Chao Yvonne, Wu Qian, Acquafondata Marie, Dhir Rajiv, Wells Alan
Department of Pathology, Pittsburgh VAMC and University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Cancer Microenviron. 2012 Apr;5(1):19-28. doi: 10.1007/s12307-011-0085-4. Epub 2011 Sep 3.
Epithelial to mesenchymal transition (EMT) is an oft-studied mechanism for the initiation of metastasis. We have recently shown that once cancer cells disseminate to a secondary organ, a mesenchymal to epithelial reverting transition (MErT) may occur, which we postulate is to enable metastatic colonization. Despite a wealth of in vitro and in vivo studies, evidence supportive of MErT in human specimens is rare and difficult to document because clinically detectable metastases are typically past the micrometastatic stage at which this transition is most likely evident. We obtained paired primary and metastatic tumors from breast and prostate cancer patients and evaluated expression of various epithelial and mesenchymal markers by immunohistochemistry. The metastases exhibited increased expression of membranous E-cadherin compared to primary tumors, consistent with EMT at the primary site and MErT at the metastatic site. However, the re-emergence of the epithelial phenotype was only partial or incomplete. Expression of epithelial markers connexins 26 and/or 43 was also increased on the majority of metastases, particularly those to the brain. Despite the upregulation of epithelial markers in metastases, expression of mesenchymal markers vimentin and FSP1 was mostly unchanged. We also examined prostate carcinoma metastases of varied sizes and found that while E-cadherin expression was increased compared to the primary lesion, the expression inversely correlated with size of the metastasis. This not only suggests that a second EMT may occur in the ectopic site for tumor growth or to seed further metastases, but also provides a basis for the failure to discern epithelial phenotypes in clinically examined macrometastases. In summary, we report increased expression of epithelial markers and persistence of mesenchymal markers consistent with a partial MErT that readily allows for a second EMT at the metastatic site. Our results suggest that cancer cells continue to display phenotypic plasticity beyond the EMT that initiates metastasis.
上皮-间质转化（EMT）是一种常用于研究转移起始的机制。我们最近发现，一旦癌细胞扩散到继发器官，可能会发生间质-上皮逆转转化（MErT），我们推测这一过程有助于转移灶的定植。尽管有大量的体外和体内研究，但支持人类标本中存在MErT的证据很少且难以记录，因为临床上可检测到的转移灶通常已过微转移阶段，而在此阶段这种转化最可能明显。我们从乳腺癌和前列腺癌患者中获取了配对的原发性和转移性肿瘤，并通过免疫组织化学评估了各种上皮和间质标志物的表达。与原发性肿瘤相比，转移灶中膜性E-钙黏蛋白的表达增加，这与原发部位的EMT和转移部位的MErT一致。然而，上皮表型的重新出现只是部分或不完全的。大多数转移灶，尤其是脑转移灶中，上皮标志物连接蛋白26和/或43的表达也增加。尽管转移灶中上皮标志物上调，但间质标志物波形蛋白和FSP1的表达大多未改变。我们还检查了不同大小的前列腺癌转移灶，发现与原发性病变相比，E-钙黏蛋白表达增加，但这种表达与转移灶大小呈负相关。这不仅表明在异位部位可能发生第二次EMT以促进肿瘤生长或形成更多转移灶，也为在临床检查的大转移灶中难以识别上皮表型提供了依据。总之，我们报告了上皮标志物表达增加以及间质标志物持续存在，这与部分MErT一致，这种部分MErT很容易在转移部位引发第二次EMT。我们的结果表明，癌细胞在启动转移的EMT之后仍继续表现出表型可塑性。
