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)

Tumor-stroma interactions are of primary importance in determining the pathogenesis of metastasis. Here, we describe the application of sensitive competitive polymerase chain reaction (PCR) techniques for detection and quantitation of human breast cancer cells (MDA-MB-231) in an in vivo mouse model of experimental metastasis. Human-specific oligonucleotide primers in competitive PCR reactions were used to quantify the amount of MDA-MB-231 cells per tissue per organ. Using this species-specific (semi)quantitative PCR approach, gene expression patterns of (human) tumor cells or (mouse) stromal cells in metastatic lesions in the skeleton or soft tissues were investigated and compared. In all metastatic lesions, MDA-MB-231 cells express angiogenic factors (vascular endothelial growth factors [VEGFs]; VEGF-A, -B, and -C) and bone-acting cytokines (parathyroid hormone-related protein [PTHrP] and macrophage colony-stimulating factor [M-CSF]). In these metastases, PECAM-1-positive blood vessels and stromal cells of mouse origin are detected. The latter express angiogenic factors and markers of sprouting vessels (VEGF receptors flt-1/flk - 1/flk-4 and CD31/PECAM-1). Strikingly, steady-state messenger RNA (mRNA) levels of VEGF-A and -B and the major bone resorption stimulators PTHrP and M-CSF by tumor cells were elevated significantly in bone versus soft tissues (p < or = 0.05, p < or = 0.0001, p < or = 0.001, and p < or = 0.05, respectively), indicating tissue-specific expression of these tumor progression factors. In conclusion, MDA-MB-231 breast cancer cells express a variety of factors in vivo that have been implicated in metastatic bone disease and that correlate with poor survival of patients with breast cancer. We hypothesize that the observed up-regulated expression of angiogenic and bone-resorbing factors by the breast cancer cells in the skeleton underlie the clinically observed osteotropism of breast cancer cells and pathogenesis of osteolytic bone metastases. The application of the species-specific competitive PCR-based assay in vivo can provide new information concerning the involvement of gene families in tumor progression and metastatic disease and greatly facilitates the study of tumor-stroma interactions in cancer invasion and metastasis.
 ...
PMID:Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. 1139 85

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

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

p38 belongs to a family of mitogen-activated protein kinases, which transfer extracellular signals into intracellular responses. p38 is also frequently detected in clinical breast cancer specimens, but its role as a prognostic factor is not known. Of the various p38 isoforms, p38alpha has been shown to mediate the in vitro invasiveness of breast cancer cells through up-regulation of urokinase plasminogen activator (uPA). We studied the role of p38alpha in breast cancer bone metastases, using dominant negative blockade approach. Human MDA-MB-231 breast cancer clones stably expressing dominant negative p38alpha (p38/AF) exhibited decreased basal MMP-9 activity. TGF-beta1-induced MMP-9 activity was also blunted in these clones, as compared with controls in which TGF-betal up-regulated MMP-9 activity. Consistent with these findings, SB202190, a specific p38 inhibitor, also inhibited TGF-beta1-induced MMP-9 activity in parental cells. The p38/AF clones exhibited also reduced uPA production after growth on vitronectin and decreased cell motility, as compared with controls. VEGF production levels in all the studied clones were similar. The p38/AF clone, which had similar in vitro growth rate as the control pcDNA3 clone, formed significantly less bone metastases in a mouse model, as compared with the control clone. In conclusion, inhibition of the p38alpha pathway results in decreased MMP-9 activity, impaired uPA expression and decreased motility, all of which may contribute to the decreased formation of bone metastasis.
 ...
PMID:Breast cancer cells with inhibition of p38alpha have decreased MMP-9 activity and exhibit decreased bone metastasis in mice. 1567 50

HER-2 is an important prognostic factor in breast cancer, and its overexpression is observed in 20-60% of cases with micrometastases in the bone marrow. The aim of this study was to explore the potential functional role of HER-2 in primary breast tumors with bone metastases. Forty-eight primary breast tumors with simultaneous or non-simultaneous bone metastases were studied. The expression of hormone receptors, and metastasis and growth factor-related proteins were assessed by immunohistochemical staining. The correlation in statistical significance was assessed by the Chi-square test. Of the 48 breast tumors, 11 (22.9%) were HER-2-positive and 37 were HER-2-negative. There was no significant difference in HER-2 status and clinicopathologic factors between the two groups. Of the 11 HER-2-positive tumors, there were 2 and 3 cases that showed positive nuclear expression for estrogen and progesterone receptors, respectively. No extranuclear expression of HRs was detected in these tumors. For metastasis-related proteins such as c-Met, VEGF, and MTA-1, which are activated by HER-2, only some insignificant focal expression of these proteins was observed. An increased level of pAkt was observed in 9 (81.8%) of 11 tumors, and an increased expression of CXCR4 was observed in 6 (54.5%) of 11 tumors. The frequency of increased levels of pAkt and CXCR4 was not significant between HER-2-positive and -negative tumors. The increased levels of pAkt and CXCR4 are induced by factors that are both dependent and independent of HER-2, and the activation of HER-2/CXCR4/ Akt signaling pathway in primary breast tumors may contribute to the formation of bone metastases in breast cancer.
 ...
PMID:Potential role of HER-2; in primary breast tumor with bone metastasis. 1668 82

In this study we have investigated changes in circulating angiogenic factors after a single zoledronic acid intravenous infusion. Thirty consecutive patients who had histologically confirmed breast (n=20) and lung cancer (n=10) associated with confirmation of bone metastases were included in the study. Serum was also available from 10 healthy volunteers. Four mg of Zoledronic acid (Zometa, Novartis) was administered as a 15-min infusion in 100-ml normal saline on an outpatient basis. Venous blood for assessment of serum parameters was drawn just before the beginning of drug infusion and again at 7 and 28 days after the zoledronic acid infusion. Serum levels of VEGF and bFGF were assayed with ELISA kits. Serum VEGF and bFGF levels were not significantly different from healthy control groups (P>0.05). However, we found that serum VEGF levels in lung cancer patients were significantly higher than in patients with breast cancer and controls (P=0.009, and P=0.022, respectively). We found no significant correlation between serum VEGF and bFGF levels. No statistically significant changes were seen following infusion of zoledronic acid in patients with bone metastases for both serum VEGF and bFGF levels (P>0.05). Unlike previous studies, zoledronic acid did not appear to exert an angiogenic activity as there was no reduction of VEGF and bFGF circulating levels after zoledronic acid infusion.
 ...
PMID:Effect of zoledronic acid on serum angiogenic factors in patients with bone metastases. 1820 21

Local therapies such as radiofrequency ablation (RFA) represent a valuable choice in limited hepatocellular carcinoma (HCC) and are increasingly used also in advanced tumors. Medical treatments generally gave frustrating results in advanced HCC especially if comorbidities exist. Several biologic non-chemotherapeutic drugs are currently tested in HCC and, among them, octreotide was evaluated in single series of HCC patients reporting conflicting results. We have treated a series of 35 patients affected by advanced HCC (26 M and 9 F; age range: 55-85 years, median: 73 years) with RFA followed by octreotide to primarily evaluate the safety of combined treatment and to give preliminary evaluation on its activity. We have also evaluated serum VEGF changes during the study. Child A and Child B represented 60% and about 34% of the cases, respectively. Only two patients with Child C compensated cirrhosis were included in this study. All patients have multiple liver HCC nodules and one had bone metastases. Two complete responses, 3 partial responses and 23 disease stabilization for at least three months were obtained (overall response rate, 14,2%; clinical benefit, 80%). Mean overall survival was 31.4 months. The combined treatment was well tolerated. Statistically significant correlation was found between serum VEGF and tumor progression. In conclusion, the combination of RFA and octreotide was active in advanced HCC, however, confirmation in a larger series is required.
 ...
PMID:Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: a single center experience. 1863 2

As current classification systems for the assessment of treatment response in bone metastasis do not meet the needs of oncologists, new imaging biomarkers are desirable. Therefore, the diagnostic impact of dynamic contrast enhanced (DCE)-volumetric computed tomography (VCT) (descriptive analysis), DCE-MRI (two-compartment model) and diffusion weighted imaging (DWI) for monitoring anti-angiogenic therapy effects of the VEGF antibody bevacizumab in breast cancer bone metastases in rats was studied. Nude rats (n=8 animals treated with bevacizumab and n=9 untreated control rats) with site-specific osteolytic bone metastasis of the hind leg were imaged with a 1.5T clinical MRI-scanner in an animal coil as well as in a volumetric CT-scanner at days 30, 40, 50 and 60 after inoculation of MDA-MB-231 human breast cancer cells. From these data, osteolytic lesion size (OLS), peak enhancement (PE), area under the curve (AUC), amplitude (A), exchange rate constant (k(ep)) and apparent diffusion coefficient (ADC) were determined in bone metastases. Prior to changes in OLS (p< or =0.05 at days 50 and 60) there was already a significant decrease in PE, AUC and A (p< or =0.05 at days 40-60) in treated animals compared to controls. However, for k(ep) and ADC there were no significant differences between the groups at any time point (p>0.05 at days 40-60). In conclusion, anti-angiogenic treatment response in osteolytic breast cancer bone metastases can be assessed early with surrogate markers of vascularization, while DWI appears to be insensitive.
 ...
PMID:Imaging anti-angiogenic treatment response with DCE-VCT, DCE-MRI and DWI in an animal model of breast cancer bone metastasis. 1907 Apr 45

Metastatic bone disease caused by renal cell carcinoma (RCC) occurs frequently and becomes more and more prevalent presumably because survival times among patients with disseminated cancers are increasing. Patients with bone metastases from renal cell carcinoma suffer from severe pain, nerve compression syndromes and pathologic fractures. Very little is known about the mechanisms of skeletal metastases of RCC. Thus, to better understand the molecular mechanism of renal cell cancer (RCC) bone metastasis, it is crucial to develop new animal models. We have established a new animal model of RCC metastasis to bone by inoculation of human 786-O/luciferase cells into the left cardiac ventricle of athymic nude mice. The animals developed aggressive osteolytic bone destruction as monitored by radiography and micro-CT-scans with the mean endpoint at 62 +/- 8 days. The extensive bone destruction observed was comparable to the clinical setting and mainly occurred in hind limbs, forelimbs and the spine. The tumors were primarily located within the bone and resulted in destruction of cortical bone. No soft tissue metastases were detected by BLI or histomorphometry. To increase the bone-metastatic potential of the 786-O cell line, an in vivo selection was done yielding a subpopulation causing osteolytic lesions with the mean endpoint of 47 +/- 3 days. The selected subline secreted more proangiogenic factors VEGF and bFGF in vitro compared to the parental cell line suggesting that these tumors are highly vascular. This model provides a reliable reproduction of the clinical situation and therefore, is suitable for designing and evaluating more effective treatments for RCC bone metastasis.
 ...
PMID:Characterization of a new renal cell carcinoma bone metastasis mouse model. 2044 33

Bone metastasis is a serious complication of patients with tumor, and most primary tumors can metastasize to bone. And the main threat and the reason for most cancer deaths are not the primary neoplasias, but secondary tumors, the metastases. To minimize the morbidity and economic expenditure associated with bone metastases, it is important to decrease the etiological factors of bone metastasis. Although current evidence suggested that the therapies to the underlying malignancy bone metastasis might result in bone loss leading to osteoporosis, no studies have shown direct evidence the successful seeding of bone metastases of cancer cells is the part played by osteoporosis. In the state of osteoporosis, for the enhancement of the osteolysis, the increased inflammatory factors could make blood vessels leakier, resulting in the easier hematogenous metastasis to bone and bone marrow. Moreover, leptin, which was positive correlation with osteoporosis, has been showed to exert angiogenic effects and could regulate VEGF expression, promoting the proliferation of the cancer blood vessel. In addition, the increased growth factors in osteoporosis could enrich the local microenvironment, promoting the growth of the metastasis mass. Given the above background, we hypothesize that osteoporosis may be a potential contributor to the bone metastases.
 ...
PMID:Osteoporosis as a potential contributor to the bone metastases. 2067 58


1 2 Next >>