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

Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in breast cancer. Osteoclast activation and differentiation are regulated by bone marrow stromal cells (BMSC), a heterogeneous cell compartment that comprehends undifferentiated mesenchymal stem cells (MSC) and their specialized progeny. In this regard, we found that human primary BMSCs express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in two human, continuous MSC-like cell lines, HDS-1 and HDS-2 cells. Treatment of HDS cells with EGF produced a significant increase in the levels of activated EGFR which was not observed in the presence of gefitinib. A significant reduction in the basal levels of activation of the EGFR and of Akt was observed in HDS cells following treatment with gefitinib. Treatment of HDS cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony-stimulating factor (M-CSF) and cell-associated receptor activator of NF-kappaB ligand (RANKL) in both cell lines, as assessed by using specific ELISA and Western blotting techniques. Finally, the ability to sustain the differentiation of pre-osteoclasts of conditioned medium from gefitinib-treated HDS cells was reduced by approximately 45% as compared with untreated HDS cells. These data have demonstrated for the first time that the EGFR regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease.
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PMID:Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis. 1594 17

Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.
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PMID:Regulation of cancer cell migration and bone metastasis by RANKL. 1731 31

Disseminated carcinimatosis of the bone marrow is accompanied by solid tumors, and gastric cancer accounts for the majority. The prognosis of this condition is poor, however, the pathogenesis for wide-spread bone lesions has yet to be elucidated. In 9 patients with gastric cancer demonstrating disseminated carcinomatosis of the bone marrow, the characteristic clinicopathological features were examined. Immunohistochemistry for receptor activator of NF-kappaB ligand (RANKL) and parathyroid hormone-related protein was also performed on gastric cancer tissue and bone marrow specimens to identify the factors responsible for the occurrence of bone lesions in patients presenting with this condition. The characteristic features of disseminated carcinomatosis of the bone marrow due to gastric cancer include a yonger patient age, an elevation of serum alkaline phosphatase and/or lactate dehydrogenase levels, wide-spread bone metastases with osteolytic bone destruction, a low incidence of hypercalcemia and a histological gastric cancer type of either signet ring cell carcinoma or poorly diffentiated adenocarcinoma. The expression of RANKL, which is one of the master regulators of osteoclastic bone resorption in bone metastasis, was also found in gastric cancer cells obtained from such patients. The RANKL expressed in gastric cancer may therefore play a critical role in the promotion of osteoclast formation, which has been suggested to be involved in the pathogenesis of bone lesions.
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PMID:Characteristic features of disseminated carcinomatosis of the bone marrow due to gastric cancer: the pathogenesis of bone destruction. 1696 87

The maintenance of skeletal integrity in a healthy individual requires a balanced regulation of the processes of bone formation, mediated by osteoblasts, and bone resorption, mediated by osteoclasts. This balanced process of bone remodeling becomes co-opted in the skeleton by tumor cells and this dramatically accelerates the process of remodeling and disrupts the normal equilibrium resulting in a spectrum of osteolytic to osteoblastic bone lesions. Certain tumor types, such as breast and prostate, frequently metastasize to the bone. It is now widely understood that the molecular triad--receptor activator of NF-kappaB ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL inhibitor, osteoprotegerin (OPG)--play direct and essential roles in the formation, function, and survival of osteoclasts. Osteoclastic bone resorption contributes to the majority of skeletal sequelae, or skeletal-related events (SREs), in patients with bone metastases. In addition, osteoclastic bone resorption also contributes to the establishment of tumors in the skeleton. Therefore, blocking osteoclast activity and differentiation via RANKL inhibition may not only provide a beneficial treatment for skeletal complications of malignancy, but may also prevent bone metastases. In this review, we will first describe the operative role of osteoclasts and the RANK/RANKL/OPG triad in the pathophysiology of cancer-induced bone diseases, specifically solid tumor metastases to the bone. Secondly, we will describe a therapeutic approach that specifically targets the RANKL molecule.
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PMID:The RANK/RANKL/OPG triad in cancer-induced bone diseases. 1718 Jul 11

Fundamental cytokine regulating remodelation of the skeleton is receptor activator of nuclear factor kappa B ligand (RANKL). RANKL is counter regulated by soluble receptor osteoprotegerin (OPG). While RANKL activates osteoclastic bone resorption, the OPG stimulates bone formation. RANKL/OPG system (TRANCE axis) is activated in favour of RANKL in estrogen deficiency, inflammation, bone malignancies and during the treatment with glucocorticoids. TRANCE axis is functional also in other tissues including vessel wall, where dysbalance with superiority of RANKL leads to atherogenesis. Molecules blocking RANKL (specific antibodies and OPG) are potential drugs for treatment of osteoporosis, atherosclerosis, inflammation diseases, myeloma or osteolytic bone metastases. This review is focused on pathogenetic role of TRANCE axis in the development of osteoporosis and atherosclerosis and on its use in diagnosis and treatment of both degenerative diseases.
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PMID:[Osteoporosis and aterosclerosis--is there any pathogenetic association?]. 1741 8

Bone metastases are a major cause of morbidity for men with prostate cancer. Although typical bone metastases from prostate cancer appear osteoblastic by radiographic imaging, excess number and activity of both osteoblasts and osteoclasts characterize most "osteoblastic" bone metastases. Additionally, pathological osteoclast activation is associated with increased risk of skeletal complications, disease progression, and death. Zoledronic acid, a potent intravenous bisphosphonate, reduces markers of osteoclast activity and significantly decreases the risk of skeletal complications in men with androgen-independent prostate cancer and bone metastases. Additional studies are needed to determine the optimal timing, schedule, and duration of bisphosphonate treatment in men with bone metastases as well as the potential role of bisphosphonates in other settings, including the prevention of bone metastases. Denosumab is a human monoclonal antibody that binds and neutralizes human receptor activator of NF-kappaB ligand (RANKL), a critical mediator of osteoclast activation, differentiation, and survival. Three ongoing pivotal studies involving more than 4,500 subjects will evaluate the role of denosumab for prevention of treatment-related fractures, bone metastases, and disease-related skeletal complications in men with prostate cancer.
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PMID:Osteoclast targeted therapy for prostate cancer: bisphosphonates and beyond. 1859 21

To clarify the mechanisms of bone destruction associated with bone metastases, we studied an animal model in which inoculation of MDA-MB-231 human breast cancer cells into the left cardiac ventricle of female nude mice causes osteolytic lesions in bone using morphological techniques. On the bone surfaces facing the metastatic tumor cells, there existed many tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts. TRAP-positive mononuclear osteoclast precursor cells were also observed in the tumor nests. Immunohistochemical studies showed that the cancer cells produced parathyroid hormone-related protein (PTHrP) but not receptor activator of NF-kappaB ligand (RANKL). Histochemical and immunohistochemical examinations demonstrated that alkaline phosphatase and RANKL-positive stromal cells were frequently adjacent to TRAP-positive osteoclast-like cells. Immunoelectron microscopic observation revealed that osteoclast-like cells were in contact with RANKL-positive stromal cells. MDA-MB-231 cells and osteoclast-like cells in the tumor nests showed CD44-positive reactivity on their plasma membranes. Hyaluronan (HA) and osteopontin (OPN), the ligands for CD44, were occasionally colocalized with CD44. These results suggest that tumor-producing osteoclastogenic factors, including PTHrP, upregulate RANKL expression in bone marrow stromal cells, which in turn stimulates the differentiation and activation of osteoclasts, leading to the progression of bone destruction in the bone metastases of MDA-MB-231 cells. Because the interactions between CD44 and its ligands, HA and OPN, have been shown to upregulate osteoclast differentiation and function, in addition to the cell-cell interactions mediated by RANK and RANKL, the cell-matrix interactions mediated by these molecules may also contribute to the progression of osteoclastic bone destruction.
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PMID:Involvement of cell-cell and cell-matrix interactions in bone destruction induced by metastatic MDA-MB-231 human breast cancer cells in nude mice. 1897 65

Approximately 30 to 40% of patients with advanced lung cancer will develop bone metastases in the course of their disease, resulting in a significant negative impact on both morbidity and survival. Skeletal complications of bone metastases include pain, pathologic fractures, spinal cord compression, and hypercalcemia. Total medical care costs are greater among patients with bone metastases who develop skeletal complications. A randomized phase III trial of the third generation bisphosphonate zoledronic acid has shown clinical benefit in the management of a subgroup of patients with bone metastases from lung cancer. Zoledronic acid treatment was associated with a reduction in both the risk of, and time to, a skeletal-related event. One of the markers of bone resorption, N-telopeptide, is both prognositic for development of skeletal-related events and predictive for benefit from zoledronic acid. In preclinical models, bisphosphonates have also demonstrated antitumor activity and are therefore currently being evaluated in adjuvant trials. Inhibition of the receptor activator of nuclear factor kappa B ligand-RANK pathway can reduce osteoclast-mediated bone resorption, and trials comparing receptor activator of nuclear factor kappa B ligand inhibitors with bisphosphonates are ongoing, including patients with lung cancer. In this article, we review the management of bone metastases and hypercalcemia as well as potential future directions for bone directed therapies in patients with lung cancer.
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PMID:Prevention and management of bone metastases in lung cancer: a review. 1917 5

Bone metastases are the most common skeletal complication of malignancy. Tumor cells disrupt normal bone remodeling to promote bone destruction and its associated morbidity. In the August 15, 2009, issue of Genes & Development, Lu and colleagues (pp. 1882-1894) propose a novel molecular mechanism by which tumor-produced metalloproteinases release epidermal growth factor (EGF) ligands to activate the central osteoclastogenic pathway receptor activator of NF-kappaB ligand (RANKL) to promote breast cancer osteolysis. This work has important therapeutic applications that may quickly translate to more effective treatment for bone metastases.
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PMID:Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases. 1960 65


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