Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancers commonly cause osteolytic metastases in bone, a process that is dependent upon osteoclast-mediated bone resorption. Recently the osteoclast differentiation factor (ODF), better termed RANKL (receptor activator of NF-kappaB ligand), expressed by osteoblasts has been cloned as well as its cognate signaling receptor, receptor activator of NFkappaB (RANK), and a secreted decoy receptor osteoprotegerin (OPG) that limits RANKL's biological action. We determined that the breast cancer cell lines MDA-MB-231, MCF-7, and T47D as well as primary breast cancers do not express RANKL but express OPG and RANK. MCF-7, MDA-MB-231, and T47D cells did not act as surrogate osteoblasts to support osteoclast formation in coculture experiments, a result consistent with the fact that they do not express RANKL. When MCF-7 cells overexpressing PTH-related protein (PTHrP) were added to cocultures of murine osteoblasts and hematopoietic cells, osteoclast formation resulted without the addition of any osteotropic agents; cocultures with MCF-7 or MCF-7 cells transfected with pcDNAIneo required exogenous agents for osteoclast formation. When MCF-7 cells overexpressing PTHrP were cultured with murine osteoblasts, osteoblastic RANKL messenger RNA (mRNA) levels were enhanced and osteoblastic OPG mRNA levels diminished; MCF-7 parental cells had no effect on RANKL or OPG mRNA levels when cultured with osteoblastic cells. Using a murine model of breast cancer metastasis to bone, we established that MCF-7 cells that overexpress PTHrP caused significantly more bone metastases, which were associated with increased osteoclast formation, elevated plasma PTHrP concentrations and hypercalcaemia compared with parental or empty vector controls.
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PMID:Breast cancer cells interact with osteoblasts to support osteoclast formation. 1049 98

Skeletal mass is maintained by a balance between cells which resorb bone (osteoclasts) and cells which form bone (osteoblasts). Bone development and growth is an on-going, life-long process. Bone is formed during embryonic life, grows rapidly through childhood, and peaks around 20 years of age (formation exceeds resorption). For humans the skeleton then enters a long period, approximately 40 years, when bone mass remains relatively stable. Skeletal turnover continues but the net effect of resorption and formation on bone mass is zero. For women this ends when they enter menopause and similar bone loss occurs for men, but later in life. These opposite functions are coupled, resorption precedes formation, and osteoblasts, or their precursors, stromal cells, regulate osteoclast formation and activity. Until recently, the molecular nature of this regulation, was poorly understood. However, recent observations have identified members of the TNF family of ligands and receptors as critical regulators of osteoclastogenesis. Osteoprotegerin (OPG) a decoy receptor was first identified. Its ligand, receptor activator of nuclear factor-kappaB ligand (RANKL), was quickly found, and shown to be expressed on stromal cells and osteoblasts. Its cognate receptor, RANK, was found to be expressed in high levels on osteoclast precursors. The interaction between RANKL and RANK was shown to be required for osteoclast formation. These observations have provided a molecular understanding of the coupling between osteoclastic bone resorption and osteoblastic bone formation. Moreover, they provide a framework on which to base a clear understanding of normal (e.g. postmenopausal osteoporosis and age associated bone loss) and pathologic skeletal changes (e.g. osteopetrosis, glucocorticoid-induced osteoporosis, periodontal disease, bone metastases, Paget's disease, hyperparathyroidism, and rheumatoid arthritis).
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PMID:Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. 1131 14

Receptor activator of nuclear factor (NF-kappaB) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways. The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor alpha, interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor gamma, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.
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PMID:Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. 1148 16

Bone metastases appear frequently in patients with advanced breast cancer. They are associated with substantial morbidity and occasionally produce life-threatening complications. Systemic anticancer therapies (chemotherapy and hormonal therapies) represent the treatment of choice for these and other distant metastases from breast cancer. Aggressive use of prophylactic and therapeutic orthopedic surgery is warranted, especially for lesions in weight-bearing areas. Judicious use of external radiotherapy and bone-seeking radionuclides contributes to the control of pain and local control of lesions in strategic locations. In recent years, the development of osteoclast-inhibitory therapy added a new dimension to symptom control and prevention of skeletal complications. The bisphosphonates, clodronate, pamidronate, and zoledronic acid, are potent osteoclast inhibitors with marked clinical effects. They represent the drugs of choice for control of hypercalcemia of malignancy, and they are critical adjuvants to systemic anticancer therapy of metastatic disease. More recently, the development of recombinant osteoprotegerin and an anti-parathyroid hormone-related protein monoclonal antibody represent promising new options for the treatment of patients with bone metastases.
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PMID:Novel approaches to the management of bone metastases in patients with breast cancer. 1213 8

Metastasis of prostate cancer to bone is a common complication of progressive prostate cancer. Skeletal metastases are often associated with severe pain and thus demand therapeutic interventions. Although often characterized as osteoblastic, prostate cancer skeletal metastases usually have an underlying osteoclastic component. Advances in osteoclast biology and pathophysiology have led toward defining putative therapeutic targets to attack tumor-induced osteolysis. Several factors have been found to be important in tumor-induced promotion of osteoclast activity. One key factor is the protein receptor activator of nuclear factor-kappa B ligand (RANKL), which is required to induce osteoclastogenesis. RANKL is produced by prostate cancer bone metastases, enabling these metastases to induce osteolysis through osteoclast activation. Another factor, osteoprotegerin, is a soluble decoy receptor for RANKL and inhibits RANKL-induced osteoclastogenesis. Osteoprotegerin has been shown in murine models to inhibit tumor-induced osteolysis. In addition to RANKL, parathyroid hormone-related protein and interleukin-6 are produced by prostate cancer cells and can promote osteoclastogenesis. Finally, matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of the nonmineralized bone matrix. MMP inhibitors have been shown to diminish tumor establishment in bone in murine models. Thus, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The importance of osteoclasts in the establishment and progression of skeletal metastases has led to clinical evaluation of therapeutic agents to target them for slowing metastatic progression. Bisphosphonates are a class of compounds that decrease osteoclast life span by promoting their apoptosis. The bisphosphonate pamidronate has proven clinical efficacy for relieving bone pain associated with breast cancer metastases and has a promising outlook for prostate cancer metastases. Another bisphosphonate, zoledronic acid, appears to directly target prostate cancer cells in addition to diminishing osteoclast activity at the metastatic site. In addition to bisphosphonates, other novel therapies based on studies that delineate mechanisms of skeletal metastases establishment and progression will be developed in the near future.
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PMID:The role of osteoclastic activity in prostate cancer skeletal metastases. 1253 87

Human prostate cancer frequently metastasizes to bone, where it gives rise to osteoblastic bone metastases with an underlying osteoclastic component and subsequent bone pain. However, the importance of osteoclastogenesis in the development of prostate cancer bone lesions in humans is unclear. Osteoprotegerin/osteoclastogenesis inhibitory factor (OCIF) is a member of the tumor necrosis factor receptor family and a novel secreted protein, and it is a negative regulator of osteoclast differentiation, activation, and survival both in vitro and in vivo. In the present study we used a model in which human LNCaP prostate cancer cells that give rise to osteoblastic bone tumors were injected directly into the intramedullary space of human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice to investigate whether the new bone-resorption inhibitor osteoprotegerin/OCIF would inhibit the development of new bone tumors and the progression of established osteoblastic bone tumors. The mice were given consecutive daily s.c. injections of recombinant human OCIF (rhOCIF; 100 micro g/mouse/day) for 2 weeks starting either immediately or 2 weeks after injection of the LNCaP cells. In both protocols, rhOCIF markedly inhibited both the development of bone tumors and the progression of established bone tumor foci quantified by histological examination. Histomorphometrical analysis revealed that rhOCIF markedly reduced the number of osteoclasts and the size of the tumors at the bone sites, but that it had no effect on the local growth of s.c. LNCaP tumors or on LNCaP cell proliferation in culture. These findings demonstrate that osteoclasts play an important role in bone tumor by prostate cancer, and that rhOCIF decreases the LNCaP prostate cancer burden selectively in bone, suppresses the progression of established tumor lesions, and prevents the development of new lesions. These results suggest that inhibition of osteoclastic bone resorption may be an effective therapy for the treatment of prostate cancer that has colonized bone.
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PMID:Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice. 1272 25

Standard management of breast cancer metastatic to bone includes systemic chemotherapy and, if applicable, hormone therapy, as well as radiotherapy for control of pain or prevention of pathologic fractures. In addition, orthopedic surgical procedures are used to prevent or correct pathologic fractures in weight-bearing areas of the osseous skeleton. Inhibitors of osteoclast function, including bisphosphonates and gallium nitrate, have been shown in clinical trials to decrease bone-related complications. Consequently, bisphosphonates have become an integral part of the management of bone metastases from breast cancer. Improved understanding of the biology of osteoclastogenesis led to the identification of osteoprotegerin as a critical modulator of osteoclast activity. The clinical evaluation of several osteoprotegerin preparations has shown therapeutic effects as measured by significant reductions in biochemical markers of bone resorption. Monoclonal antibodies to RANK ligand and parathyroid hormone-related protein, as well as Src kinase inhibitors, are also currently under clinical evaluation.
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PMID:Novel approaches to the management of bone metastases. 1461 37

Prostate cancer is the most commonly diagnosed malignancy in men and is often associated with bone metastases. Prostate cancer bone lesions can be lytic or schlerotic, with the latter predominating. Bone morphogenetic proteins (BMPs) are a family of growth factors, which may play a role in the formation of prostate cancer osteoblastic bone metastases. This study evaluated the effects of BMPs on prostate cancer cell lines. We observed growth inhibitory effects of BMP-2 and -4 on LNCaP, while PC-3 was unaffected. Flow cytometric analysis determined that LNCaP cell growth was arrested in G(1) after bone morphogenetic protein-2 treatment. Treatment of LNCaP and PC-3 with BMP-2 and -4 activated downstream signaling pathways involving SMAD-1, up-regulation of p21(CIP1/WAF1) and changes in retinoblastoma (Rb) phosphorylation. Interestingly, bone morphogenetic protein-2 treatment stimulated a 2.7-fold increase in osteoprotegerin (OPG), a molecule, which inhibits osteoclastogenesis, production in PC-3.
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PMID:Bone morphogenetic protein signaling in prostate cancer cell lines. 1468 87

Our aim was to assess the diagnostic accuracy of bone markers in serum of patients with prostate cancer (PCa) for early detection of bone metastases and their usefulness as predictors of PCa-caused mortality. In sera of 117 PCa patients (pN0M0, n = 39; pN1M0, n = 34; M1, n = 44), 35 healthy men and 35 patients with benign prostatic hyperplasia, bone formation markers [total and bone-specific alkaline phosphatase (tALP, bALP), amino-terminal procollagen propeptides of type I collagen (P1NP), osteocalcin (OC)], bone resorption markers [bone sialoprotein (BSP), cross-linked C-terminal (CTX) and cross-linked N-terminal (NTX) telopeptides of type I collagen, tartrate-resistant acid phosphatase isoenzyme 5b (TRAP)] and osteoclastogenesis markers [osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL)] were measured. tALP, bALP, BSP, P1NP, TRAP, NTX and OPG were significantly increased in PCa patients with bone metastases compared to patients without metastases. OPG showed the best discriminatory power to differentiate between these patients. Logistic regression analysis resulted in a model with OPG and TRAP as variables that predicted bone metastasis with an overall correct classification of 93%. Patients with concentrations of OPG, P1NP, tALP, bALP, BSP, NTX, TRAP and CTX above cut-off levels showed significantly shorter survival than patients with low marker concentrations. Multivariate Cox proportional hazards regression revealed that only OPG and BSP were independent prognostic factors for PCa-related death. Thus, the importance of serum OPG in detecting bone metastatic spread, alone or in combination with other bone markers, and predicting survival in PCa patients has been clearly demonstrated.
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PMID:Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. 1525 51

Advanced breast cancer is often associated with metastatic bone disease, causing a number of serious complications for the patients such as hypercalceamia, pain, nerve compression and fractures. The formation of bone metastases depends on complex interactions between tumour cells and the cells of the bone microenvironment, but the precise molecular mechanisms involved in the development of tumour-induced bone disease have not been identified. We have investigated the ability of bone marrow stromal cells (BMSC) isolated from breast cancer patients to generate osteoprotegerin (OPG), a molecule involved both in bone turnover and cell survival. The potential survival effects of OPG are mediated through binding to a member of the TNF super family, TNF-related Apoptosis Inducing Ligand (TRAIL), preventing association between TRAIL and its death-inducing receptors present on a number of tumour cell types. In the present report we show that bone marrow stromal cells isolated from breast cancer patients produce OPG when grown in culture. The levels of OPG present in BMSC conditioned medium is sufficient to protect breast cancer cells from undergoing TRAIL induced apoptosis. Our data suggest that bone-derived OPG may increase survival of breast cancer cells that reach the bone microenvironment as part of the metastatic process.
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PMID:Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis. 1556 43


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