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RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization.
Chu, Gina Chia-Yi; Zhau, Haiyen E; Wang, Ruoxiang; Rogatko, André; Feng, Xu; Zayzafoon, Majd; Liu, Youhua; Farach-Carson, Mary C; You, Sungyong; Kim, Jayoung; Freeman, Michael R; Chung, Leland W K.
Afiliação
  • Chu GC; Uro-Oncology Research, Department of Medicine, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8750 Beverly Blvd., Atrium 103, Los Angeles, California 90048, USA Departments of Surgery Biomedical Sciences Biostatistics and Bioinformatics Center, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA Department of Pathology, School of Medicine, University of Alabama, Birmingham, Alabama, USA Department of Pathology, University
Endocr Relat Cancer ; 21(2): 311-26, 2014 Apr.
Article em En | MEDLINE | ID: mdl-24478054
Prostate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model for studying the mechanisms underlying the metastatic process. Here, we report that receptor activator of NF-κB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed-forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor (TF) deletion/interference assays identified common TF complexes, c-Myc/Max, and AP4 as critical regulatory nodes. RANKL-RANK signaling activated a number of master regulator TFs that control the epithelial-to-mesenchymal transition (Twist1, Slug, Zeb1, and Zeb2), stem cell properties (Sox2, Myc, Oct3/4, and Nanog), neuroendocrine differentiation (Sox9, HIF1α, and FoxA2), and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α, and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non metastatic LNCaP cells to express RANKL, c-Met/activated c-Met, while downregulating AR expression. These initially non-metastatic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK-RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic bystander dormant cells.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Neoplasias Ósseas / Proteínas Proto-Oncogênicas c-met / Ligante RANK / Receptor Ativador de Fator Nuclear kappa-B Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Neoplasias Ósseas / Proteínas Proto-Oncogênicas c-met / Ligante RANK / Receptor Ativador de Fator Nuclear kappa-B Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2014 Tipo de documento: Article