UMLS:C0153690 - FACTA Search

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Query: UMLS:C0153690 (bone metastases)
6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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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 metastases and the strong interaction between osseous and metastatic cell populations require interdisciplinary thought and actions. If it were possible to interrupt the malignant dialogue between tumour and bone at an early stage, this might not only reduce the amount of bone destruction, but could also reduce the incidence of osseous metastases and remove the source of secondary metastases to other organs. Studies into the preventive effects of bisphosphonates are currently running or are planned. Most of these studies are in breast cancer patients with involvement of the axillary lymph nodes. The prognostic factors of lymph node status, tumour size and grading are better than none, but do not select patients at a high risk of skeletal metastasis. This would be much better done by using immunohistochemical methods to investigate the primary tumour for bone sialoprotein and parathyroid hormone-related protein (PTHrP). However, these methods are complicated, have not been validated in large numbers of patients and are not standardized. Serum tests for bone sialoprotein, PTHrP and collagen fragments are currently still under development and cannot be recommended generally. The clinical importance of tumour cells in the bone marrow has been demonstrated but is still only used at a few centres.
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PMID:Prognostic factors for skeletal relapse in breast cancer. 1141 65

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.
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PMID:Biology of osteoclast activation in cancer. 1177 96

Breast cancer has a predilection for spreading to bone. The mechanism of preferential metastasis of breast cancer to bone is unknown. We hypothesize that breast cancer cells that develop bone metastases have the capacity to facilitate their colonization in bone. To examine this hypothesis, we established bone-seeking (MDA-231BO) and brain-seeking (MDA-231BR) clones of the human breast cancer cell line MDA-MB-231 by repeated sequential passages in nude mice and in vitro of metastatic cells obtained from bone and brain metastases, respectively. These clones were examined for distinguishing biological characteristics and compared with the MDA-231 parental cells (MDA-231P) in vivo and in vitro. Both the MDA-231BR and the MDA-231BO showed identical tumorigenicity to MDA-231P at the orthotopic site. MDA-231P that was inoculated into the heart developed metastases in bone, brain, ovary, and adrenal glands. On the other hand, MDA-231BO exclusively metastasized to bone with larger osteolytic lesions than MDA-231P. MDA-231BR exclusively disseminated to brain and failed to develop bone metastases. In culture, MDA-231BO produced greater amounts of parathyroid hormone-related protein (PTH-rP) than MDA-231BR and MDA-231P in the absence or presence of transforming growth factor beta (TGF-beta). Furthermore, the anchorage-independent growth of MDA- 231BO in soft agar was not inhibited by TGF-beta, whereas TGF-beta profoundly inhibited the growth of MDA-231P and MDA-231BR. Insulin-like growth factor I (IGF-I) markedly promoted the anchorage-independent growth of MDA-231BO, whereas marginal or no stimulation was observed in MDA-231BR or MDA-231P, respectively. Our data suggest that these phenotypic changes allow breast cancer cells to promote osteoclastic bone resorption, survive, and proliferate in bone, which consequently leads to the establishment of bone metastases.
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PMID:A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. 1149 71

Tumour-induced hypercalcaemia (TIH) is a frequent complication of advanced cancer but has been rarely reported in patients with malignant melanoma, and its pathogenesis remains unexplored. We studied eight patients with TIH and melanoma. We determined the incidence and pathogenesis of this complication and the effects of bisphosphonate therapy. The incidence of TIH in 751 patients with melanoma was 1.1%. All patients had liver and bone metastases at the time of hypercalcaemia. All patients had osteolytic lesions, most often multiple. The median survival was 30 days (range 4-136 days). After rehydration, the mean (+/- SEM) corrected calcium was 3.42 +/- 0.17 mmol/l. Parathyroid hormone levels were adequately suppressed and vitamin D concentrations were normal. Serum osteocalcin, a marker of bone formation, was low, except in the two patients with renal insufficiency, whereas fasting urinary calcium and hydroxyproline were increased, indicating inhibition of bone formation and stimulation of bone resorption. Increased parathyroid hormone-related protein secretion was noted in only one patient. Three of four patients became normocalcaemic after bisphosphonate therapy for a median duration of 2 weeks. In conclusion, hypercalcaemia is a rare complication of melanoma. It occurs in the context of far advanced disease and is essentially due to aggressive lytic bone metastases with an uncoupling in bone turnover. Bisphosphonates can offer short-term palliation.
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PMID:Hypercalcaemia of melanoma: incidence, pathogenesis and therapy with bisphosphonates. 1159 84

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.
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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

Parathyroid hormone-related peptide (PTHrP) has a high homology with the N-terminal portion of the parathyroid hormone (PTH). The gene of PTHrP is complex and can generate by alternative splicing at least three mature peptides containing 139, 141 and 173 amino acids. PTHrP acts via a common receptor with PTH but also via specific receptors. In physiological circumstances, PTHrP is produced locally in many normal tissues where it has autocrine/paracrine functions, particularly during embryonic development, growth regulation and differentiation of many cellular types. PTHrP has endocrine action on bone and kidney. The humoral hypercalcemia of malignancy is mainly mediated by PTHrP. Most hypercalcemic patients with solid tumors have increased plasma PTHrP, whereas PTHrP is not detectable in healthy subjects. During treatment with bisphosphonates, elevated plasma levels of PTHrP are associated with a weak response. PTHrP has also a significant role in the pathophysiology of bone metastases. PTHrP can induce a local osteolysis near the bone metastases, which favours their progression and thus participates in the autocrine regulation of tumor growth. In breast cancer, PTHrP is detected in about 60% of primary tumors and in more than 70% of bone metastases, whereas only 17% of nonbone metastases express PTHrP. A higher expression of PTHrP and its mRNA 1-139, is positively correlated with an invasive tumor phenotype and the development of bone metastases. PTHrP is an effector of transforming growth factor (TGFbeta) in the development and progression of osteolytic bone metastases. TGFbeta, which is released in bone matrix during osteolytic resorption, enhances tumor cells PTHrP production. Then, PTHrP stimulates bone resorption and develops tumor cells metastatic potential. Thus a feedback loop exists between carcinoma cells and the bone microenvironment, leading to a vicious circle.
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PMID:[PTHrP and breast cancer]. 1174 1

Bone metastases are one of the most common events in patients with prostate carcinoma. PTH-rP, a protein produced by prostate carcinoma and other epithelial cancers, is a key agent for the development of bone metastases. A PTH-rP-derived peptide, designated PTR-4 was identified, which is capable to bind HLA-A2.1 molecules and to generate PTH-rP-specific cytotoxic T cell (CTL) lines from healthy HLA-A2.1(+) individual peripheral-blood-mononuclear-cells (PBMC). In this model, we investigated the in vitro possibility of generating an efficient PTH-rP specific CTL response by cyclical stimulations with IL-2 and PTR-4 peptide-pulsed autologous dendritic cells (DC), of HLA-A2.1(+) tumour infiltrating lymphocytes (TIL) derived from a patient with metastatic prostate carcinoma. A T cell line generated in this way (called TM-PTR-4) had a CD3(+), CD5(+), CD4(-), CD8(+), CD45(Ro+), CD56(-) immunophenotype and a HLA-A2.1 restricted cytotoxic activity to PTR-4-peptide pulsed CIR-A2 (HLA-A2.1(+)) target cells, PTH-rP(+)/HLA-A2.1(+) CIR-A2 transfected with PTH-rP gene, prostate carcinoma LNCaP cells, and autologous metastatic prostate cancer cells (M-CaP). These lymphocytes were not cytotoxic to HLA-A2.1(+) targets not producing PTH-rP, such as peptide-unpulsed CIR-A2 and colon carcinoma SW-1463, cell lines. Our results provide evidence that PTR-4 peptide-pulsed autologous DC may break the tolerance of human TIL against the autologous tumour by inducing a PTH-rP-specific CTL immune reaction. In conclusion PTR-4 peptide-pulsed autologous DC may be a promising approach for vaccine-therapy and antigen-specific CTL adoptive immunotherapy of hormone-resistant prostrate cancer.
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PMID:A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-dose IL-2. 1174 94

Transforming growth factor (TGF)-beta promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta type I receptor. Treatment of the mice with a PTHrP-neutralizing antibody greatly decreased osteolytic bone metastases. There were fewer osteoclasts and significantly decreased tumor area in the antibody-treated mice. TGF-beta can signal through both Smad and mitogen-activated protein (MAP) kinase pathways. Stable transfection of wild-type Smad2, Smad3, or Smad4 increased TGF-beta-stimulated PTHrP secretion, whereas dominant-negative Smad2, Smad3, or Smad4 only partially reduced TGF-beta-stimulated PTHrP secretion. When the cells were treated with a variety of protein kinases inhibitors, only specific inhibitors of the p38 MAP kinase pathway significantly reduced both basal and TGF-beta-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 MAP kinase inhibition resulted in complete inhibition of TGF-beta-stimulated PTHrP production. Furthermore, TGF-beta treatment of MDA-MB-231 cells resulted in a rapid phosphorylation of p38 MAP kinase. Thus, the p38 MAP kinase pathway appears to be a major component of Smad-independent signaling by TGF-beta and may provide a new molecular target for anti-osteolytic therapy.
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PMID:Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. 1196 7

The skeleton is the most common site of metastatic disease in breast cancer and the most common site of first distant relapse. Bone metastases in breast cancer are the source of considerable morbidity, including severe pain, pathological fractures, need for radiotherapy or surgery, and hypercalcemia. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, and it is well known that breast cancer cells in bone can stimulate osteoclast formation and activity leading to the release of growth factors and cytokines, which will further stimulate cancer cell growth and their secretion of osteolytic factors. We are thus typically dealing with a vicious cycle, as the bone resorption-induced release of growth factors from the bone matrix will stimulate breast cancer cell growth (probably mainly by IGFs) and the production of the osteolytic factor PTHrP (probably mainly by TGF-beta but also by extracellular calcium). Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for osteoclasts. Nitrogen-containing bisphosphonates, such as pamidronate, ibandronate, and zoledronate, interfere with the mevalonate pathway that is crucial to maintain cell membrane integrity. The net result, regardless of the mechanism, is osteoclast apoptosis, notably through the induction of caspase-3. Bisphosphonates are now the standard treatment for cancer hypercalcemia. Repeated bisphosphonate infusions also exert clinically relevant analgesic effects in at least one half of the patients with metastatic bone pain. Most importantly, prolonged administration of bisphosphonates (for at least 1 year) reduces the frequency of morbid skeletal events by 30-40% in breast cancer metastatic to bone and in up to 50% in patients with multiple myeloma. Newer bisphosphonates, such as ibandronate and zoledronate, will simplify the current therapeutic schemes and improve the cost-effectiveness ratio, and they have the potential to improve the therapeutic efficacy, at least in patients with aggressive osteolytic disease or in the adjuvant setting.
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PMID:Bisphosphonates in the treatment of metastatic breast cancer. 1201 36

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