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众所周知，正常的上皮细胞通过上皮→间质转化，丧失细胞极性和黏附能力，获得浸润、运动和转移能力，可以进一步形成肿瘤细胞，进入血液循环，或者播散进入骨髓等组织；不过，上皮→间质转化异质性对于肿瘤进展过程的影响仍然存在争议。 2019年6月19日，美国科学促进会《科学》旗下《科学进展》发表德国慕尼黑大学医院、上海交通大学医学院附属第一人民医院、美国赛特生物、南京医科大学公共卫生学院、慕尼黑亥姆霍兹研究中心、复旦大学生命科学学院的研究报告，发现间质转化受限的上皮型循环肿瘤细胞反而是乳腺肿瘤转移主要来源。 该研究对转移性乳腺癌同源小鼠模型离体培养的循环肿瘤细胞和播散肿瘤细胞进行上皮→间质转化状态分析，发现间质转化受限的上皮型循环肿瘤细胞肺转移形成能力最强，而间质型循环肿瘤细胞的转移能力有限。 随后，该研究将上皮细胞黏附分子表达作为替代标志，对转移性乳腺癌临床标本（包括转移灶、循环肿瘤细胞、播散肿瘤细胞）上皮→间质转化的异质性进行评估。结果发现，上皮型循环肿瘤细胞的比例，尤其与播散肿瘤细胞之比，与转移性乳腺癌患者的远处转移和不良结局相关。 因此，该研究结果表明，上皮→间质转化表现型异质性可以作为肿瘤预后和治疗的重要指标。此外，上皮细胞黏附分子依赖型循环肿瘤细胞分离系统虽然可能低估循环肿瘤细胞数量，但是可以对有临床意义的转移细胞进行量化。 Sci Adv. 2019 Jun 19;5(6):eaav4275. Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis. Xiao Liu, Junjian Li, Bruno Loureiro Cadilha, Anamarija Markota, Cornelia Voigt, Zhe Huang, Peter P. Lin, Daisy D. Wang, Juncheng Dai, Gisela Kranz, Anna Krandick, Darko Libl, Horst Zitzelsberger, Isabella Zagorski, Herbert Braselmann, Min Pan, Sibo Zhu, Yuanchi Huang, Sebastian Niedermeyer, Christoph A. Reichel, Bernd Uhl, Daria Briukhovetska, Javier Suarez, Sebastian Kobold, Olivier Gires, Hongxia Wang. University Hospital, Ludwig-Maximilians University of Munich, Munich, Germany; Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Klinikum der Ludwig-Maximilians-Universitat München, Munich, Germany; Cytelligen, San Diego, CA, USA; School of Public Health, Nanjing Medical University, Nanjing, China; Helmholtz Zentrum München, Neuherberg, Germany; School of Life Sciences, Fudan University, Shanghai, China. Carcinoma cells undergo epithelial-mesenchymal transition (EMT); however, contributions of EMT heterogeneity to disease progression remain a matter of debate. Here, we addressed the EMT status of ex vivo cultured circulating and disseminated tumor cells (CTCs/DTCs) in a syngeneic mouse model of metastatic breast cancer (MBC). Epithelial-type CTCs with a restricted mesenchymal transition had the strongest lung metastases formation ability, whereas mesenchymal-type CTCs showed limited metastatic ability. EpCAM expression served as a surrogate marker to evaluate the EMT heterogeneity of clinical samples from MBC, including metastases, CTCs, and DTCs. The proportion of epithelial-type CTCs, and especially DTCs, correlated with distant metastases and poorer outcome of patients with MBC. This study fosters our understanding of EMT in metastasis and underpins heterogeneous EMT phenotypes as important parameters for tumor prognosis and treatment. We further suggest that EpCAM-dependent CTC isolation systems will underestimate CTC numbers but will quantify clinically relevant metastatic cells. DOI: 10.1126/sciadv.aav4275
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