1. RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro
- Author
-
Theresa A. Guise, Joana Tato-Costa, Ricardo A. Pires, Khalid S. Mohammad, Sandra Casimiro, Rui Pedro A. G. Teixeira, Allan Lipton, Luis Costa, Antonio J. F. Carvalho, Sofia Ribeiro, Irina Alho, and Repositório da Universidade de Lisboa
- Subjects
Male ,lcsh:Medicine ,Biochemistry ,Metastasis ,Bone remodeling ,Mice ,0302 clinical medicine ,Cell Movement ,Molecular Cell Biology ,Basic Cancer Research ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,biology ,Receptor Activator of Nuclear Factor-kappa B ,Prostate Cancer ,Bone metastasis ,Obstetrics and Gynecology ,Cell migration ,Immunohistochemistry ,medicine.anatomical_structure ,Oncology ,RANKL ,030220 oncology & carcinogenesis ,Medicine ,Female ,Matrix Metalloproteinase 1 ,Research Article ,musculoskeletal diseases ,medicine.medical_specialty ,Bone and Mineral Metabolism ,Blotting, Western ,Bone Neoplasms ,Breast Neoplasms ,Real-Time Polymerase Chain Reaction ,Bone resorption ,Cell Line ,03 medical and health sciences ,Rheumatology ,Osteoclast ,Internal medicine ,Cell Line, Tumor ,Breast Cancer ,medicine ,Animals ,Humans ,Biology ,030304 developmental biology ,RANK Ligand ,lcsh:R ,Prostatic Neoplasms ,Cancers and Neoplasms ,medicine.disease ,Genitourinary Tract Tumors ,Endocrinology ,Metabolism ,Cancer cell ,Cancer research ,biology.protein ,lcsh:Q - Abstract
Copyright: © 2013 Casimiro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., 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., The work was supported in part by grants from the National Institutes of Health (National Cancer Institute) CA69158 and CA143057 (to TAG and KM); and FCT Fellowships SFRH/BPD/34801/2007, SFRH/BD/45219/2008 and SFRH/BD/44716/2008 (to SC, JT-C and IA).
- Published
- 2013