Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Vascular endothelial growth factor (VEGF) is a proangiogenic cytokine that is expressed highly in many solid tumours often correlating with a poor prognosis. In this study, we investigated the expression of VEGF and its receptors in bone metastases from primary human breast tumours and further characterised its effects on osteoclasts in vitro. Breast cancer metastases to bone were immunohistochemically stained for VEGF, its receptors VEGFR1 and 2 (vascular endothelial growth factor receptor 1 and 2), demonstrating that breast cancer metastases express VEGF strongly and that surrounding osteoclasts express both VEGFR1 and VEGFR2. RAW 264.7 cells (mouse monocyte cell line) and human peripheral blood mononuclear cells (PBMCs) were cultured with VEGF, RANKL and M-CSF. VEGF and RANKL together induced differentiation of multinucleated, tartrate-resistant acid phophatase (TRAP)-positive cells in similar numbers to M-CSF and RANKL. The PBMCs were also able to significantly stimulate resorption of mineralised matrix after treatment with M-CSF with RANKL and VEGF with RANKL. We have shown that VEGF in the presence of RANKL supports PBMC differentiation into osteoclast-like cells, able to resorb substrate. Vascular endothelial growth factor may therefore play a role in physiological bone resorption and in pathological situations. Consequently, VEGF signalling may be a therapeutic target for osteoclast inhibition in conditions such as tumour osteolysis.
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PMID:Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. 1581 59

Positron emission tomography (PET) is increasingly used to diagnose, grade, and stage different types of tumors and to assess tumor response to therapy. Metabolic data acquired by fluorine-18-fluorodeoxyglucose (18FDG)-PET may facilitate accurate grading of sarcomas and have prognostic value when combined with other grading methods and various clinical/radiological features. In addition, 18FDG-PET is currently being evaluated in several cancer types for its utility in biopsy guidance. Whole-body 18FDG-PET also appears to be superior to other imaging modalities in detecting bone metastases in certain sarcoma patients. New PET tracers currently being investigated include 18F-fluorothymidine (18F-FLT) and 18F-misonidazole. 18F-FLT can help to determine tumor growth, rather than tumor shrinkage, which could be used to evaluate treatment response in sarcomas. PET imaging offers invaluable information to help maximize the clinical benefit of patients with sarcoma. This article reviews the use of PET in sarcoma management and its potential applications in the near future.
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PMID:PET for sarcomas other than gastrointestinal stromal tumors. 1843 35

When renal cell carcinoma (RCC) metastasizes to bone (a frequent site of systemic spread of this cancer) it becomes highly resistant to radiation therapy and chemotherapy. A better understanding of the biology of bone metastasis in RCC may permit to identify biomarkers for early detection of subclinical disease and better stratification of patients prior to treatment. We therefore investigated in this study, using a multiplex real-time RT-PCR assay, the expression of a panel of 16 biomarkers involved in angiogenesis and tumor invasion; the panel was applied to primary tumors and normal tissues obtained from clear-cell RCC patients with and without bone metastases. We identified a novel combination of biomarkers associated with the risk of bone metastasis. Among the transcripts of the genes studied, VEGFR-1, VEGFR-2, HIF-1alpha, uPA , and PA I-1 overexpression in tumor tissues was significantly associated with the presence of bone metastasis (p=0.02, p=0.02, p<0.0001, p=0.04, and p=0.03, respectively). No differences were found in the expression of these transcripts in the corresponding normal tissues. This preliminary study provides a promising tool that may help in the management of RCC patients with bone metastasis. Indeed, these predictive markers could be useful to identify subclinical disease, improve staging, and guide treatment decisions.
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PMID:Identification of a novel biomarker signature associated with risk for bone metastasis in patients with renal cell carcinoma. 2054 84

Currently, tumour response following drug treatment is based on measurement of anatomical size changes. This is often done according to Response Evaluation Criteria in Solid Tumours (RECIST) and is generally performed every 2-3 cycles. Bone metastases, being the most common site of distant metastases in breast cancer, are not measurable by RECIST. The standard response measurement provides no insight in changes of molecular characteristics. In the era of targeted medicine, knowledge of specific molecular tumour characteristics becomes more important. A potential way to assess this is by means of molecular imaging. Molecular imaging can visualise general tumour processes, such as glucose metabolism with (18)F-fluorodeoxyglucose ((18)F-FDG) and DNA synthesis with (18)F-fluorodeoxythymidine ((18)F-FLT). In addition, an increasing number of more specific targets, such as hormone receptors, growth factor receptors, and growth factors can be visualised. In the future molecular imaging may thus be of value for personalised treatment-selection by providing insight in the expression of these drug targets. Additionally, when molecular changes can be detected early during therapy, this may serve as early predictor of response. However, in order to define clinical utility of this approach results from (ongoing) clinical trials is required. In this review we summarise the potential role of molecular imaging of general tumour processes as well as hormone receptors, growth factor receptors, and tumour micro-environment for predicting and monitoring treatment response in breast cancer patients.
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PMID:Molecular imaging for monitoring treatment response in breast cancer patients. 2354 59

Positron emission tomography (PET) or PET/computed tomography (CT) using ¹⁸F-3'-fluoro-3'-deoxythymidine (¹⁸F-FLT) offers noninvasive assessment of cell proliferation in human cancers in vivo. The present review discusses the current status on clinical applications of ¹⁸F-FLT-PET (or PET/CT) in digestive and abdominal oncology by comparing with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG)-PET (or PET/CT). The results of this review show that although ¹⁸F-FLT uptake is lower in most cases of digestive and abdominal malignancies compared with ¹⁸F-FDG uptake, ¹⁸F-FLT-PET can be used to detect primary tumors. ¹⁸F-FLT-PET has shown greater specificity for N staging than ¹⁸F-FDG-PET which can show false-positive uptake in areas of inflammation. However, because of the high background uptake in the liver and bone marrow, it has a limited role of assessing liver and bone metastases. Instead, ¹⁸F-FLT-PET will be a powerful tool for monitoring response to treatment and provide prognostic information in digestive and abdominal oncology.
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PMID:Current clinical status of ¹⁸F-FLT PET or PET/CT in digestive and abdominal organ oncology. 2777 Jan 60

Renal cell carcinoma bone metastases (RCCBM) are typically osteolytic. We previously showed that BIGH3 (beta Ig-h3/TGFBI), secreted by 786-O renal cell carcinoma, plays a role in osteolytic bone lesion in RCCBM through inhibition of osteoblast (OSB) differentiation. To study this interaction, we employed three-dimensional (3D) hydrogels to coculture bone-derived 786-O (Bo-786) renal cell carcinoma cells with MC3T3-E1 pre-OSBs. Culturing pre-OSBs in the 3D hydrogels preserved their ability to differentiate into mature OSB; however, this process was decreased when pre-OSBs were cocultured with Bo-786 cells. Knockdown of BIGH3 in Bo-786 cells recovered OSB differentiation. Furthermore, treatment with bone morphogenetic protein 4, which stimulates OSB differentiation, or cabozantinib (CBZ), which inhibits VEGFR1 and MET tyrosine kinase activities, also increased OSB differentiation in the coculture. CBZ also inhibited pre-osteoclast RAW264.7 cell differentiation. Using RCCBM mouse models, we showed that CBZ inhibited Bo-786 tumor growth in bone. CBZ treatment also increased bone volume and OSB number, and decreased osteoclast number and blood vessel density. When tested in SN12PM6 renal cell carcinoma cells that have been transduced to overexpress BIGH3, CBZ also inhibited SN12PM6 tumor growth in bone. These observations suggest that enhancing OSB differentiation could be one of the therapeutic strategies for treating RCCBM that exhibit OSB inhibition characteristics, and that this 3D coculture system is an effective tool for screening osteoanabolic agents for further in vivo studies.
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PMID:Cabozantinib Reverses Renal Cell Carcinoma-mediated Osteoblast Inhibition in Three-dimensional Coculture In Vitro and Reduces Bone Osteolysis In Vivo. 3222 Sep 69

Bone metastatic prostate cancer significantly impacts patient quality of life and overall survival, and despite available therapies, it is presently incurable with an unmet need for improved treatment options. As mediators of tumor progression, matrix metalloproteinases (MMPs) can degrade extracellular matrix components and regulate growth factor and cytokine bioactivity. Depending on tissue context, MMPs can either promote or inhibit tumorigenesis. Therefore, it is essential to study individual MMPs in specific cancer contexts and microenvironments to support the design and application of selective MMP inhibitors. Here we report that tumor-derived MMP-3 contributes to bone metastatic prostate cancer progression via intrinsic and extrinsic routes. MMP-3 ablation in prostate cancer cell lines significantly reduced in vitro growth combined with lowered AKT and ERK phosphorylation and total VEGFR1 and FGFR3 protein levels. In vivo, MMP-3 ablated tumors grew at a slower rate and were significantly less vascularized. Quantitative PCR analyses of wild type and MMP-3 silenced prostate cancer cells also demonstrate downregulation of a wide array of angiogenic factors. The extrinsic role for MMP-3 in angiogenesis was supported by in vitro endothelial tube formation assays where the lack of MMP-3 in prostate cancer conditioned media resulted in slower rates of tube formation. Taken together, our results suggest that tumor-derived MMP-3 contributes to prostate cancer growth in bone. These data indicate that selective inhibition of MMP-3 and/or targeting MMP generated products could be efficacious for the treatment of prostate to bone metastases.
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PMID:Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis. 3289 61

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