The Wnt/β-catenin pathway regulates growth and maintenance of colonospheres

Molecular Cancer

Research

Yingjie Yu¹  Shailender S Kanwar¹  Jyoti Nautiyal²  Bhaumik B Patel²  Adhip PN Majumdar² 

[1] Department of Internal Medicine, School of Medicine, Wayne State University, 48201, Detroit, MI, USA;John D. Dingell V A Medical Center, 48201, Detroit, MI, USA;Department of Internal Medicine, School of Medicine, Wayne State University, 48201, Detroit, MI, USA;John D. Dingell V A Medical Center, 48201, Detroit, MI, USA;Karmanos Cancer Institute, 48201, Detroit, MI, USA;

关键词: Veteran Affair Medical;    Stem Cell Medium;    Colon Cancer Stem Cell;    Karmanos Cancer Institute;    Term Cancer Stem Cell;   

DOI  :  10.1186/1476-4598-9-212

 received in 2010-02-16, accepted in 2010-08-06,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundRecent 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.ResultsColonospheres 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.ConclusionOur 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.

【 授权许可】

Unknown   
© Kanwar et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.