title: Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts.
abstract: Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how androgen ablation induces CXCL13 expression. In both allografted and spontaneous mouse PC, CXCL13 is expressed by tumor-associated myofibroblasts that are activated on androgen ablation through a hypoxia-dependent mechanism. The same cells produce CXCL13 after chemotherapy. Myofibroblast activation and CXCL13 expression also occur in the normal prostate after androgen deprivation, and CXCL13 is expressed by myofibroblasts in human PC. Hypoxia activates hypoxia-inducible factor 1 (HIF-1) and induces autocrine TGF-β signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-β receptor kinase inhibitors, myofibroblast activation and CXCL13 induction are blocked by phosphodiesterase 5 (PDE5) inhibitors. Both inhibitor types and myofibroblast immunodepletion block the emergence of castration-resistant PC in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous metastatic PC with neuroendocrine differentiation.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, and Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ammirante
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, and Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Shalapour
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, and Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093.
authors.forename: Christina A M
authors.initials: CA
authors.lastname: Jamieson
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, and Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093 karinoffice@ucsd.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D054382:Chemokine CXCL13 / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000728:Androgens; C526317:CCN2 protein, human; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058986:Phosphodiesterase 5 Inhibitors; D053219:Receptors, Tumor Necrosis Factor, Member 25; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D007334:Insulin-Like Growth Factor I
keywords: cancer; cancer-associated fibroblasts; inflammation; tumor microenvironment