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

Bone resorption resulting from the metastatic human melanoma cell line (A375) was investigated morphologically using an experimental model of bone metastases in nude mice. An injection of A375 (1 x 10(5)) in the left ventricle produced multiple osteolytic lesions. Many TRAPase-positive multinucleated cells, identified by EM as osteoclasts, were observed on the bone surface at the site of metastases. The findings suggest that bone resorption was caused by osteoclasts developed in the presence of tumor cells. Even where tumor cells were juxtaposed to bone surface, small and flat TRAPase-positive cells were shown to exist on the bone surface. Thus, bone resorption was mainly associated with the occurrence of osteoclasts. A large number of osteoclast progenitor cells were also observed adjacent to tumor cells and/or stromal cells located apart from bone, indicating possible participation of tumor cells and/or stromal cells in the differentiation of osteoclasts. Ultrastructurally, stromal cells and/or extracellular matrices were present between tumor cells and osteoclast progenitor cells. Immunohistochemical observation clarified the localization of heparan sulfate proteoglycan (HSPG) and fibronectin (FN) around osteoclast progenitor cells. These findings suggest that they play an important role in providing a microenvironment favorable for osteoclast differentiation and activation. The immunohistochemical localization of IL-6, PGE2, and TGF-alpha also indicates that they are involved in osteoclast differentiation and activation. In conclusion, bone resorption at the metastatic sites of A375 is mediated via osteoclasts and A375 cells may be involved in the differentiation and activation of osteoclasts in association with stromal cells, extracellular matrices (HSPG, FN) and osteotropic cytokines (IL-6, PGE2, TGF-alpha).
 ...
PMID:Bone resorption induced by a metastatic human melanoma cell line. 778 38

Bisphosphonates are potent inhibitors of bone resorption and are commonly used in the treatment of bone metastases. In addition, they seem to influence cytokine secretion. Since the efficacy of IL-2 cancer immunotherapy, in part, depends on endogenous cytokine secretion, bisphosphonates could be effective in modulating IL-2 activity. High pretreatment levels of IL-6 seem to correlate with resistance to IL-2. On this basis, a pilot study was performed to evaluate the in vivo effects of the bisphosphonate, pamidronate, on blood levels of IL-6. The study included 7 patients with bone metastases due to solid tumours. Pamidronate was injected intravenously at 60 mg over 3 h. Venous blood samples were drawn before, at 1-h intervals during pamidronate infusion, then after 1 and 3 days. Mean serum levels of IL-6 significantly decreased during pamidronate infusion, then after 1 and 3 days, IL-6 mean levels still remained lower than control level, but differences were not significant. This preliminary study shows that pamidronate infusion induces a rapid but transient decline in IL-6 blood concentrations, and suggests a possible use of bisphosphonates to modulate the efficacy of IL-2 cancer immunotherapy.
 ...
PMID:Acute effects of pamidronate administration on serum levels of interleukin-6 in advanced solid tumour patients with bone metastases and their possible implications in the immunotherapy of cancer with interleukin-2. 913 6

Recently serum S-100beta has shown promise as a tumour marker in melanoma; however, its use as a prognostic marker in the advanced stage needs to be confirmed. Interleukins (ILs) may mediate regression or progression of cancer. In order to study their relation to the metastatic profile and survival, we evaluated the association between pretreatment serum levels of S-100beta, IL-6, IL-10 and IL-12 and metastatic site and survival in 50 patients with advanced melanoma who were to receive chemoimmunotherapy. Patients with liver and/or bone metastases had significantly higher median concentrations of S-100beta, IL-6 and IL-10 than those with only skin, nodal and/or lung involvement. The differences in IL-12 levels were unremarkable. Using univariate analysis, the S-100beta level and metastatic profile were found to be statistically significant prognostic factors for survival. Using multivariate analysis the S-100beta level was the most powerful prognostic indicator, while the metastatic profile was found to be significant after exclusion of S-100beta. The findings suggest that elevated serum levels of S-100beta, IL-6 and IL-10 reflect concurrent liver or bone metastases in melanoma. S-100beta is also an independent prognostic marker. Pretreatment IL levels were not associated with outcome.
 ...
PMID:The value of serum S-100beta and interleukins as tumour markers in advanced melanoma. 1089 Mar 77

Lung cancer is commonly associated with multiorgan metastasis, and bone is a frequent metastatic site for lung cancer. Nevertheless, no bone metastasis model of lung cancer with multiorgan dissemination is available, which could provide opportunity to study the molecular pathogenesis. We examined the abilities of eight human lung cancer cell lines injected intravenously into natural killer (NK) cell-depleted SCID mice to generate metastatic nodules in bone and multiple organs, and explored the correlation of the parathyroid hormone-related protein (PTHrP) with the bone metastasis. Although all the small-cell carcinoma cell lines (SBC-5, SBC-3, SBC-3/ADM, H69, H69/VP) formed metastatic nodules in multiple organs (liver, kidney, and lymph nodes), only SBC-5 cells reproducibly developed bone metastases. Squamous cell carcinoma (RERF-LC-AI) cells metastasized mainly into the liver and kidneys, whereas adenocarcinoma (PC-14, A549) mainly produced colonies in the lungs. As assessed by X-ray photography, the osteolytic bone metastases produced by SBC-5 cells were detected as early as on day 28, and all recipient mice developed bone metastasis by day 35. The expression of PTHrP in eight cell lines was directly correlated with the formation of bone metastasis. No correlation was observed between the formation of bone metastasis and the expression of other metastasis-related cytokines (IL-1, IL-6, IL-8, IL-10, IL-11, TNF-alpha, VEGF, M-CSF). Consistent with the formation of bone metastasis by SBC-5 cells, the levels of PTHrP and calcium in the mouse serum were increased in a time-dependent manner, suggesting that PTHrP produced by human lung cancer may play a crucial role in the formation of bone metastasis and hypercalcemia. These findings indicate that a bone metastasis model of SBC-5 cells may be useful for clarifying the molecular aspects of the metastatic processes in different organ microenvironments and the development of therapeutic modalities for lung cancer patients with bone metastases.
 ...
PMID:Bone metastasis model with multiorgan dissemination of human small-cell lung cancer (SBC-5) cells in natural killer cell-depleted SCID mice. 1141 46

Bone is a frequent site of cancer metastasis. Bone metastases can result in bone destruction or new bone formation. Bone destruction is mediated by factors produced or induced by tumor cells that stimulate formation and activation of osteoclasts, the normal bone-resorbing cells. Local bone destruction also occurs in patients with osteoblastic metastases and may precede or occur simultaneously with increased bone formation. Several factors, including interleukin (IL)-1, IL-6, receptor activator of NF-kappaB (RANK) ligand, parathyroid hormone-related protein (PTHrP), and macrophage inflammatory protein-1-alpha (MIP-1alpha), have been implicated as factors that enhance osteoclast formation and bone destruction in patients with neoplasia. PTHrP seems to be the major factor produced by breast cancer cells that induces osteoclast formation through upregulation of RANK ligand. Enhanced RANK ligand expression also plays an important role in bone destruction in patients with myeloma. RANK ligand can act to enhance the effects of other factors produced by myeloma cells or in response to myeloma cells, such as MIP-1alpha and/or IL-6, to induce osteoclast formation. Understanding of the molecular mechanisms responsible for osteoclast activation in osteolytic metastases should lead to development of novel therapeutic approaches for this highly morbid and potentially fatal complication of cancer.
 ...
PMID:Biology of osteoclast activation in cancer. 1177 96

Paget's disease and bone metastases in cancer patients share many common properties. Both are characterized by a localized increase in osteoclast (OCL) formation leading to bone resorption. In both Paget's disease and bone metastases the increased OCL formation and the increased osteoclastogenic nature of the bone microenvironment are mediated by common factors, namely interleukin (IL)-6 and RANK ligand (RANKL). Available data suggest that in the case of Paget's disease there is increased RANKL and IL-6 production, and IL-6 enhances the responsivity of the OCL precursors to RANKL, contributing to the elevated numbers of OCLs. In patients with multiple myeloma, 95% to 100% of whom develop bone lesions, both IL-6 and RANKL levels are increased. Bisphosphonates bind locally to the surfaces of the bone undergoing osteoclastic resorption to inhibit this process. Paget's disease has in the past and will continue in the future to provide a model to test the efficacy of bisphosphonates in inhibiting bone resorption. Paget's disease provides an ideal model in which to investigate the efficacy of the new third-generation bisphosphonates in the treatment of bone metastases as well as nonmalignant bone disease.
 ...
PMID:Studies in Paget's disease and their relevance to oncology. 1154 71

Cachexia often causes deterioration in the quality of life in cancer patients; however, its mechanism remains poorly understood. Cachexia has often been observed in experimental animals with bone metastases, and parathyroid hormone-related protein (PTHrP) plays an important role in the formation of such metastases. We therefore investigated the possible involvement of PTHrP in an experimental cachexia model using human lung-cancer cells (HARA-B). HARA-B cells produce a high amount of PTHrP but no TNF-alpha, IL-6 or leukemia inhibitory factor. The s.c. inoculation of HARA-B cells into nude mice caused reductions in body weight, adipose tissue weight, muscle weight and serum glucose levels. Serum levels of calcium and PTHrP increased. Neutralization of PTHrP with antibody caused rapid weight gain along with a rapid decrease in serum calcium levels. Our findings suggest that PTHrP plays an important role in the development of cancer cachexia. PTHrP therefore is a possible target molecule for the treatment of cancer cachexia.
 ...
PMID:Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen. 1166 74

Prostate cancer metastasis to bone may be mediated by preferential proliferation of these cells in the bone's microenvironment. We hypothesize that this preferential proliferation is mediated by bone-associated growth factors (GFs) and cytokines. To test our hypothesis, human prostate cancer cells, derived from both soft tissue (LNCaP, DuCaP, DU145) and bone metastases (PC-3, VCaP, MDA-2a, MDA-2b), were treated with bone-associated GFs and cytokines (PDGF, IGF-1, TGF-beta, EGF, bFGF, TNF-alpha, IL-1, and IL-6) for 48 h, and their growth responses were compared. The responses of soft tissue-derived prostate cancer cell lines to bone GFs and cytokines were variable. LNCaP cell growth was stimulated by IGF-1 but was inhibited by TNF-alpha. DU145 cell growth was stimulated with EGF. Prostate cancer cell lines derived from bone metastases also responded variably to bone GFs and cytokines. IL-1 stimulated the growth of MDA-2a and 2b cell lines in a dose-dependent manner. PDGF and bFGF both demonstrated variable effects on bone-derived prostate cancer cell lines. TNF-alpha inhibited proliferation of the VCaP cells. These findings demonstrate that human prostate cancer cell lines derived from bone metastases may not respond preferentially to bone-associated GFs and cytokines.
 ...
PMID:The effect of bone-associated growth factors and cytokines on the growth of prostate cancer cells derived from soft tissue versus bone metastases in vitro. 1263 88

Mouse bone marrow cells cultured with human breast cancer MCF-7 cell-conditioned media showed osteoclastogenesis with an increment of bone resorption, although conditioned media from an adriamycin-selected MCF-7 clone (MCF-7ADR) had no effect. Consistently, MCF-7 cells induced 5-fold more in vivo experimental osteolytic bone metastases, with no soft tissue lesions, compared to MCF-7ADR cells. Paracrine factors stimulating (interleukin (IL)-6, IL-1beta, tumor necrosis factor-alpha (TNF-alpha)) or inhibiting (IL-12, IL-18, granulocyte macrophage-colony stimulating factor (GM-CSF)) osteoclastogenesis were significantly increased in MCF-7ADR relative to MCF-7 cells, suggesting that the inhibitory cytokines could selectively overwhelm the effects of the stimulatory ones. Treatment of osteoblast primary cultures with MCF-7-conditioned medium induced a selective upregulation of IL-6 expression, suggesting an indirect stimulation of osteoclastogenesis via the osteoblasts. MCF-7 and MCF-7ADR showed no difference in proliferation rate. However, a higher ability to migrate and invade gelatin and matrigel was observed in MCF-7ADR. Enhanced invasiveness might result from increased metalloproteinase (MMP) activity and cytoskeleton rearrangement. MCF-7ADR cells expressed higher levels of c-Src, focal adhesion kinase (FAK), and protein tyrosine kinase 2 (PYK2) involved in cell adhesion and motility. MCF-7 and MCF-7ADR expressed high and faint levels of functional estrogen receptor alpha (ERalpha), respectively. MCF-7ADR also showed significantly higher levels of the protein kinase C (PKC) alpha and beta2 and a selective activation of PKC compared to MCF-7, where the most abundant isoforms were beta1 and delta. Heat shock protein 27 (Hsp27) was more abundant in MCF-7 cells, but failed to translocate to the nucleus in response to heat shock. In conclusion, we have demonstrated that despite the fact that MCF-7ADR cells showed a more invasive phenotype relative to MCF-7, they have low potential to induce osteolytic bone lesions and stimulate osteoclastogenesis and osteoclast activity. Therefore, we believe that reduced aggressiveness of breast carcinomas could correlate with a greater osteolytic activity featuring their bone metastases.
 ...
PMID:In vivo bone metastases, osteoclastogenic ability, and phenotypic characterization of human breast cancer cells. 1505 Sep 1

Prognosis of pancreatic cancer is one of the worst among various cancers, however, incidence of bone metastasis has been increased even in pancreatic cancer in recent years. Therefore, we examined clinical features of pancreatic cancer presenting bone metastases who were treated in our cancer center, and propose how to manage these patients. We experienced 13 patients (7.3%) with pancreatic cancer with bone metastases during 2000-2003. Among these patients, pancreatic cancer was located at pancreatic body to tail in 10 cases, while it was located at pancreatic head in 3 cases. Liver metastasis was noted in 7 of 13 cases with bone metastases. Radiographical imagings of bone lesions revealed osteolytic bone destruction, and serum levels of bone resorption marker, 1CTP, were elevated in these patients. Stimulation of osteoclastic bone resorption is a critical step for bone metastasis, thus, serum levels of cytokines (PTHrP, IL-6, VEGF), which exert a promotive effect on bone resorption, were measured. Serum levels of IL-6 and VEGF were elevated in most of these patients, while elevation of serum PTHrP levels was found in 3 of 13 patients with bone metastases. Survival periods of pancreatic cancer patients with bone metastases was not long, however, treatment for bone metastases is important in terms of quality of life (QOL). An earlier diagnosis is essential to prevent deterioration in the QOL of pancreatic cancer patients presenting bone metastases. Periodical measurement of serum 1CTP in addition to bone scintigraphy is helpful for the earlier diagnosis for bone metastases.
 ...
PMID:[Clinical features and management of pancreatic cancer with bone metastases]. 1538 5


1 2 3 Next >>