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Targeting stem cell behavior in desmoid tumors (aggressive fibromatosis) by inhibiting hedgehog signaling.
MedLine Citation:
PMID:  23814483     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Desmoid tumor (also called aggressive fibromatosis) is a lesion of mesenchymal origin that can occur as a sporadic tumor or a manifestation of the preneoplastic syndrome, familial adenomatous polyposis caused by a mutation in adenomatous polyposis coli (APC). This tumor type is characterized by the stabilization of β-catenin and activation of Tcf-mediated transcription. Cell transplantation data suggest that desmoid tumors are derived from mesenchymal progenitor cells (MSCs). As such, modulating cell signaling pathways that regulate MSC differentiation or proliferation, such as hedgehog (Hh) signaling, could alter the tumor phenotype. Here, we found that Hh signaling is activated in human and murine desmoid tumors. Inhibiting Hh signaling in human cell cultures decreased cell proliferation and β-catenin protein levels. Apc(+)/Apc(1638N) mice, which develop desmoid tumors, develop smaller and fewer tumors when Hh signaling was inhibited either genetically (by crossing Apc(+)/Apc(1638N) mice with mice lacking one copy of a Hh-activated transcription factor, Gli2 (+/-) mice) or using a pharmacologic inhibitor. Both in mice and in human tumor cell cultures, β-catenin and Hh-mediated signaling positively regulate each other's activity. These data show that targeting a pathway that regulates MSC differentiation influences desmoid tumor behavior, providing functional evidence supporting the notion that these tumors are derived from mesenchymal progenitors. It also suggests Hh blockade as a therapeutic approach for this tumor type.
Authors:
Ronak Ghanbari-Azarnier; Shingo Sato; Qingxia Wei; Mushriq Al-Jazrawe; Benjamin A Alman
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  15     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  712-9     Citation Subset:  IM    
Affiliation:
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
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