Dynamic molecular changes associated with epithelial-mesenchymal transition and subsequent mesenchymal-epithelial transition in the early phase of metastatic tumor formation
Dynamic molecular changes associated with epithelial-mesenchymal transition and subsequent mesenchymal-epithelial transition in the early phase of metastatic tumor formation
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DOI：
10.1002/ijc.25500
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发表时间：
2011-04-01
影响因子：
6.4
通讯作者：
Ochiai, Atsushi
中科院分区：
文献类型：
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作者：
Aokage, Keiju;Ishii, Genichiro;Ochiai, Atsushi
经血管途径形成的转移性肿瘤始于癌细胞从管腔渗出，向血管周围的结缔组织迁移，并侵袭靶器官实质。上皮-间充质转化(EMT)和间质-上皮转化(MET)在肿瘤转移过程中起着重要作用，但这些生物学变化在肿瘤转移的早期阶段如何发生以及在何处发生，目前尚不清楚。我们对34例癌细胞从淋巴管渗出后形成的肺内小转移(淋巴源性转移)和40例在没有渗出的情况下形成的肺内小转移(气源性转移)进行了形态学评估，发现淋巴转移中经常观察到孤立的或小的侵袭性癌细胞簇(肿瘤萌芽)(24/34；71%)，但在气源性转移中从未观察到。我们对34例淋巴转移瘤的13个EMT分子标志物进行了免疫组织化学染色，并对癌细胞漂浮在淋巴管(LV)、向血管周围结缔组织(BVB)迁移和在肺实质(LP)生长的癌细胞进行了MET和免疫染色强度评分。与LV中的癌细胞相比，BVB中的癌细胞对E-钙粘附素(p<；0.001)、β-连环素(p<；0.001)和双黄素(p<；0.001)的染色更弱，而对基质金属蛋白酶-7(p=0.046)和层粘连蛋白-5-伽马2(p=0.037)的染色更强。然而，与BVB中的癌细胞相比，LP中的癌细胞E-钙粘附素(p=0.011)、β-连环素(p<；0.001)和双黄素(p=0.037)的表达恢复，而基质金属蛋白酶-7(p=0.038)和层粘连蛋白-5-γ2(p=0.001)的表达降低。我们的结果表明，在转移性肿瘤形成的早期阶段，癌细胞经历了与EMT和随后的MET相关的动态表型变化。癌细胞生物学
Metastatic tumor formation via vessel route begins with cancer cell extravasation from vessel lumen, migration into the connective tissue surrounding vessels, and invasion into target organ parenchyma. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) have been recognized to play an important role in metastatic process, however, how and where these biological changes take place in the early phase of metastatic tumor development has never been clarified. We morphologically evaluated 34 small intrapulmonary metastases formed after cancer cell extravasation from lymphatics (lymphogenic metastasis) and 40 formed in the absence of extravasation (aerogenous metastasis) in human specimens and found that isolated or small clusters of invasive cancer cells (tumor budding) were frequently observed in lymphogenic metastasis (24/34; 71%), but were never observed within aerogenous metastasis. We immunostained 34 lymphogenic metastases for 13 molecular markers of EMT and MET and scored the immunostaining intensity of cancer cells floating in lymphatic vessels (LVs), migrating into the connective tissue surrounding vessels [bronchovascular bundle (BVB)], and growing in lung parenchyma (LP). Cancer cells within BVBs stained more weakly for E-cadherin (p < 0.001), beta-catenin (p < 0.001), and Geminin (p < 0.001) and more strongly for MMP-7 (p = 0.046) and Laminin-5 gamma 2 (p = 0.037) than tumor cells in LVs. However, cancer cells in LP exhibited resurgent E-cadherin (p = 0.011), beta-catenin (p < 0.001), and Geminin (p = 0.037) expression and reduced MMP-7 (p = 0.038) and Laminin-5 gamma 2 (p = 0.001) expression in comparison with cancer cells in BVBs. Our results suggested that in the early phase of metastatic tumor formation cancer cells undergo dynamic phenotypic change associated with EMT and subsequent MET. Cancer Cell Biology