title: Stromal hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer.
abstract: It is widely appreciated that reactive stroma or carcinoma-associated fibroblasts can influence epithelial tumor progression. In prostate cancer (PCa), the second most common male malignancy worldwide, the amount of reactive stroma is variable and has predictive value for tumor recurrence. By analyzing human PCa protein and RNA expression databases, we found smooth muscle cells (SMCs) are decreased in advanced tumors, whereas fibroblasts are maintained. In three mouse models of PCa, PB-MYC, ERG/PTEN and TRAMP, we found the composition of the stroma is distinct. SMCs are greatly depleted in advanced PB-MYC tumors and locally reduced in ERG/PTEN prostates, whereas in TRAMP tumors the SMC layers are increased. In addition, interductal fibroblast-like cells expand in PB-MYC and ERG/PTEN tumors, whereas in TRAMP PCa they expand little and stromal cells invade into intraductal adenomas. Fate mapping of SMCs showed that in PB-MYC tumors the cells are depleted, whereas they expand in TRAMP tumors and interestingly contribute to the stromal cells in intraductal adenomas. Hedgehog (HH) ligands secreted by epithelial cells are known to regulate prostate mesenchyme expansion differentially during development and regeneration. Any possible role of HH signaling in stromal cells during PCa progression is poorly understood. We found that HH signaling is high in SMCs and fibroblasts near tumor cells in all models, and epithelial Shh expression is decreased whereas Ihh and Dhh are increased. In human primary PCa, expression of IHH is the highest of the three HH genes, and elevated HH signaling correlates with high stromal gene expression. Moreover, increasing HH signaling in the stroma of PB-MYC PCa resulted in more intact SMC layers and decreased tumor progression (micro-invasive carcinoma). Thus, we propose HH signaling restrains tumor progression by maintaining the smooth muscle and preventing invasion by tumor cells. Our studies highlight the importance of understanding how HH signaling and stromal composition impact on PCa to optimize drug treatments.
authors.affiliation: Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.|Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.|Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Peng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gopalan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA joynera@mskcc.org.|Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Alexandra L
authors.identifier: 0000-0001-7090-9605
authors.initials: AL
authors.lastname: Joyner
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D000071676:Zinc Finger Protein GLI1
keywords: Fibroblasts; HH; PCa; Reactive stroma