Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells
Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells
复制标题
DOI：
10.1038/sj.onc.1209327
复制
发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Tang, DG
中科院分区：
文献类型：
--
作者：
Patrawala, L;Calhoun, T;Tang, DG
CD44是一种参与细胞黏附和信号转导的多功能蛋白。CD44在前列腺癌(PCa)发生发展中的作用一直存在争议，有研究表明CD44既有促癌作用，也有抑瘤作用。这些研究大多使用批量培养的PCa细胞或PCa组织来进行相关或过度表达的实验。使用预期纯化的细胞进行的关键实验还没有进行。在这里，我们使用流式细胞术从多个PCA细胞培养和四个异种移植瘤中获得均一的CD44(+)和CD44(-)肿瘤细胞群，以比较它们的体外和体内肿瘤相关特性。我们的结果表明，CD44(+)的PCA细胞比同基因的CD44(-)的PCA细胞更具增殖性、克隆性、致瘤性和转移性。随后的分子生物学研究表明，CD44(+)的Pca细胞具有祖细胞的某些固有特性。首先，BrdU脉冲追逐实验显示CD44(+)细胞与一群中间标记保留细胞共存。其次，CD44(+)的PCa细胞表达较高水平的几种“干性”基因，包括Oct-3/4、BMI、β-catenin和SMO。第三，CD44(+)的PCa细胞在体外和体内都能产生CD44(-)细胞。第四，CD44(+)的Pca细胞是AR(-)，可以分化为AR(+)的肿瘤细胞。最后，在克隆分析中，CD44(+)的PCA细胞中似乎有很小的比例经历了不对称的细胞分裂。综上所述，我们的结果提示CD44(+)的Pca细胞群富含致瘤和转移的前体细胞。
CD44 is a multifunctional protein involved in cell adhesion and signaling. The role of CD44 in prostate cancer (PCa) development and progression is controversial with studies showing both tumor-promoting and tumor-inhibiting effects. Most of these studies have used bulk-cultured PCa cells or PCa tissues to carry out correlative or overexpression experiments. The key experiment using prospectively purified cells has not been carried out. Here we use FACS to obtain homogeneous CD44(+) and CD44(-) tumor cell populations from multiple PCa cell cultures as well as four xenograft tumors to compare their in vitro and in vivo tumor-associated properties. Our results reveal that the CD44(+) PCa cells are more proliferative, clonogenic, tumorigenic, and metastatic than the isogenic CD44(-) PCa cells. Subsequent molecular studies demonstrate that the CD44(+) PCa cells possess certain intrinsic properties of progenitor cells. First, BrdU pulse-chase experiments reveal that CD44(+) cells colocalize with a population of intermediate label-retaining cells. Second, CD44(+) PCa cells express higher mRNA levels of several 'stemness' genes including Oct- 3/4, Bmi, beta-catenin, and SMO. Third, CD44(+) PCa cells can generate CD44(-) cells in vitro and in vivo. Fourth, CD44(+) PCa cells, which are AR(-), can differentiate into AR(+) tumor cells. Finally, a very small percentage of CD44(+) PCa cells appear to undergo asymmetric cell division in clonal analyses. Altogether, our results suggest that the CD44(+) PCa cell population is enriched in tumorigenic and metastatic progenitor cells.