Leiden University Medical Center, Department of Urology J3-100, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Bone. 2011 Jan;48(1):37-43. doi: 10.1016/j.bone.2010.07.023. Epub 2010 Jul 27.
Acquisition of an invasive phenotype of cancer cells in primary tumors is an absolute requirement for bone metastasis. The majority of bone metastases is derived from epithelial cancers, particularly those of the breast and prostate. Accumulating evidence suggest that transformed epithelial cells can activate embryonic programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype also referred to as epithelial-to-mesenchymal transition (EMT). Induction of EMT can, therefore, lead to invasion of surrounding stroma, intravasation, dissemination and colonization of distant sites. In bone/bone marrow disseminated tumor cells can partially regain their original epithelial characteristics via a mesenchymal-to-epithelial transition (MET) as glandular structures in bone metastasis are frequently observed. To date, the importance of epithelial plasticity in cancer cells disseminated to the bone/bone marrow microenvironment has remained largely elusive. Interestingly, a number of growth factors that play a prominent role in EMT induction in the primary tumor have been identified as important stimulators of skeletal metastasis formation. Recent studies have demonstrated that EMT may render cancer cells with properties of stem cells, which in turn can lead to escape from immune surveillance, increased resistance to apoptosis, diminished senescence and, last-but-not least, therapy resistance. This review will discuss current concepts regarding the role of epithelial plasticity in the multistep processes of bone metastasis, the issue of minimal residual disease, cancer stem cells and the importance of EMT in the development of novel targeted drug therapy.
癌细胞在原发性肿瘤中获得侵袭表型是发生骨转移的绝对必要条件。大多数骨转移来自上皮性癌症，特别是乳腺癌和前列腺癌。越来越多的证据表明，转化的上皮细胞可以激活上皮可塑性的胚胎程序，并从静止的上皮表型转变为运动的间质表型，也称为上皮间质转化（EMT）。因此，EMT 的诱导可导致周围基质的侵袭、血管内渗、远处部位的播散和定植。在骨/骨髓中，播散的肿瘤细胞可以通过间质上皮转化（MET）部分恢复其原始上皮特征，因为骨转移中的腺状结构经常被观察到。迄今为止，上皮可塑性在播散到骨/骨髓微环境中的癌细胞中的重要性在很大程度上仍然难以捉摸。有趣的是，许多在原发性肿瘤中 EMT 诱导中起重要作用的生长因子已被确定为骨骼转移形成的重要刺激物。最近的研究表明，EMT 可使癌细胞具有干细胞的特性，这反过来又可以导致逃避免疫监视、增加对细胞凋亡的抵抗力、减少衰老，最后但并非最不重要的是，对治疗产生耐药性。这篇综述将讨论上皮可塑性在骨转移的多步骤过程、微小残留疾病、癌症干细胞以及 EMT 在新型靶向药物治疗发展中的作用的当前概念。
