title: FGFR1-WNT-TGF-β signaling in prostate cancer mouse models recapitulates human reactive stroma.
abstract: The reactive stroma surrounding tumor lesions performs critical roles ranging from supporting tumor cell proliferation to inducing tumorigenesis and metastasis. Therefore, it is critical to understand the cellular components and signaling control mechanisms that underlie the etiology of reactive stroma. Previous studies have individually implicated fibroblast growth factor receptor 1 (FGFR1) and canonical WNT/β-catenin signaling in prostate cancer progression and the initiation and maintenance of a reactive stroma; however, both pathways are frequently found to be coactivated in cancer tissue. Using autochthonous transgenic mouse models for inducible FGFR1 (JOCK1) and prostate-specific and ubiquitously expressed inducible β-catenin (Pro-Cat and Ubi-Cat, respectively) and bigenic crosses between these lines (Pro-Cat × JOCK1 and Ubi-Cat × JOCK1), we describe WNT-induced synergistic acceleration of FGFR1-driven adenocarcinoma, associated with a pronounced fibroblastic reactive stroma activation surrounding prostatic intraepithelial neoplasia (mPIN) lesions found both in in situ and reconstitution assays. Both mouse and human reactive stroma exhibited increased transforming growth factor-β (TGF-β) signaling adjacent to pathologic lesions likely contributing to invasion. Furthermore, elevated stromal TGF-β signaling was associated with higher Gleason scores in archived human biopsies, mirroring murine patterns. Our findings establish the importance of the FGFR1-WNT-TGF-β signaling axes as driving forces behind reactive stroma in aggressive prostate adenocarcinomas, deepening their relevance as therapeutic targets.
authors.affiliation: Authors' Affiliations: Departments of Pathology and Immunology and Molecular and Cellular Biology; and Dan L Duncan Cancer Center, Baylor College of Medicine, Houston; M.E. DeBakey, Department of Veterans Affairs Medical Center, Houston, Texas.
authors.forename: Julienne L
authors.initials: JL
authors.lastname: Carstens
authors.forename: Payam
authors.initials: P
authors.lastname: Shahi
authors.forename: Susan
authors.initials: S
authors.lastname: Van Tsang
authors.forename: Billie
authors.initials: B
authors.lastname: Smith
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Amber
authors.initials: A
authors.lastname: Seamans
authors.forename: Mamatha
authors.initials: M
authors.lastname: Seethammagari
authors.forename: Indira
authors.initials: I
authors.lastname: Vedula
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Levitt
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: David R
authors.initials: DR
authors.lastname: Rowley
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D001706:Biopsy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity; D017154:Stromal Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1