Abstract:
:Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Lonardo E,Hermann PC,Mueller MT,Huber S,Balic A,Miranda-Lorenzo I,Zagorac S,Alcala S,Rodriguez-Arabaolaza I,Ramirez JC,Torres-Ruíz R,Garcia E,Hidalgo M,Cebrián DÁ,Heuchel R,Löhr M,Berger F,Bartenstein P,Aicher A,Heedoi
10.1016/j.stem.2011.10.001subject
Has Abstractpub_date
2011-11-04 00:00:00pages
433-46issue
5eissn
1934-5909issn
1875-9777pii
S1934-5909(11)00481-4journal_volume
9pub_type
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