A CD44v(+) subpopulation of breast cancer stem-like cells with enhanced lung metastasis capacity.
A CD44v(+) subpopulation of breast cancer stem-like cells with enhanced lung metastasis capacity.
复制标题
具有增强肺转移能力的乳腺癌干细胞样细胞的 CD44v 亚群。
DOI：
10.1038/cddis.2017.72
复制
发表时间：
2017-03-16
影响因子：
9
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Hu J;Li G;Zhang P;Zhuang X;Hu G
癌症干细胞样细胞（CSC）是负责肿瘤生长的癌细胞亚群，最近的证据表明CSC也有助于癌症转移。然而，乳腺癌中CSC转移能力的异质性仍不清楚。在这里，我们发现在CD 24-/CD 44+乳腺CSC中，表达CD 44变体（CD 44 v）的亚群比表达标准CD 44亚型CD 44 s的亚群显示出显著更高的肺转移能力。通过调节上皮剪接调节蛋白1（ESRP 1）的表达来增加或降低乳腺癌细胞的CD 44 v/CD 44 s比率导致促进或抑制肺转移而不影响癌细胞的干细胞性。直接抑制CD 44 v表达可显著减轻肺转移负荷。在机械上，CD 44 v而不是CD 44 s响应于肺环境中的骨桥蛋白（OPN），以增强癌细胞侵袭力并促进肺转移。在临床样本中，ESRP 1和CD 44 v的表达，而不是CD 44 s或总CD 44，与远处转移呈正相关。总体而言，我们的数据确定了一个以CD 44 v表达为特征的转移性乳腺CSC子集，并表明CD 44 v和ESRP 1可能是乳腺癌转移的更好预后标志物和治疗靶点。
Cancer stem-like cells (CSCs) are a subpopulation of cancer cells responsible for tumor growth, and recent evidence suggests that CSCs also contribute to cancer metastasis. However, the heterogeneity of CSCs in metastasis capacities is still unclear in breast cancer. Here we show that among the CD24−/CD44+ breast CSCs, a subset expressing the variant isoform of CD44 (CD44v) displays significantly higher capacity of lung metastasis than that expressing the standard CD44 isoform CD44s. Increasing or reducing the CD44v/CD44s ratio of breast cancer cells by regulating the expression of epithelial splicing regulatory protein 1 (ESRP1) leads to promotion or suppression of lung metastasis without influencing cancer cell stemness. Directly suppressing CD44v expression significantly alleviates the metastasis burden in lungs. Mechanically, CD44v, but not CD44s, responds to osteopontin (OPN) in the lung environment to enhance cancer cell invasiveness and promote lung metastasis. In clinical samples expression of ESRP1 and CD44v, rather than CD44s or total CD44, positively correlates with distant metastasis. Overall, our data identify a subset of metastatic breast CSCs characterized by CD44v expression, and suggest that CD44v and ESRP1 might be better prognosis markers and therapeutic targets for breast cancer metastasis.