Department of Internal Medicine, Center for Research, Transfer and High Education, DENOthe, University of Florence, Florence, Italy.
Oncogene. 2013 May 23;32(21):2649-60. doi: 10.1038/onc.2012.268. Epub 2012 Jul 2.
Chemoresistance is an important concern in the treatment of metastatic colon cancer. It may emerge through selection of clones that are inherently resistant from the outset or through mechanisms acquired during treatment. Cell fusion represents an efficient means of rapid phenotypic evolution that make cells with new properties at a rate exceeding that achievable by random mutagenesis. Here, we first identified a number of proteins involved in cell fusion using a shotgun proteomics approach, then we investigated the role of these proteins namely tetraspanin CD81/CD9, ADAM10, GTP-binding protein α13, radixin, myosin regulatory light chain and RhoA in the regulation of colon cancer cell fusion. We also found a previously unrecognized role of ADAM10, Gα13 and RhoA in promoting cell fusion. Finally, we show that the occurrence of cell fusion in a metastatic model of colon carcinoma causes the appearance of cells resistant to both 5-fluorouracil and oxaliplatin. These findings highlight the importance of cell fusion in cancer progression and raise significant implications for overcoming chemoresistance in metastatic colon cancer.
化学耐药性是转移性结直肠癌治疗中的一个重要关注点。它可能通过从一开始就具有固有耐药性的克隆选择，或通过治疗过程中获得的机制而出现。细胞融合代表了一种快速表型进化的有效手段，使细胞以超过随机突变的速度获得新的特性。在这里，我们首先使用鸟枪法蛋白质组学方法鉴定了一些参与细胞融合的蛋白质，然后研究了这些蛋白质（即四跨膜蛋白 CD81/CD9、ADAM10、G 蛋白 α13、radixin、肌球蛋白调节轻链和 RhoA）在调节结肠癌细胞融合中的作用。我们还发现了 ADAM10、Gα13 和 RhoA 在促进细胞融合中的先前未被认识到的作用。最后，我们表明，在结肠癌转移模型中细胞融合的发生导致对 5-氟尿嘧啶和奥沙利铂均具有耐药性的细胞出现。这些发现强调了细胞融合在癌症进展中的重要性，并对克服转移性结直肠癌的化学耐药性提出了重大影响。
