title: RANK-mediated signaling network and cancer metastasis.
abstract: Cancer metastasis is highly inefficient and complex. Common features of metastatic cancer cells have been observed using cancer cell lines and genetically reconstituted mouse and human tumor xenograft models. These include cancer cell interaction with the tumor microenvironment and the ability of cancer cells to sense extracellular stimuli and adapt to adverse growth conditions. This review summarizes the coordinated response of cancer cells to soluble growth factors, such as RANKL, by a unique feed forward mechanism employing coordinated upregulation of RANKL and c-Met with downregulation of androgen receptor. The RANK-mediated signal network was found to drive epithelial to mesenchymal transition in prostate cancer cells, promote osteomimicry and the ability of prostate cancer cells to assume stem cell and neuroendocrine phenotypes, and confer the ability of prostate cancer cells to home to bone. Prostate cancer cells with activated RANK-mediated signal network were observed to recruit and even transform the non-tumorigenic prostate cancer cells to participate in bone and soft tissue colonization. The coordinated regulation of cancer cell invasion and metastasis by the feed forward mechanism involving RANKL, c-Met, transcription factors, and VEGF-neuropilin could offer new therapeutic opportunities to target prostate cancer bone and soft tissue metastases.
authors.affiliation: Departments of Medicine and Surgery, Samuel Orchin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA, Chia-Yi.Chu@cshs.org.
authors.forename: Gina Chia-Yi
authors.initials: GC
authors.lastname: Chu
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D060066:Protein Interaction Maps; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053246:Receptor Activator of Nuclear Factor-kappa B; D001613:beta 2-Microglobulin