title: RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro.
abstract: The osteolytic nature of bone metastasis results from a tumor-driven increased bone resorption. Bone remodeling is orchestrated by the molecular triad RANK-RANKL-OPG. This process is dysregulated in bone metastases, mostly via induction of RANKL by tumor-derived factors. These factors increase expression of RANKL, which induce osteoclast formation, function, and survival, thereby increasing bone resorption. RANK is unexpectedly expressed by cancer cells, and the activation of RANKL-RANK pathway correlates with an increased invasive phenotype. To investigate the interaction between RANK expression in human breast and prostate cancer cells and their pro-metastatic phenotype we analyzed the activation of RANKL-RANK pathway and its effects on cell migration, invasion, gene expression in vitro, and osteolysis-inducing ability in vivo. RANKL activates kinase signaling pathways, stimulates cell migration, increases cell invasion, and up-regulates MMP-1 expression. In vivo, MMP-1 knockdown resulted in smaller x-ray osteolytic lesions and osteoclastogenesis, and decreased tumor burden. Therefore, RANKL inhibition in bone metastatic disease may decrease the levels of the osteoclastogenesis inducer MMP-1, contributing to a better clinical outcome.
authors.affiliation: Clinical and Translational Oncology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisbon, Portugal. scasimiro@fm.ul.pt
authors.forename: Sandra
authors.initials: S
authors.lastname: Casimiro
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pires
authors.forename: Joana
authors.initials: J
authors.lastname: Tato-Costa
authors.forename: Irina
authors.initials: I
authors.lastname: Alho
authors.forename: Rui
authors.initials: R
authors.lastname: Teixeira
authors.forename: António
authors.initials: A
authors.lastname: Carvalho
authors.forename: Sofia
authors.initials: S
authors.lastname: Ribeiro
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: Luis
authors.initials: L
authors.lastname: Costa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*
chemical_list: D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020781:Matrix Metalloproteinase 1