Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden.
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.
Int J Mol Sci. 2018 Nov 20;19(11):3672. doi: 10.3390/ijms19113672.
Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.
肿瘤细胞从恶性肿瘤的原发部位转移到邻近的基质组织或远处的局部区域，在某些情况下需要，但并非在所有情况下都需要上皮-间充质转化（EMT）。EMT 削弱了分化上皮细胞之间的强粘附力，使癌细胞能够实现单独或集体运动，这使得 EMT 成为肿瘤转移起始的直观机制。EMT 在原发性致癌事件导致细胞因子的二次分泌后开始。肿瘤分泌的细胞因子与致癌刺激之间的相互作用促进了 EMT 的进展。这种机制的一个典型例子是致癌 Ras 与转化生长因子 β（TGFβ）之间的合作。TGFβ 在转移过程中介导 EMT 的能力取决于多功能信号串扰以及许多其他细胞因子的表达的连续波的调节和促进通过基底膜运动的细胞外基质的渐进性重塑。由于转移涉及体内许多器官，而 EMT 局部影响癌细的分化，因此经常存在争议 EMT 是否真的有助于转移。尽管存在争议，但循环肿瘤细胞的研究、转移性细胞获得化疗耐药性的研究以及几种（但不是全部）转移性动物模型支持 EMT 与转移之间的联系，TGFβ 通常是这种联系的共同因素。本文旨在讨论 TGFβ 信号转导和 EMT 促进肿瘤细胞扩散的机制案例。
