Format

Send to

Choose Destination
Br J Cancer. 2017 Oct 24;117(9):1314-1325. doi: 10.1038/bjc.2017.305. Epub 2017 Sep 7.

Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands.

Author information

1
Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
2
Institute of Human Genetics, University of Goettingen, Goettingen 37073, Germany.
3
Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim 68167, Germany.
4
Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia 46010, Spain.
5
Sarcoma Research Group, Laboratori d'Oncologia Molecular, Oncobell, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), CIBERONC, L'Hospitalet de Llobregat 08908, Spain.
6
Pathology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
7
Cell Cycle and Cancer Laboratory, Biomedical Research Unit in Gynaecology, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
8
Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00165, Italy.
9
Pediatric Oncology and Hematology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.

Abstract

BACKGROUND:

Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood.

METHODS:

The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made.

RESULTS:

The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported.

CONCLUSIONS:

The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers.

PMID:
28881358
PMCID:
PMC5672936
DOI:
10.1038/bjc.2017.305
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center