The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres.
The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres.
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DOI：
10.1186/1476-4598-9-212
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发表时间：
2010-08-06
期刊：
影响因子：
37.3
通讯作者：
Majumdar AP
中科院分区：
文献类型：
--
作者：
Kanwar SS;Yu Y;Nautiyal J;Patel BB;Majumdar AP
最近的证据表明，包括结直肠癌在内的上皮癌是由称为癌症干细胞（CSC）的自我更新的多能细胞的小亚群驱动的，这些细胞被认为是癌症复发的原因。CSC的特征之一是它们在无血清限定培养基中在非锚定条件下形成漂浮球状体的能力。本研究旨在探讨Wnt/β-catenin通路在结肠微球生长和维持中的作用。使用人结肠癌细胞HCT-116（p53野生型; K-ras突变体）、HCT-116（p53无效; K-ras突变体）和HT-29（p53突变体）。与相应的亲本癌细胞相比，体外形成的结肠球表现出结肠CSC标志物LGR 5、CD 44、CD 166和Musashi-1沿着推定的CSC标志物EpCAM的更高表达，并且还表现出在极端有限稀释下形成球状体的能力，表明结肠球中CSC的优势。由HCT-116细胞形成的结肠球显示超过80%的细胞为CD 44阳性，而相应的亲本细胞中的CD 44阳性率≤ 1%。此外，结肠微球显示膜结合β-连环蛋白减少，但总β-连环蛋白、细胞周期蛋白-D1和c-myc水平增加，轴蛋白-1和磷酸化β-连环蛋白下调。β-catenin的表达增加与TCF/LEF的显著转录激活相关。后者在通过相应的siRNA下调β-连环蛋白后大大降低，导致CD 44阳性细胞以及结肠球形成的显著减少。与此相反，上调c-myc，TCF/LEF的下游效应大大增强了结肠球的形成。我们的数据表明，结肠癌细胞系形成的结肠球高度富集CSCs，Wnt/β-catenin通路在结肠球的生长和维持中起着关键作用。
Recent evidence suggests that epithelial cancers, including colorectal cancer are driven by a small sub-population of self-renewing, multi-potent cells termed cancer stem cells (CSCs) which are thought to be responsible for recurrence of cancer. One of the characteristics of CSCs is their ability to form floating spheroids under anchorage-independent conditions in a serum-free defined media. The current investigation was undertaken to examine the role of Wnt/β-catenin pathway in regulating the growth and maintenance of colonospheres. Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant), HCT-116 (p53 null; K-ras mutant) and HT-29 (p53 mutant) were used. Colonospheres formed in vitro exhibited higher expression of colon CSCs markers LGR5, CD44, CD166 and Musashi-1 along with putative CSC marker EpCAM, compared to the corresponding parental cancer cells and also exhibit the ability to form spheroids under extreme limiting dilution, indicating the predominance of CSCs in colonospheres. Colonospheres formed by HCT-116 cells show over 80% of the cells to be CD44 positive, compared to ≤ 1% in the corresponding parental cells. Additionally, colonospheres showed reduced membrane bound β-catenin but had increased levels of total β-catenin, cyclin-D1 and c-myc and down regulation of axin-1 and phosphorylated β-catenin. Increased expression of β-catenin was associated with a marked transcriptional activation of TCF/LEF. The latter was greatly decreased following down regulation of β-catenin by the corresponding siRNA, leading to a marked reduction in CD44 positive cells as well as colonospheres formation. In contrast, upregulation of c-myc, a down-stream effector of TCF/LEF greatly augmented the formation of colonospheres. Our data suggest that colonospheres formed by colon cancer cell lines are highly enriched in CSCs and that Wnt/β-catenin pathway plays a critical role in growth and maintenance of colonospheres.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
11.2
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
通讯作者：
Boman BM
影响因子：
3.8
作者：
Kakarala, Madhuri;Brenner, Dean E.;Korkaya, Hasan;Cheng, Connie;Tazi, Karim;Ginestier, Christophe;Liu, Suling;Dontu, Gabriela;Wicha, Max S.
通讯作者：
Wicha, Max S.
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
ALDH1A1 是恶性前列腺干细胞的标记物，也是前列腺癌患者预后的预测因子。
DOI：
10.1038/labinvest.2009.127
发表时间：
2010-02
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
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