hedgehog signalling pathway: carcinogenesis and targeted therapy

Authors

abdolali ebrahimi dept. of pathology, shahid beheshti university of medical sciences, tehran, iran

laila larijani cancer research center, shahid beheshti university of medical sciences, tehran, iran

afshin moradi cancer research center, shahid beheshti university of medical sciences, tehran, iran

mohamad reza ebrahimi red crescent society of islamic republic of iran, tehran, iran

abstract

hedgehog signalling pathway has not only a critical role in cell proliferation, differentiation and tissue polarity at embryonic period but also has a vital role in stem cell proliferation, tissue healing and carcinogenesis. recent research has increased our understanding of this pathway and its relation to other signalling pathways. in addition, a large number of studies confirmed the alteration of hh signalling pathway in various types of human malignancies including basal cell carcinomas, medulloblastomas, lung, gastrointestinal, ovarian, breast, prostate cancers and leukemia. more than 50 small biomolecules have been introduced which have inhibitory effects on hh signalling pathway. although, in many tumors some acceptable results have been showed in phase i clinical trial, closer studies are required to improve drug bioavailability, to decrease the side effects and to find the right small molecules for specific types of cancers, considering patients overall benefits as well.

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Journal title:
iranian journal of cancer prevention

جلد ۶، شماره ۱، صفحات ۳۶-۴۳

Keywords
[ ' h e d g e h o g ' , ' n e o p l a s m ' , ' m o l e c u l a r t a r g e t e d t h e r a p y p l e a s e c i t e t h i s a r t i c l e a s ' , ' e b r a h i m i a ' , ' l a r i j a n i l ' , ' m o r a d i a ' , ' e b r a h i m i m r . h e d g e h o g s i g n a l l i n g p a t h w a y ' , ' c a r c i n o g e n e s i s a n d t a r g e t e d t h e r a p y . i r a n j c a n c e r p r e v . 2 0 1 3 ' , ' 6 ( 1 ) ' , 3 6 , ' 4 3 . r e f e r e n c e s 1 . l i u h ' , ' g u d ' , ' x i e j . c l i n i c a l i m p l i c a t i o n s o f h e d g e h o g s i g n a l l i n g p a t h w a y i n h i b i t o r s . c h i n j c a n c e r . 2 0 1 1 ' , ' 3 0 ( 1 ) ' , 1 3 , ' 2 6 . 2 . h e r e t s c h p h i l i p p ' , ' t z a g k a r o u l a k i l i t o ' , ' g i a n n i s a t h a n a s s i o s . m o d u l a t o r s o f t h e h e d g e h o g s i g n a l l i n g p a t h w a y . b i o o r g m e d c h e m . 2 0 1 0 ' , ' 1 8 ( 1 8 ) ' , 6 6 1 3 , ' 2 4 . 3 . l e e j j ' , ' e k k e r s c ' , ' v o n k e s s l e r d p ' , ' p o r t e r j a ' , ' s u n b i ' , ' b e a c h y p a . a u t o p r o t e o l y s i s i n h e d g e h o g p r o t e i n b i o g e n e s i s . s c i e n c e . 1 9 9 4 ' , ' 2 6 6 ( 5 1 9 0 ) ' , 1 5 2 8 , ' 3 7 . 4 . b u g l i n o j a ' , ' r e s h m d . h h a t i s a p a l m i t o y l a c y l t r a n s f e r a s e w i t h s p e c i f i c i t y f o r n ' , ' p a l m i t o y l a t i o n o f s o n i c h e d g e h o g . j b i o l c h e m . 2 0 0 8 ' , ' 2 8 3 ( 3 2 ) ' , 2 2 0 7 6 , ' 8 8 . 5 . k e l l e y r l ' , ' r o e s s l e r e ' , ' h e n n e k a m r c ' , ' f e l d m a n g l ' , ' k o s a k i k ' , ' j o n e s m c ' , ' e t a l . h o l o p r o s e n c e p h a l y i n r s h / s m i t h ' , ' l e m l i ' , ' o p i t z s y n d r o m e ' , ' d o e s a b n o r m a l c h o l e s t e r o l m e t a b o l i s m a f f e c t t h e f u n c t i o n o f s o n i c h e d g e h o g ? a m j m e d g e n e t . 1 9 9 6 ' , ' 6 6 ( 4 ) ' , 4 7 8 , ' 8 4 . 6 . d i e r k e r t ' , ' d 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[ 2 1 6 1 4 0 2 6 ] 3 4 . p a r s o n s d w ' , ' l i m ' , ' z h a n g x ' , ' j o n e s s ' , ' l e a r y r j ' , ' l i n j c ' , ' e t a l . t h e g e n e t i c l a n d s c a p e o f t h e c h i l d h o o d c a n c e r m e d u l l o b l a s t o m a . s c i e n c e . 2 0 1 1 ' , ' 3 3 1 ( 6 0 1 6 ) ' , 4 3 5 , ' 9 . 3 5 . g i b s o n p ' , ' t o n g y ' , ' r o b i n s o n g ' , ' t h o m p s o n m c ' , ' c u r r l e d s ' , ' e d e n c ' , ' e t a l . s u b t y p e s o f m e d u l l o b l a s t o m a h a v e d i s t i n c t d e v e l o p m e n t a l o r i g i n s . n a t u r e . 2 0 1 0 ' , ' 4 6 8 ( 7 3 2 7 ) ' , 1 0 9 5 , ' 9 . 3 6 . y a n g s h ' , ' a n d l t ' , ' g r a c h t c h o u k v ' , ' w a n g a ' , ' l i u j ' , ' s y u l j ' , ' e t a l . p a t h o l o g i c a l r e s p o n s e s t o o n c o g e n i c h e d g e h o g s i g n a l l i n g i n s k i n a r e d e p e n d e n t o n c a n o n i c a l w n t / ' , ' c a t e n i n s i g n a l l i n g . n a t g e n e t . 2 0 0 8 . 4 0 ( 9 ) ' , 1 1 3 0 , ' 5 . 3 7 . y a n a i k ' , ' n a k a m u r a m ' , ' a k i y o s h i t ' , ' n a g a i s ' , ' w a d a j ' , ' k o g a k ' , ' e t a l . c r o s s t a l k o f h e d g e h o g a n d w n t p a t h w a y s i n g a s t r i c c a n c e r . c a n c e r l e t t . 2 0 0 8 ' , ' 2 6 3 ( 1 ) ' , 1 4 5 , ' 5 6 . 3 8 . e h t e s h a m m ' , ' s a r a n g i a ' , ' v a l a d e z j g ' , ' c h a n t h a p h a y c h i t h s ' , ' b e c h e r m w ' , ' a b e l t w ' , ' e t a l . l i g a n d ' , ' d e p e n d e n t a c t i v a t i o n o f t h e h e d g e h o g p a t h w a y i n g l i o m a p r o g e n i t o r c e l l s . o n c o g e n e . 2 0 0 7 ' , ' 2 6 ( 3 9 ) ' , 5 7 5 2 , ' 6 1 . 3 9 . l i n d e m a n n r k . s t r o m a ' , ' i n i t i a t e d h e d g e h o g s i g n a l l i n g t a k e s c e n t e r s t a g e i n b ' , ' c e l l l y m p h o m a . c a n c e r r e s . 2 0 0 8 ' , ' 6 8 ( 4 ) ' , 9 6 1 , ' 4 . 4 0 . f i a s c h i m ' , ' r o z e l l b ' , ' b e r g s t r o m a ' , ' t o f t g a r d r . d e v e l o p m e n t o f m a m m a r y t u m o r s b y c o n d i t i o n a l e x p r e s s i o n o f g l i 1 . c a n c e r r e s . 2 0 0 9 ' , ' 6 9 ( 1 1 ) ' , 4 8 1 0 , ' 7 . 4 1 . k a s p e r m ' , ' j a k s v ' , ' f i a s c h i m ' , ' t o f t g a r d r . h e d g e h o g s i g n a l l i n g i n b r e a s t c a n c e r . c a r c i n o g e n e s i s . 2 0 0 9 ' , ' 3 0 ( 6 ) ' , 9 0 3 , ' 1 1 . 4 2 . l i a o x ' , ' s i u m k ' , ' a u c w ' , ' w o n g e s ' , ' c h a n h y ' , ' i p p p ' , ' e t a l . a b e r r a n t a c t i v a t i o n o f h e d g e h o g s i g n a l l i n g p a t h w a y i n o v a r i a n c a n c e r s ' , ' e f f e c t o n p r o g n o s i s ' , ' c e l l i n v a s i o n a n d d i f f e r e n t i a t i o n . c a r c i n o g e n e s i s . 2 0 0 9 ' , ' 3 0 ( 1 ) ' , 1 3 1 , ' 4 0 . 4 3 . p a u l s o n v ' , ' c h a n d l e r g ' , ' r a k h e j a d ' , ' g a l i n d o r l ' , ' w i l s o n k ' , ' a m a t r u d a j f ' , ' e t a l . h i g h ' , ' r e s o l u t i o n a r r a y c g h i d e n t i f i e s c o m m o n m e c h a n i s m s t h a t d r i v e e m b r y o n a l r h a b d o m y o s a r c o m a p a t h o g e n e s i s . g e n e s c h r o m o s o m e s c a n c e r . 2 0 1 1 ' , ' 5 0 ( 6 ) ' , 3 9 7 , ' 4 0 8 . 4 4 . s c h n e i d e r s ' , ' t h u r n h e r d ' , ' k l o i m s t e i n p ' , ' l e i t n e r v ' , ' p e t z e l b a u e r p ' , ' p a m m e r j ' , ' e t a l . e x p r e s s i o n o f t h e s o n i c h e d g e h o g p a t h w a y i n s q u a m o u s c e l l c a r c i n o m a o f t h e s k i n a n d t h e m u c o s a o f t h e h e a d a n d n e c k . h e a d n e c k . 2 0 1 1 ' , ' 3 3 ( 2 ) ' , 2 4 4 , ' 5 0 . 4 5 . d a s s ' , ' h a r r i s l g ' , ' m e t g e b j ' , ' l i u s ' , ' r i k e r a i ' , ' s a m a n t r s ' , ' e t a l . t h e h e d g e h o g p a t h w a y t r a n s c r i p t i o n f a c t o r g l i 1 p r o m o t e s m a l i g n a n t b e h a v i o r o f c a n c e r c e l l s b y u p ' , ' r e g u l a t i n g o s t e o p o n t i n . j b i o l c h e m . 2 0 0 9 ' , ' 2 8 4 ( 3 4 ) ' , 2 2 8 8 8 , ' 9 7 . 4 6 . a l e x a k i v i ' , ' j a v e l a u d d ' , ' v a n k e m p e n l c ' , ' m o h a m m a d k s ' , ' d e n n l e r s ' , ' l u c i a n i f ' , ' e t a l . g l i 2 ' , ' m e d i a t e d m e l a n o m a i n v a s i o n a n d m e t a s t a s i s . j n a t l c a n c e r i n s t . 2 0 1 0 ' , ' 1 0 2 ( 1 5 ) ' , 1 1 4 8 , ' 5 9 . 4 7 . b a i l e y j m ' , ' m o h r a m ' , ' h o l l i n g s w o r t h m a . s o n i c h e d g e h o g p a r a c r i n e s i g n a l l i n g r e g u l a t e s m e t a s t a s i s a n d l y m p h a n g i o g e n e s i s i n p a n c r e a t i c c a n c e r . o n c o g e n e . 2 0 0 9 ' , ' 2 8 ( 4 0 ) ' , 3 5 1 3 , ' 2 5 . 4 8 . f e l d m a n n g ' , ' d h a r a s ' , ' f e n d r i c h v ' , ' b e d j a d ' , ' b e a t y r ' , ' m u l l e n d o r e m ' , ' e t a l . b l o c k a d e o f h e d g e h o g s i g n a l l i n g i n h i b i t s p a n c r e a t i c c a n c e r i n v a s i o n a n d m e t a s t a s e s ' , ' a n e w p a r a d i g m f o r c o m b i n a t i o n t h e r a p y i n s o l i d c a n c e r s . c a n c e r r e s . 2 0 0 7 ' , ' 6 7 ( 5 ) ' , 2 1 8 7 , ' 9 6 . 4 9 . m a x ' , ' s h e n g t ' , ' z h a n g y ' , ' z h a n g x ' , ' h e j ' , ' h u a n g s ' , ' e t a l . h e d g e h o g s i g n a l l i n g i s a c t i v a t e d i n s u b s e t s o f e s o p h a g e a l c a n c e r s . i n t j c a n c e r . 2 0 0 6 ' , ' 1 1 8 ( 1 ) ' , 1 3 9 , ' 4 8 . 5 0 . x u m ' , ' l i x ' , ' l i u t ' , ' l e n g a ' , ' z h a n g g . p r o g n o s t i c v a l u e o f h e d g e h o g s i g n a l l i n g p a t h w a y i n p a t i e n t s w i t h c o l o n c a n c e r . m e d o n c o l . 2 0 1 1 . [ 2 1 4 2 4 3 2 6 ] 5 1 . c h a n g h h ' , ' c h e n b y ' , ' w u c y ' , ' t s a o z j ' , ' c h e n y y ' , ' c h a n g c p ' , ' e t a l . h e d g e h o g o v e r e x p r e s s i o n l e a d s t o t h e f o r m a t i o n o f p r o s t a t e c a n c e r s t e m c e l l s w i t h m e t a s t a t i c p r o p e r t y i r r e s p e c t i v e o f a n d r o g e n r e c e p t o r e x p r e s s i o n i n t h e m o u s e m o d e l . j b i o m e d s c i . 2 0 1 1 ' , ' 1 8 ( 1 8 ) ' , ' 6 . [ 2 1 2 4 1 5 1 2 ] 5 2 . o i s h i n ' , ' w a n g x w . n o v e l t h e r a p e u t i c s t r a t e g i e s f o r t a r g e t i n g l i v e r c a n c e r s t e m c e l l s . i n t j b i o l s c i . 2 0 1 1 ' , 2 6 , ' 7 ( 5 ) ' , 5 1 7 , ' 3 5 . 5 3 . d i e r k s c ' , ' b e i g i r ' , ' g u o g r ' , ' z i r l i k k ' , ' s t e g e r t m r ' , ' m a n l e y p ' , ' e t a l . e x p a n s i o n o f b c r ' , ' a b l ' , ' p o s i t i v e l e u k e m i c s t e m c e l l s i s d e p e n d e n t o n h e d g e h o g p a t h w a y a c t i v a t i o n . c a n c e r c e l l . 2 0 0 8 ' , ' 1 4 ( 3 ) ' , 2 3 8 , ' 4 9 . 5 4 . z h a o c ' , ' c h e n a ' , ' j a m i e s o n c h ' , ' f e r e s h t e h m ' , ' a b r a h a m s s o n a ' , ' b l u m j ' , ' e t a l . h e d g e h o g s i g n a l l i n g i s e s s e n t i a l f o r m a i n t e n a n c e o f c a n c e r s t e m c e l l s i n m y e l o i d l e u k a e m i a . n a t u r e . 2 0 0 9 ' , ' 4 5 8 ( 7 2 3 9 ) ' , 7 7 6 , ' 9 . 5 5 . s i m s ' , ' m o u r t a d a j ' , ' i z z o j g ' , ' a p i s a r n t h a n a r a x s ' , ' w u t t ' , ' m a l h o t r a u ' , ' l u t h r a r ' , ' e t a l . h e d g e h o g ' , ' a n a t t r i b u t e t o t u m o r r e g r o w t h a f t e r c h e m o r a d i o t h e r a p y a n d a t a r g e t t o i m p r o v e r a d i a t i o n r e s p o n s e . c l i n c a n c e r r e s . 2 0 0 6 ' , ' 1 2 ( 2 1 ) ' , 6 5 6 5 , ' 7 2 . 5 6 . o l i v e k p ' , ' j a c o b e t z m a ' , ' d a v i d s o n c j ' , ' g o p i n a t h a n a ' , ' m c i n t y r e d ' , ' h o n e s s d ' , ' e t a l . i n h i b i t i o n o f h e d g e h o g s i g n a l l i n g e n h a n c e s d e l i v e r y o f c h e m o t h e r a p y i n a m o u s e m o d e l o f p a n c r e a t i c c a n c e r . s c i e n c e . 2 0 0 9 ' , ' 3 2 4 ( 5 9 3 3 ) ' , 1 4 5 7 , ' 6 1 . 5 7 . p a s c a d i m a g l i a n o m ' , ' s e k i n e s ' , ' e r m i l o v a ' , ' f e r r i s j ' , ' d l u g o s z a a ' , ' h e b r o k m . h e d g e h o g / r a s i n t e r a c t i o n s r e g u l a t e e a r l y s t a g e s o f p a n c r e a t i c c a n c e r . g e n e s d e v . 2 0 0 6 ' , ' 2 0 ( 2 2 ) ' , 3 1 6 1 , ' 7 3 . 5 8 . k o g a k ' , ' n a k a m u r a m ' , ' n a k a s h i m a h ' , ' a k i y o s h i t ' , ' k u b o m ' , ' s a t o n ' , ' e t a l . n o v e l l i n k b e t w e e n e s t r o g e n r e c e p t o r a l p h a a n d h e d g e h o g p a t h w a y i n b r e a s t c a n c e r . a n t i c a n c e r r e s . 2 0 0 8 ' , ' 2 8 ( 2 a ) ' , 7 3 1 , ' 4 0 . 5 9 . j i z ' , ' m e i f c ' , ' x i e j ' , ' c h e n g x . o n c o g e n i c k r a s s u p r e s s e s g l i 1 d e g r a d a t i o n a n d a c t i v a t e s h e d g e h o g s i g n a l l i n g p a t h w a y i n p a n c r e a t i c c a n c e r c e l l s . j b i o l c h e m . 2 0 0 7 ' , ' 2 8 2 ( 1 9 ) ' , 1 4 0 4 8 , ' 5 5 . 6 0 . k a s p e r c z y k h ' , ' b a u m a n n b ' , ' d e b a t i n k m ' , ' f u l d a s . c h a r a c t e r i z a t i o n o f s o n i c h e d g e h o g a s a n o v e l n f ' , ' k a p p a b t a r g e t g e n e t h a t p r o m o t e s n f ' , ' k a p p a b ' , ' m e d i a t e d a p o p t o s i s r e s i s t a n c e a n d t u m o r g r o w t h i n v i v o . f a s e b j . 2 0 0 9 ' , ' 2 3 ( 1 ) ' , 2 1 , ' 3 3 . 6 1 . z w e r n e r j p ' , ' j o o j ' , ' w a r n e r k l ' , ' c h r i s t e n s e n l ' , ' h u ' , ' l i e s k o v a n s ' , ' t r i c h e t j ' , ' e t a l . t h e e w s / f l i 1 o n c o g e n i c t r a n s c r i p t i o n f a c t o r d e r e g u l a t e s g l i 1 . o n c o g e n e . 2 0 0 8 ' , ' 2 7 ( 2 3 ) ' , 3 2 8 2 , ' 9 1 . 6 2 . k a s a i k ' , ' i n a g u m a s ' , ' y o n e y a m a a ' , ' y o s h i k a w a k ' , ' i k e d a h . s c l / t a l 1 i n t e r r u p t i n g l o c u s d e r e p r e s s e s g l i 1 f r o m t h e n e g a t i v e c o n t r o l o f s u p p r e s s o r ' , ' o f ' , ' f u s e d i n p a n c r e a t i c c a n c e r c e l l . c a n c e r r e s . 2 0 0 8 ' , ' 6 8 ( 1 9 ) ' , 7 7 2 3 , ' 9 . 6 3 . n o l a n ' , ' s t e v a u x o ' , ' l a u j ' , ' t r u i t t m l ' , ' c h u g c ' , ' h e b r o k m ' , ' f e r n á n d e z ' , ' z a p i c o m e ' , ' e t a l . g l i 1 i s r e g u l a t e d t h r o u g h s m o o t h e n e d ' , ' i n d e p e n d e n t m e c h a n i s m s i n n e o p l a s t i c p a n c r e a t i c d u c t s a n d m e d i a t e s p d a c c e l l s u r v i v a l a n d t r a n s f o r m a t i o n . g e n e s d e v . 2 0 0 9 ' , ' 2 3 ( 1 ) ' , 2 4 , ' 3 6 . 6 4 . s t e c c a b ' , ' r u i z i a l t a b a a . x a 0 a g l i 1 ' , ' p 5 3 i n h i b i t o r y l o o p c o n t r o l s n e u r a l s t e m c e l l a n d t u m o u r c e l l n u m b e r s . e m b o j . 2 0 0 9 ' , ' 2 8 ( 6 ) ' , 6 6 3 , ' 7 6 . 6 5 . l a n e r ' , ' p l a m b e r g e r s ' , ' k a s e r a ' , ' p a u l i s c h t a m ' , ' h a u s e r ' , ' k r o n b e r g e r c ' , ' e i c h b e r g e r t ' , ' f r i s c h a u f a m . c o o p e r a t i o n b e t w e e n g l i a n d j u n e n h a n c e s t r a n s c r i p t i o n o f j u n a n d s e l e c t e d g l i t a r g e t g e n e s . o n c o g e n e . 2 0 0 9 ' , ' 2 8 ( 1 3 ) ' , 1 6 3 9 , ' 5 1 . 6 6 . v o n h o f f d d ' , ' l o r u s s o p m ' , ' r u d i n c m ' , ' r e d d y j c ' , ' y a u c h r l ' , ' t i b e s r ' , ' e t a l . i n h i b i t i o n o f t h e h e d g e h o g p a t h w a y i n a d v a n c e d b a s a l ' , ' c e l l c a r c i n o m a . n e n g l j m e d . 2 0 0 9 ' , ' 3 6 1 ( 1 2 ) ' , 1 1 6 4 , ' 7 2 . 6 7 . c h e n j k ' , ' t a i p a l e j ' , ' c o o p e r m k ' , ' b e a c h y p a . i n h i b i t i o n o f h e d g e h o g s i g n a l l i n g b y d i r e c t b i n d i n g o f c y c l o p a m i n e t o s m o o t h e n e d . g e n e s d e v . 2 0 0 2 ' , ' 1 6 ( 2 1 ) ' , 2 7 4 3 , ' 8 . 6 8 . y a u c h r l ' , ' g o u l d s e ' , ' s c a l e s s j ' , ' t a n g t ' , ' t i a n h ' , ' a h n c p ' , ' e t a l . a p a r a c r i n e r e q u i r e m e n t f o r h e d g e h o g s i g n a l l i n g i n c a n c e r . n a t u r e . 2 0 0 8 ' , ' 4 5 5 ( 7 2 1 1 ) ' , 4 0 6 , ' 1 0 . 6 9 . r u d i n c m ' , ' h a n n c l ' , ' l a t e r r a j ' , ' y a u c h r l ' , ' c a l l a h a n c a ' , ' f u l ' , ' e t a l . t r e a t m e n t o f m e d u l l o b l a s t o m a w i t h h e d g e h o g p a t h w a y i n h i b i t o r g d c ' , ' 0 4 4 9 . n e n g l j m e d . 2 0 0 9 ' , ' 3 6 1 ( 1 2 ) ' , 1 1 7 3 , ' 8 . 7 0 . s t e p h e n s o n j ' , ' r i c h a r d s d a ' , ' w o l p i n b m ' , ' b e c e r r a c ' , ' h a m m j t ' , ' m e s s e r s m i t h w a ' , ' e t a l . t h e s a f e t y o f i p i ' , 9 2 6 , ' a n o v e l h e d g e h o g p a t h w a y i n h i b i t o r ' , ' i n c o m b i n a t i o n w i t h g e m c i t a b i n e i n p a t i e n t s ( p t s ) w i t h m e t a s t a t i c p a n c r e a t i c c a n c e r . j c l i n o n c o l . 2 0 1 1 ( s u p p l ' , ' a b s t r 4 1 1 4 ) . 7 1 . p e a c o c k c d ' , ' w a n g q ' , ' g e s e l l g s ' , ' c o r c o r a n ' , ' s c h w a r t z i m ' , ' j o n e s e ' , ' k i m j ' , ' e t a l . h e d g e h o g s i g n a l l i n g m a i n t a i n s a t u m o r s t e m c e l l c o m p a r t m e n t i n m u l t i p l e m y e l o m a . p r o c n a t l a c a d s c i u s a . 2 0 0 7 ' , ' 1 0 4 ( 1 0 ) ' , 4 0 4 8 , ' 5 3 . 7 2 . l ö h r j m . m e d i c a l t r e a t m e n t o f p a n c r e a t i c c a n c e r . e x p e r t r e v a n t i c a n c e r t h e r . 2 0 0 7 ' , ' 7 ( 4 ) ' , 5 3 3 , ' 4 4 . 7 3 . j o n e s s ' , ' z h a n g x ' , ' p a r s o n s d w ' , ' l i n j c ' , ' l e a r y r j ' , ' a n g e n e n d t ' , ' e t a l . c o r e s i g n a l l i n g p a t h w a y s i n h u m a n p a n c r e a t i c c a n c e r s r e v e a l e d b y g l o b a l g e n o m i c a n a l y s e s . x a 0 s c i e n c e . 2 0 0 8 ' , ' 3 2 1 ( 5 8 9 7 ) ' , 1 8 0 1 , ' 6 . 7 4 . f e l d m a n n g ' , ' h a b b e n ' , ' d h a r a s ' , ' b i s h t s ' , ' a l v a r e z h ' , ' f e n d r i c h v ' , ' e t a l . h e d g e h o g i n h i b i t i o n p r o l o n g s s u r v i v a l i n a g e n e t i c a l l y e n g i n e e r e d m o u s e m o d e l o f p a n c r e a t i c c a n c e r . g u t . 2 0 0 8 ' , ' 5 7 ( 1 0 ) ' , 1 4 2 0 , ' 3 0 . 7 5 . g a o j ' , ' g r a v e s s ' , ' k o c h u ' , ' l i u s ' , ' j a n k o v i c v ' , ' b u o n a m i c i s ' , ' e t a l . h e d g e h o g s i g n a l l i n g i s d i s p e n s a b l e f o r a d u l t h e m a t o p o i e t i c s t e m c e l l f u n c t i o n . c e l l s t e m c e l l . 2 0 0 9 ' , ' 4 ( 6 ) ' , 5 4 8 , ' 5 8 . 7 6 . h o f m a n n i ' , ' s t o v e r e h ' , ' c u l l e n d e ' , ' m a o j ' , ' m o r g a n k j ' , ' l e e b h ' , ' e t a l . h e d g e h o g s i g n a l l i n g i s d i s p e n s a b l e f o r a d u l t m u r i n e h e m a t o p o i e t i c s t e m c e l l f u n c t i o n a n d h e m a t o p o i e s i s . c e l l s t e m c e l l . 2 0 0 9 ' , ' 4 ( 6 ) ' , 5 5 9 , ' 6 7 . 7 7 . h y m a n j m ' , ' f i r e s t o n e a j ' , ' h e i n e v m ' , ' z h a o y ' , ' o c a s i o c a ' , ' h a n k ' , ' e t a l . s m a l l ' , ' m o l e c u l e i n h i b i t o r s r e v e a l m u l t i p l e s t r a t e g i e s f o r h e d g e h o g p a t h w a y b l o c k a d e . p r o c n a t l a c a d s c i u s a . 2 0 0 9 ' , 1 8 , ' 1 0 6 ( 3 3 ) ' , 1 4 1 3 2 , ' 7 . 7 8 . s c a l e s s j ' , ' d e s a u v a g e f j . x a 0 m e c h a n i s m s o f h e d g e h o g p a t h w a y a c t i v a t i o n i n c a n c e r a n d i m p l i c a t i o n s f o r t h e r a p y . t r e n d s p h a r m a c o l s c i . 2 0 0 9 ' , ' 3 0 ( 6 ) ' , 3 0 3 , ' 1 2 . 7 9 . s t a n t o n b z ' , ' p e n g l f ' , ' m a l o o f n ' , ' n a k a i k ' , ' w a n g x ' , ' d u f f n e r j l ' , ' e t a l . a s m a l l m o l e c u l e t h a t b i n d s h e d g e h o g a n d b l o c k s i t s s i g n a l l i n g i n h u m a n c e l l s . n a t c h e m b i o l . 2 0 0 9 ' , ' 5 ( 3 ) ' , 1 5 4 , ' 6 . 8 0 . s a n c h e z p ' , ' h e r n á n d e z a m ' , ' s t e c c a b ' , ' k a h l e r a j ' , ' d e g u e m e a m ' , ' b a r r e t t a ' , ' e t a l . i n h i b i t i o n o f p r o s t a t e c a n c e r p r o l i f e r a t i o n b y i n t e r f e r e n c e w i t h s o n i c h e d g e h o g ' , ' g l i 1 s i g n a l l i n g . p r o c n a t l a c a d s c i u s a . 2 0 0 4 ' , ' 1 0 1 ( 3 4 ) ' , 1 2 5 6 1 , ' 6 . 8 1 . s l u s a r z a ' , ' s h e n o u d a n s ' , ' s a k l a m s ' , ' d r e n k h a h n s k ' , ' n a r u l a a s ' , ' m a c d o n a l d r s ' , ' e t a l . c o m m o n b o t a n i c a l c o m p o u n d s i n h i b i t t h e h e d g e h o g s i g n a l l i n g p a t h w a y i n p r o s t a t e c a n c e r . c a n c e r r e s . 2 0 1 0 ' , ' 7 0 ( 8 ) ' , 3 3 8 2 , 9 0 ]

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