Hedgehog inhibition with cyclopamine represses tumor growth and prolongs survival in a transgenic mouse model of islet cell tumors.
BACKGROUND
Blockade of aberrant hedgehog (Hh) activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors have not been examined. In this study, we address the role of the Hh pathway in tumor progression of murine islet cell tumors.


METHODS
To assess in vivo effects, Rip1Tag2 mice were treated with vehicle or cyclopamine (25 mg/kg/d) (n = 10 in each group). The effect of hedgehog pathway inhibition on survival was determined by continuous application of the small molecule smoothened antagonist cyclopamine.


RESULTS
Hh-inhibition was confirmed by downregulation of Hh-target genes. Cyclopamine response was associated with increased apoptosis, decreased tumor cell proliferation and reduced tumor volume. Furthermore, hedgehog inhibition with cyclopamine significantly prolonged median survival in the used transgenic mouse model (102 vs 124 days; P = 0.02).


CONCLUSIONS
Thus, Hh inhibitors may provide a new paradigm for therapy of islet cell tumors in various stages, particularly their use in conjunction with conventional antimetabolites should be further evaluated.
Department of Surgery, Philipps-University Marburg, Germany. fendrich@med.uni-marburg.de
Volker
V
Fendrich
Johannes
J
Rehm
Jens
J
Waldmann
Malte
M
Buchholz
Gerhard
G
Christofori
Matthias
M
Lauth
Emily P
EP
Slater
Detlef K
DK
Bartsch
D007516:Adenoma, Islet Cell / Q000473:pathology*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D020690:GTPase-Activating Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007124:Immunoenzyme Techniques; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D014704:Veratrum Alkaloids / Q000494:pharmacology*
D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; D053823:Hedgehog Proteins; C490620:Ralbp1 protein, mouse; D014704:Veratrum Alkaloids; C000541:cyclopamine