Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine
Cancer stem cells (CSC) have attracted attention as therapeutic targets; however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here, we demonstrate that NSC-specific and CSC-specific roles of the stem cell trans...
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Published in | Cancer research (Chicago, Ill.) Vol. 77; no. 13; pp. 3442 - 3454 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research, Inc
01.07.2017
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Subjects | |
Online Access | Get full text |
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Summary: | Cancer stem cells (CSC) have attracted attention as therapeutic targets; however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here, we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSCs and intestinal tumors. Lineage-tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5
or Bmi1
NSCs resulted in loss of self-renewal but did not perturb homeostasis. Furthermore, in Lgr5
NSC, deletion of Hes1 and β-catenin stabilization limited tumor formation and prolonged host survival. Notably, in Lgr5
or Dclk1
tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSCs and CSCs, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target.
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0008-5472 1538-7445 |
DOI: | 10.1158/0008-5472.can-16-3192 |