIMP-1蛋白，其又成功地揭示了TIMP-1的工作机制及有效抑制其功能的技术；研究人类利用动物模型进行研究发现，TIMP-1可以通过增加机体肝脏中特殊信号分子的水平来恢复机体免疫细胞的功能，肝脏中特殊信号分析可以结合一种受体为癌细胞开辟领土；研究者利用一种药物分子及抗体就可以成功阻断这种特殊信号分子和其受体的相互作用，从而在实验条件下成功抑制癌细胞的转移。
  研究者最后表示，肿瘤细胞的早期转移通常是癌症发展的关键步骤，如果我们可以抑制肝脏中肿瘤转移的形成，那么至少在动物模型研究的层面上将为开发新型癌症疗法会带来巨大帮助。（转化医学网360zhyx.com）
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TIMP-1 creates a pre-metastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice
Hepatology   DOI: 10.1002/hep.27378
Bastian Seubert1,†, Barbara Grünwald1,†, Julia Kobuch1,†, Haissi Cui1,†, Florian Schelter1, Susanne Schaten1, Jens T. Siveke2, Ngee H. Lim4, Hideaki Nagase4, Nicole Simonavicius5, Mathias Heikenwlder5, Thomas Reinheckel6, Jonathan P. Sleeman7,8, Klaus-Peter Janssen3, Percy A. Knolle1 andAchim Krüger1,*
Due to its ability to inhibit pro-metastatic matrix metalloproteinases, tissue inhibitor of metalloproteinases (TIMP)-1 has been thought to suppress tumor metastasis. However, elevated systemic levels of TIMP-1 correlate with poor prognosis in cancer patients suggesting a metastasis-stimulating role of TIMP-1. In colorectal cancer patients, tumor as well as plasma TIMP-1 levels were correlated with synchronous liver metastasis or distant metastasis-associated disease relapse. In mice, high systemic TIMP-1 levels increased the liver susceptibility towards metastasis by triggering the formation of a pre-metastatic niche. This promoted hepatic metastasis independent of origin or intrinsic metastatic potential of tumor cells. High systemic TIMP-1 led to increased hepatic SDF-1 levels, which in turn promoted recruitment of neutrophils to the liver. Both inhibition of SDF-1-mediated neutrophil recruitment and systemic depletion of neutrophils reduced TIMP-1-induced increased liver susceptibility towards metastasis. This indicates a crucial functional role of neutrophils in the TIMP-1-induced pre-metastatic niche. Conclusion: Our results identify TIMP-1 as an essential promoter of hepatic pre-metastatic niche formation. (Hepatology 2014)