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)

We have recently demonstrated that bone sialoprotein (BSP), a bone-matrix protein involved in hydroxyapatite crystal formation, is ectopically expressed in human breast cancers. We explored a possible association between expression of BSP in primary breast cancer and patients' survival. We analyzed BSP expression in 454 breast-cancer patients by immunohistochemistry on archival paraffin-embedded material using an anti-BSP polyclonal antibody. BSP expression was correlated to survival, tumor size, axillary lymph-node status and first site of distant metastasis. Of the breast cancers analyzed, 89% expressed detectable amounts of BSP. We found a statistical association between expression of BSP and poor prognosis as indicated by survival curves analyzed using the log rank and the Gehan methods. BSP expression was significantly higher in breast-cancer patients with axillary lymph-node involvement. Interestingly, survival of patients with positive lymph nodes but BSP-negative tumors was significantly higher than that of patients with no lymph-node involvement but BSP-positive cancers. The frequency of bone metastases was higher in the group of patients with BSP-positive tumors (22%) than in the group with BSP-negative cancers (7%). There was a significant increase in the incidence of lung metastases in patients whose tumors were negative for BSP. Our data show that bone sialoprotein expression in breast cancer is associated with poor prognosis. BSP detection also appears to be a valuable marker with which to identify, among the lymph-node-negative patients, those who have high risk of disease progression.
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PMID:Expression of bone sialoprotein in primary human breast cancer is associated with poor survival. 879 81

Breast cancer metastasizes to bone more frequently than to any other organ, and over 80% of advanced breast cancer patients develop bone metastases. Our recent demonstration that human breast cancer cells express bone sialoprotein (BSP), a bone matrix protein, provides a possible clue for the selective affinity of breast cancer cells for bone. We tested the hypothesis that detection of BSP in primary human breast cancer could be a potential indicator of the ability of breast cancer cells to metastasize to bone. BSP expression was evaluated in the primary breast cancers of 39 patients using immunoperoxidase and two specific anti-BSP antibodies. None of these patients presented clinically or scintigraphically detectable bone metastases at the time of surgery. In the course of their disease, 22 patients developed clinically diagnosed bone metastases. Expression of BSP in breast cancer cells from patients who developed bone metastases was significantly higher (p = 0.008, according to the Mann-Whitney test) than in patients with no bone involvement. No association was found between BSP expression in the primary breast lesions and axillary lymph node metastases. BSP expression was significantly increased in infiltrating ductal carcinoma compared with infiltrating lobular carcinoma (p = 0.0023). No correlation was found between immunoreactivity to BSP antibodies and estrogen receptor (ER) status, progesterone receptor (PR) status, or age. Our data suggest that BSP could help to identity which women will develop bone metastases and provide new bases for the understanding of the molecular mechanism(s) responsible for breast cancer cells osteotropism.
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PMID:Bone sialoprotein expression in primary human breast cancer is associated with bone metastases development. 915 81

The skeleton is the privileged target of metastatic human breast cancer cells. Bone metastases are indeed found in virtually all advanced breast cancer patients and generate major morbidity. The high osteotropism of breast cancer cells suggests that they exhibit a selective affinity for mineralized tissues. The observation that mammary malignant cells are able to induce hydroxyapatite crystals deposition within the primary tumour suggests that they can generate a microenvironment that favors the crystallization of calcium and phosphate ions into the bone specific hydroxyapatite. Osteonectin (OSN), osteopontin (OPN) and bone sialoprotein (BSP), 3 bone matrix proteins involved in bone matrix mineralization, are expressed in human breast cancers. BSP, an RGD (Arg-Gly-Asp) containing phosphoprotein, initiates hydroxyapatite deposition and mediates attachment of osteoclast to the same crystals prior to their resorption. Detection of BSP at both the protein and the mRNA levels in human breast cancer and in human breast cancer cell lines (MCF-7, T47-D and MDA-MB 231) indicates that mammary malignant cells synthesize directly BSP rather than uptaking it from the serum. Interestingly, the level of BSP expression correlates with the development of bone metastases and with poor survival. These data suggest that the ectopic expression of bone matrix proteins could be involved in conferring osteotropic properties to circulating metastatic breast cancer cells. These observations open new alleys of investigation for the identification of the molecular mechanisms responsible for the genesis of bone metastases.
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PMID:Expression of bone matrix proteins in human breast cancer: potential roles in microcalcification formation and in the genesis of bone metastases. 918 Aug 54

Lung cancer belongs to the group of malignant lesions that specifically select bone as secondary implantation site. The molecular bases for this property, defined as osteotropism, is still largely unknown. The recent demonstration that human breast cancer cells express and attach to bone sialoprotein (BSP), a sulfated phosphoprotein rich in bone and other mineralized tissues, could provide a clue to elucidating bone metastases formation. BSP contains the integrin binding peptide Arg-Gly-Asp (RGD), as well as non-RGD cell attachment domain. Using an immunoperoxidase technique and a specific polyclonal antibody directed against a BSP synthetic peptide, we examined the expression of BSP in 48 lung lesions including 25 squamous carcinoma, 21 adenocarcinoma, and 2 bronchioloalveolar cancers, as well as 38 human ovarian carcinoma that constitute a group of generally nonosteotropic cancers. BSP was not specifically detected in normal lung tissue with the exception of cartilage associated with bronchi. Most of the adenocarcinoma (74%) and all squamous carcinoma of the lung examined exhibited detectable levels of BSP. Staining was mainly cytoplasmic and membrane associated. The two bronchioloalveolar lung cancers examined did not show detectable amounts of BSP. When microcalcifications were observed in pulmonary malignant lesions, they were usually associated with cancer cells expressing BSP. Only 21% of the ovarian cancers examined contained malignant cells with 2+ or 3+ positivity for BSP. We further demonstrated that in 8 of 10 additional lung cancers, BSP was detected at the mRNA level. Our observation is the first demonstration that BSP is expressed in non-small cell lung carcinoma. Lung cancer cells are now the second type of osteotropic malignant cells described to express BSP. Added to the observation that BSP expression is not frequent in ovarian carcinoma, a low osteotropic cancer, our study supports our hypothesis that BSP could play a role in determining the affinity of cancer cells to bone.
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PMID:Expression of bone sialoprotein in human lung cancer. 926 7

Although urinary measurements of collagen degradation provide valid estimates of bone resorption, their clinical application is hampered by pronounced analytical and biological variability. Therefore, immunoassays for the determination of such parameters in serum have been developed. In this study, we assessed the performance of three new serum markers of bone turnover, i.e., C-terminal and N-terminal telopeptides of type I collagen (S-CTX and S-NTX) and bone sialoprotein. Results were compared with urinary total pyridinoline, total deoxypyridinoline, and urinary C-terminal telopeptides of type I collagen (U-CTX) and urinary N-terminal telopeptides of type I collagen (U-NTX). The study population included healthy men (n = 27), premenopausal (n = 30) and postmenopausal (n = 31) women, patients with hepatic dysfunction (HF, n = 24), renal failure (RF, n = 30), breast cancer without (BC-, n = 24) and with (BC+, n = 30) bone metastases, primary vertebral osteoporosis (OPO, n = 27), primary hyperparathyroidism (PHPT, n = 16), active Paget's disease of bone (n = 18), multiple myeloma (MM, n = 18), and patients with hypercalcemia of malignancy before and after treatment with pamidronate (HOM, n = 28). Changes in urinary and serum markers were similar in most metabolic bone diseases. However, differentiation between healthy controls and OPO, or PHPT, was improved by the serum markers. In MM, all serum and urinary markers were elevated (p < 0. 05 vs. controls). In BC+, skeletal involvement was reflected by significant increments in all indices (p < 0.01 vs. BC-), except U-CTX and S-CTX. In HOM, pamidronate-induced changes in biomarkers were most pronounced for U-CTX and S-CTX and S-NTX. HF and RF were associated with elevated levels of all serum markers (p < 0.05 vs. controls). In conclusion, measurements in serum reflect bone resorption to the same extent as the urinary indices. Since serum markers circumvent some of the limitations of urinary measurements, their use potentially improves the assessment of skeletal disorders.
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PMID:Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. 1032 May 28

The recent demonstration that bone sialoprotein (BSP) is expressed in osteotropic cancers suggests that this bone matrix protein might be implicated in the preferential seed and growth of metastatic cells in bone. High expression of BSP in breast and prostate primary carcinomas is associated with progression and bone metastases development. The exact mechanisms by which BSP may favor bone metastases formation are not clearly established yet. Although BSP expression has been detected in breast, prostate, lung, thyroid, and neuroblastoma primary tumors, no information regarding its expression in metastases is available to date. In this study, we have examined BSP expression in 15 bone and 39 visceral metastatic lesions harvested from 8 breast cancer patients and 7 prostate cancer patients who died of disseminated disease. We were able to retrieve the primary lesions from 5 of the 8 breast cancer patients as well as from all 7 prostate cancer patients. All the primary breast tumor patients and 5 of the 7 primary prostate cancer patients expressed a detectable level of BSP. Bone metastases from all 8 breast cancer patients and from 5 out of 7 prostate cancer patients exhibited detectable levels of the protein. Metastatic cells in close contact with bone trabeculae usually were highly positive for BSP. BSP also was detected in secondary lesions developed at visceral sites including liver, thyroid, lung, and adrenal glands. However, BSP expression was significantly lower in visceral metastases than in skeletal ones (Mann-Whitney test, p < 0.05). Our data represent the first demonstration of an increased expression of BSP in bone metastases compared with nonskeletal metastases in human breast and prostate cancers and add weight to the body of evidence attributing a significant role to this protein in the genesis of bone metastases.
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PMID:Increased expression of bone sialoprotein in bone metastases compared with visceral metastases in human breast and prostate cancers. 1080 12

It is well established that bone metastases comprise bone; however, the exact factors/mechanisms involved remain unknown. We hypothesized that tumor cells secreted factors capable of altering normal bone metabolism. The aims of the present study were to (1) determine the effects of secretory products isolated from HT-39 cells, a human breast cancer cell line, on osteoprogenitor cell (MC3T3-E1 cells) behavior, and (2) identify tumor-derived factor(s) that alters osteoblast activities. Conditioned media (CM) from HT-39 cells were collected following a 24-h serum-free culture. The ability of CM to alter gene expression in MC3T3-E1 cells was determined by Northern analysis. CM effects on cell proliferation and mineralization ability were determined using a Coulter counter and von Kossa stain, respectively. MC3T3-E1 cells were treated with CM plus noggin, a factor known to block bone morphogenic proteins (BMPs), to determine whether BMPs, shown to be present in CM, were linked with CM effects on MC3T3-E1 cell activity. In addition, inhibitors of MAP kinase kinase (MEK), protein kinase C (PKC), and protein kinase A were used to identify the intracellular signaling pathway(s) by which the active factors in CM regulated osteoblast behavior. CM treatment significantly enhanced BSP mRNA (2.5-fold over control), but had no effect on cell proliferation. Mineralization assay showed that CM enhanced mineral nodule formation compared to controls. Noggin inhibited CM-induced upregulation of BSP mRNA, suggesting that BMPs were responsible for upregulating BSP gene expression in MC3T3-E1 cells. The PKC inhibitor blocked CM-mediated upregulation of BSP, suggesting involvement of the PKC pathway in regulating BSP expression. BMPs secreted by HT-39 cells may be responsible for enhancing BSP expression in MC3T3-E1 cells. Continued studies targeted at determining the role of BMPs in regulating bone metabolism are important for understanding the pathogenesis of bone diseases.
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PMID:Bone morphogenetic proteins secreted by breast cancer cells upregulate bone sialoprotein expression in preosteoblast cells. 1103 27

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

Human bone sialoprotein (BSP) comprises 15% of the total noncollagenous proteins in bone and is thought to be involved in bone mineralization and remodeling. Recent data suggest a role for BSP in breast cancer and the development of bone metastases. We have produced full-length recombinant BSP in a human cell line and purified the protein from human bone retaining the native structure with proper folding and post-translational modifications. Mass spectrometry of bone-derived BSP revealed an average mass of 49 kDa and for recombinant BSP 57 kDa. The post-translational modifications contribute 30-40%. Carbohydrate analysis revealed 10 different complex-type N-glycans on both proteins and eight different O-glycans on recombinant BSP, four of those were found on bone-derived BSP. We could identify eight threonines modified by O-glycans, leaving the C terminus of the protein free of glycans. The recombinant protein showed similar secondary structures as bone-derived BSP. BSP was visualized in electron microscopy as a globule linked to a thread-like structure. The affinity for hydroxyapatite was higher for bone-derived BSP than for recombinant BSP. Cell adhesion assays showed that the binding of BSP to cells can be reversibly diminished by denaturation.
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PMID:Structural characterization of human recombinant and bone-derived bone sialoprotein. Functional implications for cell attachment and hydroxyapatite binding. 1145 48

The reasons why tumor cells metastasize to bone remain obscure. There is some evidence to support the theory that integrins (acting as cell surface adhesion receptors) play a role in mediating metastasis in certain organs. Here, we report that overexpression of a functionally active integrin alpha(v)b3 in Chinese hamster ovary (CHO) tumor cells drastically increased the incidence, number, and area of bone metastases in nude mice compared with those observed in mock-transfected CHO cells (CHO dhfr+) or in CHO cells expressing a functionally inactive integrin alpha(v)b3 (CHO beta3Delta744). Moreover, a breast cancer cell line (B02) established from bone metastases caused by MDA-MB-231 cells constitutively overexpressed integrin alpha(v)b3, whereas the cell surface expression level of other integrins remained unchanged. In vivo, the extent of bone metastases in B02-bearing mice was significantly increased compared with that of MDA-MB-231-bearing mice. In vitro, B02 cells and CHO cells expressing a functionally active integrin alpha(v)b3 exhibited substantially increased invasion of and adhesion to mineralized bone, bone sialoprotein, and collagen compared with those found with MDA-MB-231, CHO dhfr+, and CHO beta3Delta744 cells, respectively. Overall, our findings suggest that integrin alpha(v)b3 expression in tumor cells accelerates the development of osteolytic lesions, presumably through increased invasion of and adhesion to bone.
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PMID:Integrin alpha(v)beta3 expression confers on tumor cells a greater propensity to metastasize to bone. 1215 95


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