RANK–RANKL signalling in cancer

Oncogenic events combined with a favourable environment are the two main factors in the oncological process. The tumour microenvironment is composed of a complex, interconnected network of protagonists, including soluble factors such as cytokines, extracellular matrix components, interacting with fibroblasts, endothelial cells, immune cells and various specific cell types depending on the location of the cancer cells (e.g. pulmonary epithelium, osteoblasts). This diversity defines specific “niches” (e.g. vascular, immune, bone niches) involved in tumour growth and the metastatic process. These actors communicate together by direct intercellular communications and/or in an autocrine/paracrine/endocrine manner involving cytokines and growth factors. Among these glycoproteins, RANKL (receptor activator nuclear factor-κB ligand) and its receptor RANK (receptor activator nuclear factor), members of the TNF and TNFR superfamilies, have stimulated the interest of the scientific community. RANK is frequently expressed by cancer cells in contrast with RANKL which is frequently detected in the tumour microenvironment and together they participate in every step in cancer development. Their activities are markedly regulated by osteoprotegerin (OPG, a soluble decoy receptor) and its ligands, and by LGR4, a membrane receptor able to bind RANKL. The aim of the present review is to provide an overview of the functional implication of the RANK/RANKL system in cancer development, and to underline the most recent clinical studies.

[1]  W. Blizek,et al.  To the Bone , 2017, Journal of Religion & Film.

[2]  K. Pienta,et al.  The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer , 2016, Oncotarget.

[3]  Mingyao Liu,et al.  LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption , 2016, Nature Medicine.

[4]  Ruo-Pan Huang,et al.  Cytokines in cancer drug resistance: Cues to new therapeutic strategies. , 2016, Biochimica et biophysica acta.

[5]  Yao Liu,et al.  CCL20 mediates RANK/RANKL-induced epithelial-mesenchymal transition in endometrial cancer cells , 2016, Oncotarget.

[6]  Roger D Kamm,et al.  Impact of the physical microenvironment on tumor progression and metastasis. , 2016, Current opinion in biotechnology.

[7]  A. Viola,et al.  T Cells and Cancer: How Metabolism Shapes Immunity , 2016, Front. Immunol..

[8]  M. Hansen,et al.  Regulation of Osteoblast Migration Involving Receptor Activator of Nuclear Factor‐kappa B (RANK) Signaling , 2015, Journal of cellular physiology.

[9]  Ming-qing Li,et al.  RANKL/RANK interaction promotes the growth of cervical cancer cells by strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion. , 2015, Oncology reports.

[10]  S. Aiba,et al.  The Possible Interaction between Receptor Activator of Nuclear Factor Kappa-B Ligand Expressed by Extramammary Paget Cells and its Ligand on Dermal Macrophages. , 2015, The Journal of investigative dermatology.

[11]  L. Bonewald,et al.  Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone , 2015, PloS one.

[12]  K. Trieb,et al.  Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma. , 2015, Oncology letters.

[13]  S. Aiba,et al.  Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) Promotes the Production of CCL17 from RANK|[plus]| M2 Macrophages , 2015 .

[14]  Z. Werb,et al.  The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? , 2015, Cell stem cell.

[15]  C. Sotiriou,et al.  RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy , 2015, Breast Cancer Research.

[16]  Yudong Wang,et al.  MPA influences tumor cell proliferation, migration, and invasion induced by RANKL through PRB involving the MAPK pathway in endometrial cancer. , 2015, Oncology reports.

[17]  Hao Zhang,et al.  GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway , 2015, Medical Oncology.

[18]  B. Fuchs,et al.  RANK Ligand Blockade with Denosumab in Combination with Sorafenib in Chemorefractory Osteosarcoma: A Possible Step Forward? , 2014, Oncology.

[19]  H. Park,et al.  Expression of receptor activator of nuclear factor kappa‐B as a poor prognostic marker in breast cancer , 2014, Journal of surgical oncology.

[20]  Zhiping Wang,et al.  Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis. , 2014, Oncology reports.

[21]  P. Ordóñez-Morán,et al.  Complex metastatic niches: already a target for therapy? , 2014, Current opinion in cell biology.

[22]  I. Holen,et al.  Prostate Cancer Cells Preferentially Home to Osteoblast‐rich Areas in the Early Stages of Bone Metastasis: Evidence From In Vivo Models , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[23]  Yongwon Choi,et al.  Biology of the RANKL–RANK–OPG System in Immunity, Bone, and Beyond , 2014, Front. Immunol..

[24]  Q. Gao,et al.  RANKL Promotes Migration and Invasion of Hepatocellular Carcinoma Cells via NF-κB-Mediated Epithelial-Mesenchymal Transition , 2014, PloS one.

[25]  Z. Bago-Horvath,et al.  Impact of RANK signalling on survival and chemotherapy response in osteosarcoma , 2014, Pathology.

[26]  H. Gu,et al.  RANK rs1805034 T>C Polymorphism Is Associated with Susceptibility of Esophageal Cancer in a Chinese Population , 2014, PloS one.

[27]  Seema A. Khan,et al.  RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase , 2014, Breast Cancer Research and Treatment.

[28]  M. Heymann,et al.  Novel RANK Antagonists for the Treatment of Bone‐Resorptive Disease: Theoretical Predictions and Experimental Validation , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  M. De la Fuente,et al.  Chronic Inflammation and Cytokines in the Tumor Microenvironment , 2014, Journal of immunology research.

[30]  Mark S. Anderson,et al.  Brief Definitive Report , 2022 .

[31]  C. Denkert,et al.  RANK expression as a prognostic and predictive marker in breast cancer , 2014, Breast Cancer Research and Treatment.

[32]  W. Dougall,et al.  RANKL Inhibition Blocks Osteolytic Lesions and Reduces Skeletal Tumor Burden in Models of Non–Small-Cell Lung Cancer Bone Metastases , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[33]  Yibin Kang,et al.  Targeting tumor-stromal interactions in bone metastasis. , 2014, Pharmacology & therapeutics.

[34]  Zuoqin Yan,et al.  Stat3 Upregulates Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 4 Expression in Osteosarcoma Cells , 2013, BioMed research international.

[35]  Dali Li,et al.  Lgr4 is a key regulator of prostate development and prostate stem cell differentiation , 2013, Stem cells.

[36]  Klaus Pantel,et al.  Tumor metastasis: moving new biological insights into the clinic , 2013, Nature Medicine.

[37]  H. Yasuda.  RANKL, a necessary chance for clinical application to osteoporosis and cancer-related bone diseases. , 2013, World journal of orthopedics.

[38]  M. Heymann,et al.  Osteoprotegerin: multiple partners for multiple functions. , 2013, Cytokine & growth factor reviews.

[39]  T. Hagemann,et al.  Tumour-associated macrophages and cancer. , 2013, Current opinion in pharmacology.

[40]  David M. Thomas,et al.  Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. , 2013, The Lancet. Oncology.

[41]  R. Azevedo,et al.  T Cells Induce Pre-Metastatic Osteolytic Disease and Help Bone Metastases Establishment in a Mouse Model of Metastatic Breast Cancer , 2013, PloS one.

[42]  T. Akiyama,et al.  Regulations of Gene Expression in Medullary Thymic Epithelial Cells Required for Preventing the Onset of Autoimmune Diseases , 2013, Front. Immunol..

[43]  F. Tirode,et al.  Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL , 2013, Journal of bone oncology.

[44]  Daniel F. Gudbjartsson,et al.  Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits , 2013, Nature.

[45]  W. Guo,et al.  Differential Expression of the RANKL/RANK/OPG System Is Associated with Bone Metastasis in Human Non-Small Cell Lung Cancer , 2013, PloS one.

[46]  H. Kalofonos,et al.  Identification of novel human receptor activator of nuclear factor-kB isoforms generated through alternative splicing: implications in breast cancer cell survival and migration , 2012, Breast Cancer Research.

[47]  C. Mueller,et al.  Emerging Functions of RANKL in Lymphoid Tissues , 2012, Front. Immun..

[48]  David M. Thomas,et al.  Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone , 2012, Clinical Cancer Research.

[49]  F. Climent,et al.  RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. , 2012, Cancer research.

[50]  R. Khokha,et al.  Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells , 2012, Journal of Cell Science.

[51]  J. Massagué,et al.  VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. , 2011, Cancer cell.

[52]  Ye Zhang,et al.  Receptor activator for nuclear factor κ B expression predicts poor prognosis in breast cancer patients with bone metastasis but not in patients with visceral metastasis , 2011, Journal of Clinical Pathology.

[53]  E. Jimi,et al.  The inhibition of RANKL/RANK signaling by osteoprotegerin suppresses bone invasion by oral squamous cell carcinoma cells. , 2011, Carcinogenesis.

[54]  Gary D. Bader,et al.  A comprehensive manually curated reaction map of RANKL/RANK-signaling pathway , 2011, Database J. Biol. Databases Curation.

[55]  Y. Ohba,et al.  RANKL expression specifically observed in vivo promotes epithelial mesenchymal transition and tumor progression. , 2011, The American journal of pathology.

[56]  M. Heymann,et al.  The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets , 2011, Sarcoma.

[57]  Dong Ho Kim,et al.  RANKL expression is related to treatment outcome of patients with localized, high‐grade osteosarcoma , 2011, Pediatric blood & cancer.

[58]  C. Porta,et al.  Receptor Activator of NF-kB (RANK) Expression in Primary Tumors Associates with Bone Metastasis Occurrence in Breast Cancer Patients , 2011, PloS one.

[59]  I. Bièche,et al.  Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony‐forming cells properties , 2011, Journal of thrombosis and haemostasis : JTH.

[60]  T. Luger,et al.  RANK is expressed in metastatic melanoma and highly upregulated on melanoma-initiating cells. , 2011, The Journal of investigative dermatology.

[61]  C. Porta,et al.  Expression pattern of receptor activator of NFκB (RANK) in a series of primary solid tumors and related bone metastases , 2011, Journal of cellular physiology.

[62]  F. Tsai,et al.  RANKL increases migration of human lung cancer cells through intercellular adhesion molecule‐1 up‐regulation , 2011, Journal of cellular biochemistry.

[63]  William C Hines,et al.  Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression , 2011, Nature Medicine.

[64]  J. Cheng,et al.  Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling , 2011, Nature.

[65]  M. Karin,et al.  Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage , 2011, Annals of the rheumatic diseases.

[66]  D. Branstetter,et al.  RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis , 2010, Nature.

[67]  Chun-Hao Tsai,et al.  Involvement of integrin up‐regulation in RANKL/RANK pathway of chondrosarcomas migration , 2010, Journal of cellular biochemistry.

[68]  R. Domsic,et al.  Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma , 2010, Annals of the rheumatic diseases.

[69]  Yuk-Kwan Chen,et al.  Immunohistochemical expression of RANKL, RANK, and OPG in human oral squamous cell carcinoma. , 2009, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[70]  T. Wang,et al.  Chronic inflammation, the tumor microenvironment and carcinogenesis. , 2009, Cell cycle.

[71]  D. Heymann,et al.  Factor VIII-von Willebrand Factor Complex Inhibits Osteoclastogenesis and Controls Cell Survival* , 2009, The Journal of Biological Chemistry.

[72]  Y. Okada,et al.  Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas , 2009, The Journal of pathology.

[73]  M. Padrines,et al.  Proteases and bone remodelling. , 2009, Cytokine & growth factor reviews.

[74]  E. Miot-Noirault,et al.  Glycosaminoglycans as potential regulators of osteoprotegerin therapeutic activity in osteosarcoma. , 2009, Cancer research.

[75]  B. Pitard,et al.  Therapeutic efficacy of soluble receptor activator of nuclear factor-kappa B-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma , 2010 .

[76]  H. Takayanagi,et al.  The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. , 2008, Immunity.

[77]  F. Marshall,et al.  Receptor activator of NF-κB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells , 2008, Cell Research.

[78]  J. Canon,et al.  RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis , 2008, Molecular Cancer Therapeutics.

[79]  M. Heymann,et al.  OPG, RANK and RANK ligand expression in thyroid lesions , 2008, Regulatory Peptides.

[80]  W. Dalton,et al.  The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance , 2008, Clinical Cancer Research.

[81]  M. Seibel,et al.  Bone resorption increases tumour growth in a mouse model of osteosclerotic breast cancer metastasis , 2008, Clinical & Experimental Metastasis.

[82]  H. Ishii,et al.  [Cancer stem cell]. , 2007, Nihon rinsho. Japanese journal of clinical medicine.

[83]  B. Pitard,et al.  Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption. , 2007, Cancer research.

[84]  D. Heymann,et al.  RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases , 2007, Cellular and Molecular Life Sciences.

[85]  B. Le Goff,et al.  DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process. , 2007, Bone.

[86]  B. Le Goff,et al.  Human osteosarcoma cells express functional receptor activator of nuclear factor‐kappa B , 2007, The Journal of pathology.

[87]  H. Takayanagi.  Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems , 2007, Nature Reviews Immunology.

[88]  N. Mochizuki,et al.  Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice. , 2007, Blood.

[89]  H. Dinh,et al.  RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial Acini , 2006, Molecular and Cellular Biology.

[90]  Y. Kadono,et al.  Negative Regulation of Osteoclastogenesis by Ectodomain Shedding of Receptor Activator of NF-κB Ligand* , 2006, Journal of Biological Chemistry.

[91]  M. Padrines,et al.  OPG/membranous--RANKL complex is internalized via the clathrin pathway before a lysosomal and a proteasomal degradation. , 2006, Bone.

[92]  C. Dinarello,et al.  The paradox of pro-inflammatory cytokines in cancer , 2006, Cancer and Metastasis Reviews.

[93]  A. Evdokiou,et al.  RANK Expression as a Cell Surface Marker of Human Osteoclast Precursors in Peripheral Blood, Bone Marrow, and Giant Cell Tumors of Bone , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[94]  Frédéric Blanchard,et al.  Characterization of osteoprotegerin binding to glycosaminoglycans by surface plasmon resonance: Role in the interactions with receptor activator of nuclear factor κB ligand (RANKL) and RANK , 2006 .

[95]  A. Potti,et al.  Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation , 2006, Cancer.

[96]  S. M. Sims,et al.  Regulation of cancer cell migration and bone metastasis by RANKL , 2006, Nature.

[97]  S. Ricard-Blum,et al.  Characterization of osteoprotegerin binding to glycosaminoglycans by surface plasmon resonance: role in the interactions with receptor activator of nuclear factor kappaB ligand (RANKL) and RANK. , 2006, Biochemical and biophysical research communications.

[98]  J. Penninger,et al.  Receptor Activator of NF-κB Ligand Regulates the Proliferation of Mammary Epithelial Cells via Id2 , 2006, Molecular and Cellular Biology.

[99]  S. Cross,et al.  Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor κB ligand (RANKL) in human breast tumours , 2006, Journal of Clinical Pathology.

[100]  A. Kudo,et al.  Self‐Assembled RANK Induces Osteoclastogenesis Ligand‐Independently , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[101]  Sakae Tanaka,et al.  RANK‐mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis , 2005, The EMBO journal.

[102]  S. Théoleyre,et al.  The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. , 2004, Cytokine & growth factor reviews.

[103]  S. Morrison,et al.  Diverse mechanisms regulate stem cell self-renewal. , 2004, Current opinion in cell biology.

[104]  L. Papucci,et al.  In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells , 2004, International journal of cancer.

[105]  M. Padrines,et al.  RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. , 2004, Biochimica et biophysica acta.

[106]  Colin R Dunstan,et al.  A Single‐Dose Placebo‐Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal Women , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[107]  Ju-Hyun Kim,et al.  RANKL regulates endothelial cell survival through the phosphatidylinositol 3′‐kinase/Akt signal transduction pathway , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[108]  Y. Kong,et al.  Vascular Endothelial Growth Factor Up-regulates Expression of Receptor Activator of NF-κB (RANK) in Endothelial Cells , 2003, Journal of Biological Chemistry.

[109]  R. Rezzonico,et al.  The receptor activator of nuclear factor (NF)κB ligand (RANKL) is a new chemotactic factor for human monocytes , 2003 .

[110]  C. Mongini,et al.  RANKL expression in a case of follicular lymphoma , 2003, European Journal of Haematology.

[111]  P. Croucher,et al.  Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma. , 2003, Cancer research.

[112]  T. Plesner,et al.  Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. , 2002, Blood.

[113]  E. Milgrom,et al.  RANK (receptor activator of nuclear factor‐κB) and RANKL expression in multiple myeloma , 2002, British journal of haematology.

[114]  F. Hamdy,et al.  Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. , 2002, Cancer research.

[115]  Y. M. Lee,et al.  TNF-related Activation-induced Cytokine (TRANCE) Induces Angiogenesis through the Activation of Src and Phospholipase C (PLC) in Human Endothelial Cells* , 2002, The Journal of Biological Chemistry.

[116]  E. Milgrom,et al.  RANK (receptor activator of nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone. , 2002, American journal of clinical pathology.

[117]  M. Matsuoka,et al.  Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor kappaB ligand on adult T-cell leukemia cells. , 2002, Blood.

[118]  B. Aggarwal,et al.  Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. , 2001, Blood.

[119]  William Maloney,et al.  Receptor Activator of NF-κB and Osteoprotegerin Expression by Human Microvascular Endothelial Cells, Regulation by Inflammatory Cytokines, and Role in Human Osteoclastogenesis* , 2001, The Journal of Biological Chemistry.

[120]  K. Hirokawa,et al.  Determination of Three Isoforms of the Receptor Activator of Nuclear Factor-κΒ Ligand and Their Differential Expression in Bone and Thymus. , 2001, Endocrinology.

[121]  A. Nakanishi,et al.  The Effect of a Single Dose of Osteoprotegerin in Postmenopausal Women , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[122]  D. Lacey,et al.  The Osteoclast Differentiation Factor Osteoprotegerin-Ligand Is Essential for Mammary Gland Development , 2000, Cell.

[123]  D L Lacey,et al.  RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[124]  T. Miyata,et al.  Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors , 1999, The Journal of experimental medicine.

[125]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[126]  T. Martin,et al.  Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. , 1999, Bone.

[127]  W. Dougall,et al.  RANK is essential for osteoclast and lymph node development. , 1999, Genes & development.

[128]  L. Lum,et al.  Evidence for a Role of a Tumor Necrosis Factor-α (TNF-α)-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival* , 1999, The Journal of Biological Chemistry.

[129]  S. Morony,et al.  TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. , 1999, Genes & development.

[130]  M. Ueda,et al.  Cloning and characterization of the gene encoding mouse osteoclast differentiation factor. , 1999, Gene.

[131]  J. Penninger,et al.  Osteoprotegerin ligand: A common link between osteoclastogenesis, lymph node formation and lymphocyte development , 1999, Immunology and cell biology.

[132]  S. Morony,et al.  Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[133]  B. Aggarwal,et al.  Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. , 1999, The Journal of biological chemistry.

[134]  B. Kwon,et al.  Receptor activator of NF‐κB recruits multiple TRAF family adaptors and activates c‐Jun N‐terminal kinase , 1999, FEBS letters.

[135]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[136]  W. Dougall,et al.  The Involvement of Multiple Tumor Necrosis Factor Receptor (TNFR)-associated Factors in the Signaling Mechanisms of Receptor Activator of NF-κB, a Member of the TNFR Superfamily* , 1998, The Journal of Biological Chemistry.

[137]  H. Yasuda,et al.  RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. , 1998, Biochemical and biophysical research communications.

[138]  R. Steinman,et al.  The TRAF Family of Signal Transducers Mediates NF-κB Activation by the TRANCE Receptor* , 1998, The Journal of Biological Chemistry.

[139]  T. Martin,et al.  A combination of osteoclast differentiation factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteoclast formation in vitro. , 1998, Endocrinology.

[140]  John C. Lee,et al.  Osteoprotegerin Is a Receptor for the Cytotoxic Ligand TRAIL* , 1998, The Journal of Biological Chemistry.

[141]  N. Udagawa,et al.  Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. , 1998, Biochemical and biophysical research communications.

[142]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[143]  K Yano,et al.  Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[144]  R. Steinman,et al.  TRANCE (Tumor Necrosis Factor [TNF]-related Activation-induced Cytokine), a New TNF Family Member Predominantly Expressed in T cells, Is a Dendritic Cell–specific Survival Factor , 1997, The Journal of experimental medicine.

[145]  R. Dubose,et al.  A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function , 1997, Nature.

[146]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

[147]  S Paget,et al.  THE DISTRIBUTION OF SECONDARY GROWTHS IN CANCER OF THE BREAST. , 1889 .

[148]  F. Saad,et al.  Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. , 2016, European journal of cancer.

[149]  U. Weidle,et al.  Molecular Mechanisms of Bone Metastasis. , 2016, Cancer genomics & proteomics.

[150]  Yongchun Zhu,et al.  GPR48 promotes multiple cancer cell proliferation via activation of Wnt signaling. , 2013, Asian Pacific journal of cancer prevention : APJCP.

[151]  M. Mason,et al.  Expression profile of receptor activator of nuclear-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancer. , 2013, Anticancer research.

[152]  Hao Wu,et al.  Structural basis of signal transduction in the TNF receptor superfamily. , 2013, Advances in immunology.

[153]  K. Akakura.  [Inflammatory cytokines]. , 2011, Nihon rinsho. Japanese journal of clinical medicine.

[154]  W. Dougall,et al.  RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes , 2008, The Prostate.

[155]  S. Kitano,et al.  Receptor activator of nuclear factor-kappaB ligand (RANKL) expression in hepatocellular carcinoma with bone metastasis. , 2007, Annals of surgical oncology.

[156]  M. Hansen,et al.  Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[157]  G. Dranoff,et al.  Cytokines in cancer pathogenesis and cancer therapy , 2004, Nature Reviews Cancer.

[158]  Y. Kong,et al.  Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand. , 2003, The Journal of biological chemistry.

[159]  L. To,et al.  Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. , 2003, Cancer research.

[160]  D. Heymann,et al.  Receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio is increased in severe osteolysis. , 2003, The American journal of pathology.

[161]  K. Hirokawa,et al.  Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. , 2001, Endocrinology.

[162]  E. Gallico,et al.  [Tumor metastasis]. , 1955, Tumori.