MBC：干细胞与癌症关系的新进展
英国曼彻斯特大学（University of Manchester）的研究人员，利用胚胎干细胞〔embryonic stem (ES) cells〕来观察一些会转移的肿瘤细胞，因为这种型态的细胞在癌症治疗上更加困难。Chris Ward博士发现了一些癌细胞能开始转移及扩散到其他组织的线索，此研究发表于Molecular Biology of the Cell 期刊。
早期的癌细胞就像正常的上皮细胞（epithelial cells）一样，细胞之间会紧密的黏在一起形成牢固的组织层，当癌细胞更进一步的发展，有些细胞就会转变成间叶细胞（mesenchymal cells），间叶细胞彼此之间是不会黏合在一起的，反而是一团混乱又能四处移动的组织，这个过程的变化称为上皮-间叶的过渡时期（epithelial-mesenchymal transition），这种现象也能在早期的胚胎发育中看到类似的进程。在这个过渡期，细胞丧失了一些能促使彼此黏合的蛋白质，同时也产生了一些能促使癌细胞扩散的蛋白质。希望能透过对ES细胞的研究，了解癌细胞扩散的一些关键因子，为癌症转移提供一个治疗之道。
研究团队发现：“在细胞正常生长的情况下，E-cadherin蛋白能阻止细胞的转移。E-cadherin蛋白不但能协助细胞紧密黏合，也能阻止其他促进癌细胞转移的蛋白质的活性，E-cadherin蛋白的这两种功能，提供了阻止肿瘤细胞扩散的线索。”国际癌症研究协会（Association for International Cancer Research，AICR)的会长Derek Napier就表示：“这项发现将对癌细胞扩散研究的相关领域带来重大的影响，也期盼由此能找到更多新的策略，以阻止癌细胞的扩散。”
原始出处:
MBC in Press, published online ahead of print May 16, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0875
E-Cadherin Inhibits Cell Surface Localization of the Pro-Migratory 5T4 Oncofoetal Antigen in Mouse Embryonic Stem Cells
*Centre for Molecular Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Immunology Group and Cancer Research UK Stem Cell Biology Group, Paterson Institute for Cancer Research, University of Manchester, Christie Hospital National Health Service Trust, Manchester M20 4BX, United Kingdom; Materials Science Centre, The University of Manchester, Manchester M1 7HS, United Kingdom; ||Department of Molecular Embryology, Max-Planck Institute of Immunobiology, D-79108 Freiburg, Germany
Monitoring Editor: Marianne Bronner-Fraser
Abstract
Epithelial-mesenchymal transition (EMT) events occur during embryonic development and are important for the metastatic spread of epithelial tumors. We show here that spontaneous differentiation of mouse ES cells is associated with an E- to N-cadherin switch, upregulation of E-cadherin repressor molecules (Snail and Slug proteins), gelatinase activity (MMP-2 and MMP-9) and increased cellular motility, all characteristic EMT events. The 5T4 oncofoetal antigen, previously shown to be associated with very early ES cell differentiation and altered motility, is also a part of this coordinated process. E-cadherin, N-cadherin and 5T4 proteins are independently regulated during ES cell differentiation and are not required for induction of EMT-associated transcripts and proteins, as judged from the study of the respective knockout ES cells. Further, abrogation of E-cadherin mediated cell-cell contact in undifferentiated ES cells using neutralizing antibody results in a reversible mesenchymal phenotype and actin cytoskeleton rearrangement which is concomitant with translocation of the 5T4 antigen from the cytoplasm to the cell surface in an energy-dependent manner. E-cadherin null ES cells are constitutively cell surface 5T4 positive and while forced expression of E-cadherin cDNA in these cells is sufficient to restore cell-cell contact, cell surface expression of 5T4 antigen is unchanged. 5T4 and N-cadherin knockout ES cells exhibit significantly decreased motility during EMT, demonstrating a functional role for these proteins in this process. We conclude that E-cadherin protein stabilizes cortical actin cyoskeletal arrangement in ES cells and this can prevent cell surface localization of the promigratory 5T4 antigen.
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