osteoprotegerin and Lung-Neoplasms

Giant cell tumor is a relatively uncommon but painful tumor of bone, which can metastasize to the lungs. The RANK pathway is often reported to be involved in the pathogenesis of giant cell tumor of bone (GCTB). This pathway is a key signaling pathway of bone remodeling that plays a critical role in differentiation of precursors into multinucleated osteoclasts, and activation of osteoclasts leading to bone resorption. Dysregulation of RANK ligand (RANKL)-RANK-osteoprotegerin (OPG) signaling cascade induces the imbalance between bone formation and bone resorption, which leads to the changes in bone mass, increases osteoclast-mediated bone destruction, bone metastasis, and the progression of existing skeletal tumors. Recent evidences have shown that targeting the components of RANKL-RANK-OPG signaling pathway is a promising approach in the treatment of GCTB. This review study has focused on the association of RANKL-RANK-OPG pathway in the pathogenesis and progression of GCTB as well as discussed the possible therapeutic strategies by targeting this pathway.

Topics: Bone Resorption; Cell Differentiation; Gene Expression Regulation, Neoplastic; Giant Cell Tumor of Bone; Humans; Lung Neoplasms; Osteoclasts; Osteogenesis; Osteoprotegerin; RANK Ligand; Signal Transduction

Bone metastasis leads to skeletal-related events in final-stage cancer patients. The incidence of prostate and lung cancers increases yearly; these cancers readily invade the bone. Some recent studies have found that serum osteoprotegerin (OPG) levels may be altered in patients with bone metastasis, whereas other reports have produced inconsistent findings. Hence, we conducted a meta-analysis to examine the effects of lung and prostate cancer on serum OPG levels. A systematic literature search was conducted using PubMed, Medline, and CNKI to identify relevant studies. A total of 11 studies were included. The standardized mean difference (SMD) and 95% confidence interval (95% CI) of the bone metastasis (BM) group, the non-bone metastasis (BM-) group and healthy controls were calculated. In prostate cancer, serum OPG levels in the BM group were higher than in the BM- group and healthy controls. Additionally, no significant difference in serum OPG levels was found between the BM- group and healthy controls. In lung cancer, serum OPG levels in the BM and BM- groups were significantly increased compared with healthy controls. However, no significant difference in serum OPG levels was found between the BM and BM- groups. Studies with larger sample sizes are required to confirm these findings.

Topics: Bone Neoplasms; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Osteoprotegerin; Prostatic Neoplasms

Disbalance of bone homeostasis, associated with malfunctioning of RANK/RANKL/OPG system underlies the oncological processes such as the destruction of bone, metastasis development, tumor progression. Pathological activity of system was described in such conditions, as breast cancer, prostate cancer, multiple myeloma, squamous cell carcinoma, Hodgkin's disease, and also metastasis in bones from lung cancer and other malignant diseases. In the literature, there is evidence of involvement of RANK/RANKL/OPG system in the pathogenesis of bone tumors (osteosarcoma, giant cell tumor of bone, chondroblastoma). Experimental data show that RANKL inhibitors can play a role in reducing tumor-induced lesions of bone in multiple myeloma, breast cancer, prostate cancer and lung cancer. Also this review presents data from clinical studies of the drug efficacy targeted on RANK/RANKL/OPG system and results of authors' study of the levels of this system's components and proinflammatory cytokines in blood serum of primary bone sarcoma patients.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cytokines; Female; Humans; Lung Neoplasms; Male; Multiple Myeloma; Osteoprotegerin; Prostatic Neoplasms; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Chronic obstructive pulmonary disease (COPD) can no longer be considered as a disease affecting only the lungs. Increasing evidence supports the presence of a systemic inflammatory component which is thought to provide the link between COPD and the co-morbidities commonly associated with this disease. These include cardiovascular disorders, skeletal muscle dysfunction, diabetes, and osteoporosis. The majority of current therapies for COPD have been developed to improve airway obstruction or to target airway inflammation, leaving an unmet medical need with respect to the systemic inflammatory component of COPD and its extra-pulmonary manifestations. This review describes systemic biomarkers in COPD and their relationship with both the local lung and systemic manifestations of the disease. A summary is provided of the most promising biomarkers that have been investigated in COPD and its co-morbidities. Such biomarkers may be used to assess and manage the systemic effects of COPD, and may guide future development of novel therapeutic interventions to provide a more holistic approach to treating this multi-faceted disease.

Topics: Adiponectin; Aging; Airway Remodeling; Biomarkers; C-Reactive Protein; Cachexia; Cardiovascular Diseases; CD40 Ligand; Chemokines, CC; Cytokines; Desmosine; Fibrinogen; Humans; Inflammation; Intercellular Adhesion Molecule-1; Isodesmosine; Lung Neoplasms; Matrix Metalloproteinases; Natriuretic Peptide, Brain; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Serum Amyloid A Protein; Severity of Illness Index; Telomere; Uteroglobin

The most common human cancers --lung, breast and prostate -- have a great avidity for bone, leading to painful and untreatable consequences. What makes some cancers, but not others, metastasize to bone, and how do they alter its physiology? Some of the molecular mechanisms that are responsible have recently been identified, and provide new molecular targets for drug development.

Topics: Bone Neoplasms; Breast Neoplasms; Calcium; Carrier Proteins; Diphosphonates; Female; Glycoproteins; Humans; Lung Neoplasms; Male; Membrane Glycoproteins; Osteoprotegerin; Prostatic Neoplasms; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vitamin D

Epimedium is a traditional Chinese medicine that is most commonly prescribed by practitioners of Chinese medicine for the clinical treatment of malignant tumor bone metastasis. The main component of Epimedium is icariin (ICA). Studies have shown that ICA inhibits bone resorption of osteoclasts through the OPG/RANKL/RANK signaling pathway. Osteoclasts are the only cells in the body that have a bone-destroying capability. The OPG/RANKL/RANK system consists of cytokines that play major roles in osteoclast formation. Therefore, our study selected the OPG/RANKL/RANK system as the research target to investigate the effect of ICA on nude mice with lung cancer bone metastasis. We established the model of bone metastasis in nude mice, intervened the model with icariin and zoledronic acid, and detected the levels of OPG and RANKL by ELISA and western blot. The results showed that ICA had a significant inhibitory effect on bone metastases in nude mice. ICA achieved its antibone metastasis effect in nude mice with lung cancer via inhibiting RANKL expression and simultaneously increasing OPG expression. ICA not only alleviated osteolytic bone destruction caused by bone metastases, but it also reduced weight loss in tumor-bearing nude mice at the late stage of the experiment. The role of ICA in preventing bone metastasis of lung cancer merits further investigation.

Topics: Animals; Bone Neoplasms; Flavonoids; Humans; Lung Neoplasms; Mice; Mice, Nude; Osteoprotegerin; RANK Ligand

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Ligands; Lung Neoplasms; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptors, Cytoplasmic and Nuclear

Lung metastasis is one of the leading causes of death for triple-negative breast cancer (TNBC). We sought to characterize the genetic alterations underlying TNBC lung metastases by integrating whole-genome sequencing and functional screening. Furthermore, we aimed to develop a metastasis-related gene signature for TNBC patients to improve risk stratification. In this prospective observational study, we first conducted whole-genome sequencing of paired primary tumor and lung metastasis from one TNBC patient to identify potential genetic driver alterations. An in vivo gain-of-function screening using an amplified open reading frame library was then employed to screen candidate genes promoting lung metastasis. Finally, we applied Cox proportional hazard regression modeling to develop a prognostic gene signature from 14 candidate genes in TNBC. Compared to the primary tumor, copy number amplifications of chromosomes 3q and 8q were identified in the lung metastasis. We discovered an enrichment of 14 genes from chromosomes 3q and 8q in mouse lung metastases model. We further developed and validated a four-gene signature (ENY2, KCNK9, TNFRSF11B and KCNMB2) that predicts recurrence-free survival and lung metastasis in TNBC. Our data also demonstrated that upregulated expression of ENY2 could promote invasion and lung metastasis of TNBC cells both in vitro and in vivo. In conclusion, our study reveals functional genes with copy number amplifications among chromosome 3q and 8q in lung metastasis of TNBC. And we develop a functional gene signature that can effectively stratify patients into low- and high-risk subgroups of recurrence, helping frame personalized treatments for TNBC.

Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 8; Disease-Free Survival; DNA Copy Number Variations; Female; Follow-Up Studies; Gain of Function Mutation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Library; HEK293 Cells; Humans; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Osteoprotegerin; Potassium Channels, Tandem Pore Domain; Prognosis; Prospective Studies; Transcription Factors; Triple Negative Breast Neoplasms; Up-Regulation; Whole Genome Sequencing; Xenograft Model Antitumor Assays

Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of nuclear factor-kappa B ligand (sRANKL). OPG promotes endothelial cell survival and neoangiogenesis. Dysregulation of the OPG/RANKL system has been detected in several tumors. In the present study, we evaluated the clinical usefulness of OPG and sRANKL assessment in bronchoalveolar lavage fluid (BALF) of patients with advanced non-small cell lung cancer (NSCLC). We measured the concentration of OPG and sRANKL in BALF of 44 NSCLC patients and 15 healthy volunteers taken as control subjects. The OPG content was higher in the NSCLC group than that in controls [0.48 (0.12-1.45) vs. 0.23 (0.14-0.75) pmol/l; p = 0.0001]. There were no significant differences in sRANKL content between the NSCLC and control groups [1.22 (0.74-23.00) vs. 1.12 (0.79-4.39) pmol/l; p = 0.67]. However, we found that the greater the level of sRANKL in NSCLC patients, the shorter the overall survival. We found a correlation between the content of sRANKL and the percentage of lymphocytes in BALF of NSCLC patients (r = 0.52; p = 0.041). We conclude that NSCLC patients have a higher content of OPG in BALF than healthy people. A high level of sRANKL in BALF of NSCLC patients may predict worse survival.

Topics: Aged; Bronchoalveolar Lavage Fluid; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Osteoprotegerin; Prognosis; RANK Ligand; Severity of Illness Index; Survival Rate

Osteoprotegrin (OPG), a secreted protein and a member of the tumor necrosis factor receptor superfamily has been well-characterized and is an important regulator of bone remodeling by blocking osteoclast maturation thus preventing osteolysis. In recent years, OPG has been reported to have an association with the malignant capacity of various cancer types and cancer-associated bone metastasis, although the mechanisms of this are not clearly understood.. In this study, OPG expression was analyzed in human lung cancer tissue and normal tissue based on the dataset of The Cancer Genome Atlas and Oncomine. The in vitro effect of OPG on H3122 lung cancer cells was also assessed by characterizing cell function following knock-down and forced overexpression in this cell line.. The expression of OPG was significantly increased in lung cancer tissues compared to the normal control group and OPG promoted the malignant phenotypes of H3122 cells in in vitro models.. OPG may be a potential driver of lung cancer cells and therefore might have potential in therapy and diagnostics.

Topics: Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Osteoprotegerin

This is the first study to demonstrate that benzo(a)-pyrene (BaP) was able to enhance the production of parathyroid hormone‑related protein (PTHrP) by human non‑small cell lung cancer H460 cells. Such effect would further contribute to bone metastasis of lung cancer by increasing osteoclastogenesis. This study is also the first to reveal that tricetin (TCN), a flavonoid derivative found in Myrtaceae pollen and Eucalyptus honey, was able to reverse BaP‑mediated bone resorption activity of lung cancer cells. Human non‑small cell lung cancer H460 cells were treated with BaP to generate conditioned medium. When osteoblasts were cultured with BaP‑H460‑CM, their expression of osteoclastogenesis activator macrophage colony‑stimulating factor (M‑CSF) and receptor activator of nuclear factor κB ligand (RANKL) was increased. BaP‑H460‑CM reduced the production of osteoprotegerin (OPG), an osteoclastogenesis inhibitor, in osteoblasts. Osteoclastogenesis and bone resorption activity of H460 cells were increased by BaP‑H460‑CM. With BaP‑mediated PTHrP upregulation, IL‑8 secretion in H460 cells was increased contributing to human non‑small cell lung cancer‑mediated osteoclast differentiation and bone resorption. Moreover, TCN suppressed BaP‑mediated bone resorption. Therefore, TCN may be a novel agent for treatment of non‑small cell lung cancer patients with bone metastasis.

Topics: Antineoplastic Agents; Benzo(a)pyrene; Bone Neoplasms; Bone Resorption; Carcinoma, Non-Small-Cell Lung; Cells, Cultured; Chromones; Enzyme-Linked Immunosorbent Assay; Flavonoids; Humans; Interleukin-8; Lung Neoplasms; Macrophage Colony-Stimulating Factor; Osteoblasts; Osteoprotegerin; Parathyroid Hormone-Related Protein; RANK Ligand; Real-Time Polymerase Chain Reaction

Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non-small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression.. We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses.. OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts.. These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden.

Topics: Animals; Anticoagulants; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Enoxaparin; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Osteolysis; Osteoprotegerin; RANK Ligand; Survival Rate; Tumor Burden; Tumor Cells, Cultured

Bone is a common site of metastasis for lung cancer, and is associated with significant morbidity and a dismal prognosis. MicroRNAs (miRNAs) are increasingly implicated in regulating the progression of malignancies.. The efficacy of miR-33a or anti-miR-33a plasmid was assessed by Real-time PCR. Luciferase assays were using One-Glo Luciferase Assay System. Measurement of secreted factors was determined by ELISA kit.. We have found that miR-33a, which is downregulated in lung cancer cells, directly targets PTHrP (parathyroid hormone-related protein), a potent stimulator of osteoclastic bone resorption, leading to decreased osteolytic bone metastasis. We also found that miR-33a levels are inversely correlated with PTHrP expression between human normal bronchial cell line and lung cancer cell lines. The reintroduction of miR-33a reduces the stimulatory effect of A549 on the production of osteoclastogenesis activator RANKL (receptor activator of nuclear factor kappa-B ligand) and M-CSF (macrophage colony-stimulating factor) on osteoblasts, while the expression of PTHrP is decreased in A549 cells. miR-33a overexpression also reduces the inhibitory activity of A549 on the production of OPG (osteoprotegerin), an osteoclastogenesis inhibitor. In addition, miR-33a-mediated PTHrP downregulation results in decreased IL-8 secretion in A549, which contributes to decreased lung cancer-mediated osteoclast differentiation and bone resorption.. These findings have led us to conclude that miR-33a may be a potent tumor suppressor, which inhibits direct and indirect osteoclastogenesis through repression of PTHrP.. miR-33a may even predict a poor prognosis for lung cancer patients.

Topics: Bone Neoplasms; Bone Resorption; Cell Differentiation; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Interleukin-8; Lung Neoplasms; MicroRNAs; Neoplasm Metastasis; Neoplasm Proteins; Osteoclasts; Osteoprotegerin; Parathyroid Hormone-Related Protein; RANK Ligand; RNA, Neoplasm

Human non-small cell lung cancer (NSCLC) patients exhibit a high propensity to develop skeletal metastasis, resulting in excessive osteolytic activity. The RANKL/RANK/OPG system, which plays a pivotal role in bone remodeling by regulating osteoclast formation and activity, is of potential interest in this context.. Reverse transcriptase polymerase chain reaction, western blotting, and immunohistochemical analysis were used to examine the expression of RANKL, RANK, and OPG in human NSCLC cell lines with different metastatic potentials, as well as in 52 primary NSCLC samples and 75 NSCLC bone metastasis samples. In primary NSCLC patients, the expression of these proteins was correlated with clinicopathological parameters. Recombinant human RANKL and transfected RANKL cDNA were added to the PAa cell line to evaluate the promoter action of RANKL during the process of metastasis in vitro and in vivo.. Up-regulated RANKL, RANK, and OPG expression and increased RANKL:OPG ratio were detected in NSCLC cell lines and in tumor tissues with bone metastasis, and were correlated with higher metastatic potential. The metastatic potential of NSCLC in vitro and in vivo, including migration and invasion ability, was significantly enhanced by recombinant human RANKL and the transfection of RANKL cDNA, and was impaired after OPG was added. The increased expression of RANKL and OPG correlated with tumor stage, lymph node metastasis, and distant metastasis.. Differential expression of RANKL, RANK, and OPG is associated with the metastatic potential of human NSCLC to skeleton, raising the possibility that the RANKL/RANK/OPG system could be a therapeutic target for the treatment of metastatic NSCLC patients.

Topics: Adult; Aged; Animals; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice; Middle Aged; Multimodal Imaging; Osteoprotegerin; Positron-Emission Tomography; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; RNA, Messenger; Tomography, X-Ray Computed; Transfection; Transplantation, Heterologous

The impact on the survival of bone metastases (BM) in patients with neuroendocrine tumor (NET) is a matter of debate. BM have a key role in causing symptoms and in decreasing patients' quality of life. Although the mechanisms of the development of BM are not completely clear, it is now well understood that the Receptor Activator of Nuclear factor Kappa-B-/Ligand (RANK/RANKL)/osteoprotegerin (OPG) pathway plays a relevant role.. To characterize the RANK/RANKL/OPG pathway in patients affected with NET.. Two cohorts of 15 patients each were enrolled in the study; one cohort was affected with NET without BM and the second cohort was affected with NET with BM. The serum RANK/RANKL/OPG pathway was assessed in both the groups.. Serum OPG levels and RANKL/OPG ratio were lower and higher, respectively, in NET patients harboring BM than in those without BM. During the ROC analysis, a cut-off value of 1071 pg/ml for OPG and 0.62 for RANKL/OPG ratio were able to significantly distinguish between the two groups.. This study indicates that RANK/RANKL/OPG pathway is imbalanced in patients with NET harboring BM. Specific alterations of this pathway could predict an early development of BM.

Topics: Adult; Aged; Bone Neoplasms; Carcinoma, Neuroendocrine; Disease Progression; Early Diagnosis; Female; Gene Expression Regulation, Neoplastic; Humans; Intestinal Neoplasms; Lung Neoplasms; Male; Middle Aged; Osteoprotegerin; Pancreatic Neoplasms; Predictive Value of Tests; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; ROC Curve; Signal Transduction; Survival Analysis

The aim of the present study was to evaluate correlations between serum osteocalcin, osteoprotegerin and NTX (Cross-linked N-telopeptides of Type I Collagen) and urinary NTX in breast and lung cancer patients with bone metastases. These four markers are considered to have important roles in bone formation, resorption and metastases.. Four markers were determined in the sera of 60 breast cancer and 21 lung cancer patients and healthy controls (n=30). Serum levels were studied using ELISA and EIA.. The median levels of serum osteoprotegerin (p<0.001) and osteocalcin (p=0.003) were higher in patients. Significant correlations were observed between the serum NTX-osteocalcin (r=0.431; p<0.001), serum NTX- osteoprotegerin (r=0.42; p=0.003) and serum NTX - urine NTX (r=0.255; p=0.022).. We conclude that osteocalcin, osteoprotegerin and NTX are independent diagnostic tools. Due to the ease of urine collection, urine NTX may be applied routinely to allow early detection of bone metastases and indicate progression of the disease.

Topics: Adult; Aged; Biomarkers, Tumor; Bone Neoplasms; Breast Neoplasms; Case-Control Studies; Collagen Type I; Female; Humans; Lung Neoplasms; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Peptides

The role of receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) system, and osteopontin (OPN) was studied in patients with solid tumors metastatic to the bone in relation to the type of malignancy and the neoplastic burden to the skeleton. Levels of soluble RANKL (sRANKL), OPG and OPN were assessed in 61 patients with breast, lung and prostate cancer with newly-diagnosed metastasis to the bone, in parallel with bone resorption [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase-5b (TRACP-5b)] and bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)]. Patients had elevated serum levels of sRANKL, OPG, OPN, TRACP-5b, and bALP, and reduced OC levels compared to controls. OPG correlated with the extent of metastatic bone burden. Patients with breast and lung cancer shared increased levels of sRANKL, OPG, and OPN whereas prostate cancer patients had elevated values of OPG and bALP only. These results suggest that patients with solid tumors metastatic to the bone have severe disruption of the sRANKL/OPG axis. Breast and lung cancer seem to exert their osteolytic action through upregulation of the sRANKL/OPG system and OPN, whereas prostate cancer seems to provoke profound elevation of OPG levels only, thus leading to increased osteoblastic activity.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Bone and Bones; Bone Neoplasms; Bone Remodeling; Breast Neoplasms; Down-Regulation; Female; Humans; Lung Neoplasms; Male; Osteoblasts; Osteopontin; Osteoprotegerin; Prostatic Neoplasms; RANK Ligand; Skeleton; Up-Regulation

We have previously demonstrated that parathyroid hormone-related protein (PTHrP) is a cachexia inducer, but it is still not known what PTHrP effects on target tissues induce the cachexia. Therefore, we examined the effects of anti-PTHrP antibody and osteoprotegerin (OPG) on PTHrP-producing tumor-induced cachexia. Nude mice bearing PTHrP-producing human lung cancer cells (HARA-B) exhibited cachexia with hypercalcemia 3-4 weeks after inoculation, accompanied by losses in body, adipose tissue, and muscle weight. OPG ameliorated hypercalcemia, as did neutralization of PTHrP with antibody; and it increased both body and adipose tissue weights. These increases in body and adipose tissue weight, however, were significantly less than those in mice treated with anti-PTHrP antibody. Simultaneous administration of OPG and anti-PTHrP antibody caused significant increases in body, adipose tissue, and muscle weight, along with an immediate decrease in blood ionized calcium levels. The increase in body weight was similar to that observed in mice treated with anti-PTHrP antibody alone, and the decrease in the blood ionized calcium levels was significantly greater than that in mice treated with OPG or anti-PTHrP antibody alone. These results suggest that an effect of PTHrP on target tissues other than hypercalcemia is involved in the development of cachexia. Expression of cachexia-inducing proinflammatory cytokines (interleukin-6 and leukemia inhibitory factor) is stimulated by PTHrP. This might be a mechanism by which PTHrP produces tumor-induced cachexia. It is also suggested that OPG and anti-PTHrP antibody synergistically act to ameliorate hypercalcemia, although the mechanism responsible for this is unclear.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Cachexia; Disease Models, Animal; Glycoproteins; Humans; Hypercalcemia; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Osteoprotegerin; Parathyroid Hormone-Related Protein; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tumor Cells, Cultured

The pathogenesis of bone metastases may require the activation of osteoclasts by tumor-secreted factors, which promote important interactions with the bone microenvironment. We utilized an intratibial model of bone metastasis with bioluminescent imaging (BLI) to measure the effect of osteoclast inhibition on the interaction of human lung cancer cells with bone, and on tumor growth. Mice were injected with luciferase-transduced tumor cells (HARA, human pulmonary squamous carcinoma) and divided into three groups: (1) untreated, (2) twice weekly treatment with the bisphosphonate zoledronic acid (ZOL), or (3) osteoprotegerin (OPG). Histomorphometry and imaging were used to evaluate tumor burden, and parameters of osteoclast activity. Mice in the treated groups had increased bone density and decreased osteoclast numbers in nontumor-bearing tibiae. There was greater than 60% reduction in mean tumor volume in both treatment groups when evaluated by histomorphometry (P = 0.06 [OPG], P = 0.07 [ZOL]). However, bioluminescent imaging failed to show a reduction in tumor burden due to wide variability in the data. Osteoclast numbers along tumor-associated bone were significantly increased compared to tumor-free bone, and were not reduced by either treatment. Plasma calcium concentration was increased in all groups. Plasma tartrate-resistant acid phosphatase 5b was reduced in both treatment groups. Plasma PTHrP was significantly increased in the untreated tumor-bearing group, but was not significantly different in the two treatment groups compared to normal mice. OPG or ZOL did not change tumor cell proliferation, but ZOL increased HARA cell apoptosis. OPG and ZOL reduced tumor growth in the tibiae of treated mice, however, PTHrP production by HARA cells may have resulted in a high concentration in the bone microenvironment, partially overriding the antiosteoclast effects of both OPG and ZOL.

Topics: Animals; Bone Density Conservation Agents; Bone Neoplasms; Cell Division; Diphosphonates; Humans; Imidazoles; Lung Neoplasms; Mice; Mice, Nude; Osteoprotegerin; Tibia; Transplantation, Heterologous; Zoledronic Acid

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays an important role in the process of lymphocyte-mediated cytotoxicity against malignant cells. Osteoprotegerin (OPG) is a soluble decoy receptor for TRAIL, and circulating OPG has been implicated in the protection of cells from TRAIL-mediated apoptosis. Thus, OPG may protect tumor cells from lymphocyte-mediated cytotoxicity and, as a result, contribute to tumor progression. In the current study, the authors investigated this hypothesis in patients with bladder carcinoma.. Serum OPG levels for 185 patients with bladder carcinoma were determined using an enzyme-linked immunosorbent assay. These levels then were assessed for potential correlations with various disease characteristics and outcome measures.. The mean serum OPG concentration in patients with bladder carcinoma was approximately 3 times greater than the mean concentration in healthy individuals, and among patients with bladder carcinoma, higher tumor stage and grade were found to be associated with increased serum OPG levels. Within the subpopulation of patients with superficial bladder carcinoma, after a follow-up period of 5 years, those who had low serum OPG levels tended to have a longer postoperative tumor-free interval compared with those who had high serum OPG levels. Furthermore, among patients with muscle-invasive bladder carcinoma, the 5-year disease-specific survival rate was greater for those who had low serum OPG levels than for those who had high serum OPG levels.. To the authors' knowledge, the current study is the first to demonstrate that serum OPG concentration is correlated with both tumor stage and tumor grade and that elevated serum OPG levels are predictive of early recurrence in patients with bladder carcinoma. These findings suggest that serum OPG concentration may have utility as a prognostic parameter in this setting.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Carcinoma, Transitional Cell; Case-Control Studies; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Glycoproteins; Humans; Lung Neoplasms; Male; Membrane Glycoproteins; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Osteoprotegerin; Postoperative Care; Prognosis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Survival Rate; TNF-Related Apoptosis-Inducing Ligand; Transfection; Tumor Necrosis Factor-alpha; Urinary Bladder Neoplasms

The aim of our study was to evaluate the usefulness of serum OPG and ProGRP during chemotherapy of lung cancer in relation to the histological type of the tumour, its clinical stage and the response to therapy. The levels of OPG and ProGRP were determined in 39 patients (20 NSCLC, 19 SCLC) and 10 healthy subjects. Blood samples were collected from each patient before and after chemotherapy. OPG and ProGRP levels in all the patients with lung cancer were higher than those in the controls. ProGRP were higher in SCLC group than in those NSCLC. In NSCLC group (after chemotherapy), OPG level in patients with Stage IV tumour was higher than in those with Stage IIIB (p=0.03). OPG in ED SCLC were higher than those in LD SCLC (p=0.04). In SCLC group, ProGRP were higher in LD patients than those with ED (p=0.04). Concluding, the measuring of OPG and ProGRP in lung cancer patients may be useful in clinical practice.

Topics: Biomarkers, Tumor; Glycoproteins; Humans; Lung Neoplasms; Neoplasm Staging; Osteoprotegerin; Peptide Fragments; Peptides; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins