Okuyama Hiroaki, Kondo Jumpei, Sato Yumi, Endo Hiroko, Nakajima Aya, Piulats Jose M, Tomita Yasuhiko, Fujiwara Takeshi, Itoh Yu, Mizoguchi Akira, Ohue Masayuki, Inoue Masahiro
Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Am J Pathol. 2016 Apr;186(4):899-911. doi: 10.1016/j.ajpath.2015.12.011. Epub 2016 Feb 12.
Intestinal epithelial cells possess apical-basal polarity, which governs the exchange of nutrients and waste. Perturbation of cell polarity appears to be a general feature of cancers, although most colorectal cancers are differentiated adenocarcinomas, in which polarity is maintained to some extent. Little is known about the role of dysregulated polarity in cancer. The cancer tissue-originated spheroid method was applied to the preparation and culture of spheroids. Spheroids were cultured in suspension or in type I collagen gel. Polarity was assessed by IHC of apical markers and electron microscopy. Two types of polarity status in spheroids were observed: apical-in, with apical membrane located at cavities inside the spheroids in type I collagen gel; and apical-out, with apical membrane located at the outermost layer of spheroids in suspension. These polarities were highly interchangeable. Inhibitors of Src and dynamin attenuated the polarity switch. In patients, clusters of cancer cells that invaded vessels had both apical-in and apical-out morphologic features, whereas primary and metastatic tumors had apical-in features. In a mouse liver metastasis model, apical-out spheroids injected into the portal vein became apical-in spheroids in the liver within a few days. Inhibitors of Src and dynamin significantly decreased liver metastasis. Polarity switching was observed in spheroids and human cancer. The polarity switch was critical in an experimental liver metastasis model.
肠上皮细胞具有顶-基极性，这种极性控制着营养物质和废物的交换。细胞极性的扰动似乎是癌症的一个普遍特征，尽管大多数结直肠癌是分化型腺癌，其中极性在一定程度上得以维持。关于极性失调在癌症中的作用知之甚少。采用癌组织来源的球体法进行球体的制备和培养。球体在悬浮液或I型胶原凝胶中培养。通过顶端标志物的免疫组化和电子显微镜评估极性。在球体中观察到两种极性状态：顶端向内，顶端膜位于I型胶原凝胶中球体内部的腔中；顶端向外，顶端膜位于悬浮液中球体的最外层。这些极性高度可互换。Src和发动蛋白的抑制剂减弱了极性转换。在患者中，侵入血管的癌细胞簇具有顶端向内和顶端向外的形态特征，而原发性和转移性肿瘤具有顶端向内的特征。在小鼠肝转移模型中，注入门静脉的顶端向外的球体在几天内会在肝脏中变成顶端向内的球体。Src和发动蛋白的抑制剂显著降低了肝转移。在球体和人类癌症中观察到了极性转换。极性转换在实验性肝转移模型中至关重要。
