CD44 variant 6 is correlated with peritoneal dissemination and poor prognosis in patients with advanced epithelial ovarian cancer.
CD44 variant 6 is correlated with peritoneal dissemination and poor prognosis in patients with advanced epithelial ovarian cancer.
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DOI：
10.1111/cas.12765
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发表时间：
2015-10
期刊：
影响因子：
5.7
通讯作者：
Katabuchi H
中科院分区：
文献类型：
--
作者：
Tjhay F;Motohara T;Tayama S;Narantuya D;Fujimoto K;Guo J;Sakaguchi I;Honda R;Tashiro H;Katabuchi H
癌症干细胞（CSC）在几种类型的人类癌症中驱动肿瘤起始和转移。然而，卵巢肿瘤干细胞对腹膜转移的贡献仍未得到解决。细胞粘附分子CD 44已被鉴定为实体瘤（包括上皮性卵巢癌）中CSC的主要标志物。CD 44以标准形式（CD 44 s）存在，也以通过选择性mRNA剪接产生的许多变体同种型（CD 44 v）存在。在这里，我们发现盆腔腹膜中的播散性卵巢肿瘤含有高度富集的CD 44 v6阳性癌细胞，这些癌细胞驱动肿瘤转移并负责肿瘤对化疗的耐药性。临床上，原发性肿瘤中CD 44 v6阳性癌细胞数量的增加与III-IV期卵巢癌患者总生存期的缩短相关。此外，CD 44 v6阳性癌细胞亚群表现出在体内小鼠模型中在盆腔腹膜中启动肿瘤转移的能力，表明CD 44 v6阳性细胞显示出作为转移启动细胞的潜力。因此，上皮性卵巢癌的腹膜播散性转移是由CD 44 v6阳性亚群启动的，CD 44 v6表达是晚期卵巢癌患者临床结局的生物标志物。鉴于CD 44 v6阳性癌细胞的独特亚群在腹膜转移中起关键作用，确定性治疗应针对上皮性卵巢癌中的CD 44 v6阳性细胞亚群。
Cancer stem cells (CSCs) drive tumor initiation and metastasis in several types of human cancer. However, the contribution of ovarian CSCs to peritoneal metastasis remains unresolved. The cell adhesion molecule CD44 has been identified as a major marker for CSCs in solid tumors, including epithelial ovarian cancer. CD44 exists as a standard form (CD44s) and also as numerous variant isoforms (CD44v) generated by alternative mRNA splicing. Here we show that disseminated ovarian tumors in the pelvic peritoneum contain highly enriched CD44v6-positive cancer cells, which drive tumor metastasis and are responsible for tumor resistance to chemotherapy. Clinically, an increased number of CD44v6-positive cancer cells in primary tumors was associated with a shortened overall survival in stage III–IV ovarian cancer patients. Furthermore, a subpopulation of CD44v6-positive cancer cells manifested the ability to initiate tumor metastasis in the pelvic peritoneum in an in vivo mouse model, suggesting that CD44v6-positive cells show the potential to serve as metastasis-initiating cells. Thus, the peritoneal disseminated metastasis of epithelial ovarian cancer is initiated by the CD44v6-positive subpopulation, and CD44v6 expression is a biomarker for the clinical outcome of advanced ovarian cancer patients. Given that a distinct subpopulation of CD44v6-positive cancer cells plays a critical role in peritoneal metastasis, definitive treatment should target this subpopulation of CD44v6-positive cells in epithelial ovarian cancer.