演題抄録

International Symposium

開催概要
開催回
第52回・2014年・横浜
 

Dclk1, a specific marker for tumor stem cells in digestive organs

演題番号 : TIS2-5

[筆頭演者]
Seno Hiroshi:1 
[共同演者]
Nakanishi Yuki:1、Chiba Tsutomu:1

1:Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University

 

Accumulating evidence supports the existence of tumor stem cells (TSCs), resembling normal stem cells (NSCs) in terms of self-renewal and continuous supply of progeny tumor cells. Many of TSC markers also mark NSCs, and specific markers for TSCs have been desired.
To investigate the role of a putative stem cell marker, doublecortin-like kinase 1 (Dclk1), we generated Dclk1creERT2/+ knock-in mice. In the intestines of Dclk1creERT2/+; Rosa26R mice, LacZ-labeled blue cells were scattered mainly near the crypt base one day after tamoxifen injection. However, on a daily basis, blue cells shifted from the crypt base toward the villus tip, accompanied by a decrease in their numbers. Thus, Dclk1 does not mark intestinal NSCs.
We next investigated whether Dclk1 marks TSCs during intestinal tumorigenesis. Surprisingly, lineage tracing analyses of Dclk1creERT2/+; Rosa26R; ApcMin/+ mice demonstrated that intestinal tumors were occupied by LacZ-labeled blue cells ("blue tumors"), with scattered LacZ expression in the normal intestinal mucosa after tamoxifen injection. Importantly, the number of blue tumors had not decreased for a prolonged period. These results indicate that Dclk1 marks not NSCs but TSCs.
We finally investigated whether targeting TSCs marked by Dclk1 could be an antitumor therapy. In Dclk1creERT2/+; Rosa26R; ApcMin/+; Rosa26iDTR/+ mice, administration of diphtheria toxin causes the death of Dclk1-expressing cells. After tamoxifen and diphtheria toxin treatment, most tumors regressed. However, there were no significant damages to the normal intestines.
In summary, Dclk1 appears to be a unique marker that discriminates TSCs from NSCs in the mouse intestine. In this session, we would like to present the role of Dclk1-expressing cells in digestive organ tumors, and also discuss novel therapeutic strategies targeting Dclk1-positive TSCs.

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