title: An in vitro system to characterize prostate cancer progression identified signaling required for self-renewal.
abstract: Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of genes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53-/-; Rbf/f, Trp53-/-; Ptenf/f, and Trp53-/-; Rbf/f; Ptenf/fprostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53-/-prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Biochemistry, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.|Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Salah
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Nishimoto
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kohno
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kondoh
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.|Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kitajima
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Muranaka
authors.affiliation: Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Nishiuchi
authors.affiliation: Department of Biochemistry, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.|Department of Poultry Diseases, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ibrahim
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.|Department of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase
keywords: Pten; Rb; prostasphere; prostate cancer