Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors

Kunyoo Shin; Agnes Lim; Chen Zhao; Debashis Sahoo; Ying Pan; Edda Spiekerkoetter; Joseph C Liao; Philip A Beachy

doi:10.1016/j.ccell.2014.09.001

Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors

Cancer Cell. 2014 Oct 13;26(4):521-33. doi: 10.1016/j.ccell.2014.09.001.

Authors

Kunyoo Shin¹, Agnes Lim², Chen Zhao³, Debashis Sahoo⁴, Ying Pan⁵, Edda Spiekerkoetter⁶, Joseph C Liao⁵, Philip A Beachy⁷

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: shink@ohsu.edu.
² Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
⁶ Department of Medicine, Vera Moulton Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: pbeachy@stanford.edu.

Abstract

Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation*
Disease Progression
Hedgehog Proteins / metabolism*
Humans
Mice
Signal Transduction*
Stromal Cells / metabolism*
Urinary Bladder / pathology*
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism
Urinary Bladder Neoplasms / pathology*

Substances

Hedgehog Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding