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)

Bone metastases are generally associated with bone destruction which occurs in response to factors secreted by metastatic cells. Some of these factors secreted by the metastatic cells activate osteoclats while others are proteases that degrade bone collagen. To determine if Neovastat (AE-941), a naturally occurring multi-functional inhibitor of angiogenesis, is able to regulate properties that are thought to have relevance to their propensity to form bone metastases in vivo, we used the human breast cancer MDA-MB-231 cell line which can metastasize to bone. We showed that Neovastat prevented the degradation of osteoid-like radiolabeled extracellular matrices which was induced by incubation of human SaOS-2 osteoblast-like cells with MDA-MB-231 cells. Moreover, Neovastat was demonstrated to inhibit the gelatinolytic activity of matrix metalloproteinase (MMP)-9 expressed by MDA-MB-231 cells. The potential of Neovastat to retard the spread, growth, and osteolysis of MDA-MB-231 cells was then estimated in vivo. Histomorphometric analysis of the vertebral bodies indicated that MDA-MB-231 cells inoculated in nude mice (intracardiac) successfully generate osteolytic metastases with an 83% reduction of the volume of medullary bone (p< or =0.01). However, when tumor-bearing animals were treated orally with Neovastat, there was only a 19% decrease in medullary bone thus indicating that Neovastat can prevent bone metastasis in this model. Consistent with histological results, radiographic analysis indicated that Neovastat decreased the number of osteolytic lesions by 33% (p< or =0.3). Moreover, a decrease in the tumor volume in bone was observed in Neovastat-treated animals. These results indicate that Neovastat may be useful in preventing bone metastasis in cancer patients.
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PMID:The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. 1178 92

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

In the collagen type I C-telopeptide an aspartyl-glycine site within the sequence AHDGGR is susceptible to molecular rearrangement. In newly synthesized collagen this site is in the native form, denoted alpha L. During aging a spontaneous reaction occurs resulting in three age-modified forms: an isomerized form (beta L) a racemized form (alpha D), and an isomerized/racemized form (beta D). In this study, we measured the urinary excretion of the four forms of C-telopeptides (CTX) in healthy adults and in patients with bone diseases. Levels of all CTX forms were higher in healthy postmenopausal women (P<0.001) compared with premenopausal controls. Levels decreased within 3 days of bisphosphonate treatment indicating that all CTX forms reflect bone resorption. In hyperthyroidism, characterized by a generalized increased bone turnover, native (alpha L) and age-modified (beta L, alpha D and beta D) forms increased to a similar extent compared to controls, resulting in normal ratios between the alpha L and age-modified forms of CTX. Conversely, in Paget's disease and prostate cancer-induced bone metastases, conditions characterized by focal increased bone turnover, alpha L CTX levels were more elevated than those of age-related CTX forms, resulting in increased ratios between native and age-modified CTX. For example, the ratio alpha L/alpha D was increased 7-fold in Paget's disease (P<0.001) and 2-fold in prostate cancer-induced bone metastases (P<0.002). In conclusion, the study suggests that in conditions with a localized alteration in bone turnover the ratio between alpha L CTX and the age-modified forms is significantly elevated. This may provide a new diagnostic and monitoring tool for diseases such as metastatic bone cancer and Paget's disease.
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PMID:Investigation of bone disease using isomerized and racemized fragments of type I collagen. 1238 13

Prostate cancer (CaP) is the most commonly diagnosed malignancy in men and is often associated with bone metastases, which cause much of the morbidity associated with CaP. Lesions associated with CaP generally exhibit increased bone formation and resorption. Increased bone resorption may release factors from the extracellular matrix that contribute to tumor growth. Cathepsin K (cat K) is a cysteine protease that exhibits strong degradative activity against the extracellular matrix and is involved in osteoclast-mediated bone destruction. In this study, we analyzed the expression of cat K in CaP cell lines and patient samples. Cat K message was detected in CaP cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and in primary CaP and metastases by in situ hybridization. Immunohistochemistry revealed variable expression of cat K in primary CaP samples, as well as nonosseous metastases, whereas expression in bone metastases was significantly higher than in primary CaP, and normal prostate tissues were negative. Cat K protein was detected in CaP cell lines by Western blotting after immunoprecipitation. Cat K enzymatic activity was also detected in CaP cell lines by a fluorogenic assay and by an assay for degradation of collagen type I. Increased levels of NTx, a marker of bone matrix degradation mediated primarily by cat K, were also detected in sera of patients with CaP bone metastases. We hypothesize that CaP-expressed cat K may contribute to the invasive potential of CaP, while increased expression in bone metastases is consistent with a role in matrix degradation.
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PMID:Cathepsin K mRNA and protein expression in prostate cancer progression. 1256 99

Parathyroid hormone-related protein (PTHrP), which has been localized in prostate cancer tissue and cell lines, plays a role in the development of bone metastases, a frequent complication in prostate cancer patients. Tumor cell adhesion to extracellular matrix (ECM) components is mediated via integrin subunits, and plays a major role in the invasion and metastasis of tumor cells. The present experiments examined the ability of PTHrP to influence adhesion of the human prostate cancer cell line PC-3 to several ECM proteins found in normal tissues. Clonal PC-3 cells induced to overexpress PTHrP by stable transfection with PTHrP complementary DNA showed significantly higher adhesion to collagen type 1, fibronectin, and laminin than control (empty vector-transfected) cells. PTHrP-overexpressing cells also exhibited higher expression of the alpha1, alpha5, alpha6, and beta4 integrin subunits. These results suggest that PTHrP may play a role in prostate tumor invasion and metastasis by influencing cell adhesion to the ECM via upregulation of specific integrin subunits.
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PMID:PTH-related protein modulates PC-3 prostate cancer cell adhesion and integrin subunit profile. 1258 88

Deoxypyridinoline (Dpd), a crosslink product of collagen molecules found in bone and excreted in urine during bone degradation, has been described as a marker of bone turnover in metastatic breast cancer. In this study, the urine deoxypyridinoline/creatinine (Dpd/Cre) ratio was determined by enzyme immunoassay in urine samples from 116 women with breast cancer. Bone metastases were confirmed by x-ray or CT scan, with follow-up > 6 mo. The urine Dpd/Cre ratio was significantly higher in patients with bone metastasis, compared to those without bone metastasis (p < 0.05). In patients with bone metastasis, ratios of urine Dpd/Cre were higher in those with multiple lesions, compared to those with a solitary lesion, and the values also reflected therapeutic response (p < 0.05). Serial monitoring of urine Dpd/Cre revealed that an elevation was correlated with disease progression. Patients with stable bone disease under effective therapy had significant diminution of the urine Dpd/Cre ratios, compared to those with progression of bone disease (p < 0.05). In conclusion, the urine Dpd/Cre ratio may be a useful marker for detecting bone metastases and evaluating their response to therapy.
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PMID:Diagnostic value of urine deoxypyridinoline for detecting bone metastases in breast cancer patients. 1266 98

Desmoplastic mesothelioma is a rare subtype of diffuse malignant mesothelioma, and is often difficult to distinguish from reactive pleural fibrosis because of associated extensive collagen fibrosis. An 82-year-old woman with a severe cough was revealed to have pleural effusion and diffuse pleural thickening on the right side. Antibiotics were ineffective, and a compression fracture of the ninth and tenth thoracic vertebral bodies was recognized on X-ray. Autopsy revealed a diffuse pleural thickening with hyalinized collagen tissue in the central part of the pleura. However, the peripheral part of the fibrous tissue was composed of spindle and polygonal cell proliferation that were immunohistochemically positive for antibodies against cytokeratin and vimentin. In addition, the ninth and tenth thoracic spines were infiltrated by similar cells. The condition was diagnosed as desmoplastic mesothelioma with bone metastases. Asbestos bodies were detected in the thickened pleura and fibrosed alveolar septa, and it was suggested retrospectively that the patient had been exposed to asbestos. Thus, autopsy analyses of fibrous pleurisy are necessary to detect a desmoplastic variant of mesothelioma of the pleura and its association with asbestos exposure.
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PMID:Desmoplastic malignant mesothelioma of the pleura: autopsy reveals asbestos exposure. 1278 16

A 12-year-old male cat with depression and dyspnoea was presented for investigation. Radiography and computed tomography revealed hydrothorax and solid masses involving the sternum, ribs and thoracic vertebrae. The cat died two days after first presentation, and postmortem examination revealed lung masses and proliferative bony lesions. Histologically, a neoplastic proliferation of epithelial cells was seen in the lungs, with a large amount of collagen and deposits of cholesterin. The bone lesions were also composed of neoplastic epithelial cells and abundant calcified osteoid, without atypia. A diagnosis of pulmonary adenocarcinoma with osteoblastic bone metastases was made. This is the first reported case of osteoblastic metastases in the cat.
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PMID:Pulmonary adenocarcinoma with osteoblastic bone metastases in a cat. 1458 62

Bone metastasis is a frequent complication of cancer disease. The metastatic spread of cancer to bone is common to many different malignancies, particularly breast (ca. 73%), prostate (ca. 68%) and lung (ca. 36%) cancers. Metastases to bone cause increased bone resorption both from direct effects of the tumor itself and thought osteoclastic activation. The diagnosis and follow-up of bone metastatic cancer patients usually relies on skeletal X-ray and bone scintigraphy. However, the development of biochemical markers, used as indicators of bone metabolism, provides data useful in the clinical practice. The most important markers for bone remodeling process, bone formation and resorption, are bone-specific alkaline phosphatase (BAP) and N-telopeptide of type I collagen (NTx), respectively. In this report, we applied two solid-phase immunoassays used for the determination of BAP and NTx in serum of breast cancer (BC) post-menopausal women with bone metastasis and healthy individuals. BAP level in patients was found to be 45.72 +/- 12.92 U/l, while the normal range for healthy individuals was 14.2 - 42.7 U/l. The respective level of serum NTx was 19.20 +/- 8.87 nM bone collagen equivalents (BCE) for patients and 15.9 +/- 3.8 nM BCE for healthy women. Correlation of the obtained data showed elevated levels for both markers indicating high rate of bone degradation in breast metastatic cancer.
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PMID:Determination and biological relevance of serum cross-linked type I collagen N-telopeptide and bone-specific alkaline phosphatase in breast metastatic cancer. 1501 61

Degradation products of collagen type I can be measured by CrossLaps (CTX) immunoassays, providing an index of bone resorption. The CTX epitope EKAHDGGR comprises a DG-motif susceptible to post-translational modifications. In newly synthesized collagen this motif is in the native form denoted alphaCTX, but converts to an isomerized form (betaCTX) during aging of bone. Furthermore, the lysine residue (K) within the CTX epitope participates in inter-molecular cross-links in mature bone. The present paper describes an assay, ALPHA CTX ELISA for measurement of cross-linked alphaCTX molecules (alpha-alphaCTX) in urine. The ALPHA CTX ELISA demonstrated a high specificity and technical precision for measuring such fragments. The assay was evaluated in a cross-sectional study, comparing the urinary excretion of the marker in 100 breast cancer patients with bone metastases (BC+) and 15 breast cancer patients without metastases to bone (BC-) as well as 31 age-matched healthy post-menopausal women (PM). For comparison alpha, beta, and beta-betaCTX was also measured using commercially available immunoassays. In BC+ urinary alpha-alphaCTX increased significantly compared to BC- and PM with p-values of 0.005 and <0.0001, respectively. In contrast, the age-modified form beta-betaCTX, representing the degradation of old bone, was less increased. Z-score analysis was used to compare the ability of the CTX markers to discriminate between BC+ and PM. The alpha-alphaCTX marker was found to provide a far better discrimination (Z=7.5) than beta-betaCTX (Z=3.6). In conclusion, measurement of alpha-alphaCTX fragments may provide a clinically relevant assessment of bone resorption related to bone metastases.
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PMID:An immunoassay for measuring fragments of newly synthesized collagen type I produced during metastatic invasion of bone. 1520 36


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