Appolloni I, Barilari M, Caviglia S, Gambini E, Reisoli E, Malatesta P
U.O. Trasferimento Genico, IRCCS-AOU San Martino-IST, Largo Rosanna Benzi 10, Genoa, Italy.
Department of Experimental Medicine (DiMES), University of Genoa, Leon Battista Alberti 2, Genoa, Italy.
Oncogene. 2015 Apr 9;34(15):1991-2002. doi: 10.1038/onc.2014.122. Epub 2014 May 26.
Although the infiltrative behavior of malignant gliomas is one of their most critical aspects, the mechanisms underlying it have not yet been elucidated. To migrate in the brain parenchyma, malignant glioma cells need to bypass the cell-cell contact inhibitory signals. Here we propose that the blinding of cell-cell contact sensing in gliomas is caused by an unusual mechanism of cadherin switch, involving the replacement of N-cadherin with R-cadherin (Rcad) at the cell-cell junctions and the activation of ERK and p27. In our model of malignant glioma, we found that Rcad expression is necessary and sufficient to release cells from contact inhibition of proliferation, and is necessary, although not sufficient, for overriding contact inhibition of migration and for tumorigenicity. Altogether, these observations suggest that Rcad is a potential target for malignant glioma therapies.
尽管恶性胶质瘤的浸润行为是其最关键的方面之一，但其潜在机制尚未阐明。为了在脑实质中迁移，恶性胶质瘤细胞需要绕过细胞间接触抑制信号。在此我们提出，胶质瘤中细胞间接触感知的丧失是由一种不寻常的钙黏蛋白转换机制引起的，该机制涉及在细胞间连接处用R-钙黏蛋白（Rcad）取代N-钙黏蛋白，并激活ERK和p27。在我们的恶性胶质瘤模型中，我们发现Rcad的表达对于使细胞从增殖接触抑制中释放是必要且充分的，并且对于克服迁移接触抑制和肿瘤发生是必要的，尽管不是充分的。总之，这些观察结果表明Rcad是恶性胶质瘤治疗的一个潜在靶点。
