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)

FDG-PET has a limited role in diagnosis of prostate cancer mainly because of the low uptake of FDG in the tumor and normal excretion of FDG through urine. FDG-PET has shown some promise in the assessment of lymph nodes and bone metastases. There is a large degree of variability when FDG-PET is compared with bone scintigraphy. New C11-labeled radiotracers (acetate, choline, and methionine) have shown promising initial results but further studies are required to determine their role in such settings. These radiotracers provide a unique opportunity for dynamic, multitracer, and quantitative studies, which improve the sensitivity and specificity on PET in this population. Short half-lives and of C-11, however with the limits to their use requires an on-site cyclotron. Recent synthesis schemes with [18F]-labeling, however, may overcome this limitation. FDG-PET has a significant potential to assist with the diagnosis and management of testicular cancer. PET has been most useful in defining the presence or absence of disease in patients with residual masses. PET has shown promising results for the initial diagnosis of this cancer, but further for studies ar required to determine its role in the management of this malignancy. PET can be used in conjunction with conventional imaging techniques to diagnose retroperitoneal masses in patients with primary testicular cancer. FDG-PET has shown very encouraging results in a limited number of studies, and has also demonstrated a good sensitivity for initial staging. FDG-PET seems to be superior to conventional imaging modalities for detecting local disease and recurrence, and distant metastases.
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PMID:PET in the management of urologic malignancies. 1614 85

During the last decade, there has been a significant advancement in imaging of urologic diseases. Transrectal ultrasound (TRUS), computerized tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) are still experiencing new developments in urology. Despite these many technological advances, the initial diagnostic procedure for a patient with suspected prostate cancer (PC) is multiple site blind prostate biopsies. There is a need for a noninvasive metabolic imaging modality to direct the site of biopsy to decrease the sampling error. MRS seems promising but as it is a costly and more time-consuming test, further studies are needed to evaluate its clinical utility. Currently, PET does not play any role to direct biopsy. Acetate and choline appear to be better tracers than FDG for the detection of a prostate lesion, however, further well-organized studies are needed before any of these agents can be used clinically. Incidental detection of intense focal uptake in the prostate during whole body PET scanning should be evaluated with prostate-specific antigen (PSA) and TRUS-guided biopsy. Although FDG is inferior to other tracers for primary staging, it may be useful in selected patients with suspected high-grade cancer. The role of ProstaScint scan is still controversial for detection of recurrent PC. This study may be helpful for evaluating nodal metastases when PSA is elevated and bone scan is negative. Bone scan remains the study of choice when bone metastases are suspected (PSA>15-20 ng/mL+/-bone pain). Acetate and choline provide better accuracy than FDG in the detection of local soft tissue disease, nodal involvement, and distant metastases. High FDG uptake may be indicative of more aggressive and possibly androgen-independent disease. PET/CT with any of the above PET tracers will most likely be preferred to the PET scan alone due to better localization of a hot lesion in PET/CT. Nuclear medicine studies also have been used to evaluate acute scrotum and testicular neoplasms. Scrotal scintigraphy has lost its popularity to Doppler ultrasound in the evaluation of the acute scrotum. In testicular tumors, FDG-PET appears to be superior to conventional imaging modalities in initial staging, detection of residual/recurrence, and monitoring treatment response. Tumor markers after treatment occasionally are elevated and cannot locate the site of recurrence, FDG-PET can play a very important role in this regard. Nuclear medicine studies also have been used to evaluate diseases of the urinary bladder. Radionuclide cystography is more sensitive and has less than 1/20 the radiation exposure of the conventional contrast enhanced micturating cystourethrogram (MCU). However, the utility of FDG-PET in the evaluation of bladder cancer seems to be limited to the evaluation of distant metastases. 11C-Methionine and choline may be a better option for local and nodal disease due to their negligible excretion in the urine.
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PMID:Nuclear medicine studies of the prostate, testes, and bladder. 1635 96

The mechanisms that guide organ-specific metastases are not fully established. The aberrant expression of carbohydrates may play a fundamental role in defining the molecular mechanisms for metastases to distant organs and facilitate positive interactions within the target organ. The purpose of the present study was to determine the glycomic profile of a variant of the MDA-MB-231 breast cancer cell line that colonizes the bone and to ascribe mechanistic functions mediated by carbohydrates that might correlate with clinical bone metastases. The carbohydrate expression profiles of osteolytic MDA-MET breast cancer cells and non-osteolytic parental MDA-MB-231 cells were determined. MDA-MET cells were derived from MDA-MB-231 cells by in vivo selection of metastatic bone lesions following intracardiac inoculation. The two related breast cancer cell lines expressed distinct carbohydrate profiles; MDA-MET cells displayed an increased expression of alpha (2,6) linked sialic acid, N-beta1-6 GlcNAc, and sialylated Lewis-A antigen, and decreased expression of Galbeta1,3GalNAc as detected using a combination of lectins and anti-carbohydrate antibodies. Microarray analysis demonstrated an increased expression of glycosyltransferase genes, correlative for the distinct glycomic phenotype. The altered glycomic phenotypes of MDA-MET cells include effects on the differential binding to bone marrow endothelial cells, enhanced ECM binding and an increase in invasive potential. These data suggest that the glycomic phenotype of MDA-MET cells is associated with a select set of accumulated functions that collectively impact on the bone metastases and bone colonization capacity of breast cancer cells.
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PMID:Characterization of the glycosylation profile of the human breast cancer cell line, MDA-231, and a bone colonizing variant. 1659 33

Breast cancer cells preferentially metastasize to bone, leading to the formation of primarily osteolytic lesions. Osteoprotegerin (OPG) plays multifactorial roles in the development of osteolytic bone metastases. An increase in the ratio of receptor activator of nuclear factor kappaB ligand (RANKL) to OPG increases osteoclastogenesis within the bone microenvironment. OPG also acts as a survival factor for cancer cells by protecting them from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis. This study compares OPG production in vitro in a number of breast cancer cell lines exhibiting both differences in metastatic capacity and in preferential metastasis to bone. Our studies demonstrated that OPG expression by MDA-231, MDA-MET, and MDA-231/K cancer cells was directly correlated with bone specific homing and colonization potential but not with metastasis of cancer cells to other organs; both in IL-1 beta stimulated and control cells. We also demonstrated expression of other bone-related markers including type I collagen, osteocalcin, osteopontin, and Runx2 in these cells. However, the generally lower expression of these markers in the bone selective cell line MDA-MET suggested that increased OPG expression in the bone specific variant was not merely a consequence of enhanced osteomimicry by these cells but that it has a significant role in the metastatic process. Co-culture of breast cancer cells with osteoblastic cells (hFOB 1.19) led to an overall downregulation in OPG production, which was not affected by the bone homing and colonization potential of the cell lines, suggesting that OPG alone is not indicative of osteolytic bone activity by breast cancer cells.
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PMID:Osteoprotegrin and the bone homing and colonization potential of breast cancer cells. 1747 10

In prostate cancer, bone is the second most common site of metastatic disease after lymph nodes. This is related to a poor prognosis and is one of the major causes of morbidity and mortality in such patients. Early detection of metastatic bone disease and the definition of its extent, pattern, and aggressiveness are crucial for proper staging and restaging; it is particularly important in high-risk primary disease before initiating radical prostatectomy or radiation therapy. Different patterns of bone metastases, such as early marrow-based involvement, osteoblastic, osteolytic, and mixed changes can be seen. These types of metastases differ in their effect on bone, and consequently, the choice of imaging modalities that best depict the lesions may vary. During the last decades, bone scintigraphy has been used routinely in the evaluation of prostate cancer patients. However, it shows limited sensitivity and specificity. Single-photon emission computed tomography increases the sensitivity and specificity of planar bone scanning, especially for the evaluation of the spine. Positron emission tomography is increasing in popularity for staging newly diagnosed prostate cancer and for assessing response to therapy. Many positron emission tomography tracers have been tested for use in the evaluation of prostate cancer patients based on increased glycolysis ((18)F-FDG), cell membrane proliferation by radiolabeled phospholipids ((11)C and (18)F choline), fatty acid synthesis ((11)C acetate), amino acid transport and protein synthesis ((11)C methionine), androgen receptor expression ((18)F-FDHT), and osteoblastic activity ((18)F-fluoride). However, there are presently no accurate imaging modalities to directly, reproducibly, and effectively delineate bone metastases in prostate cancer.
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PMID:Prostate cancer: role of SPECT and PET in imaging bone metastases. 1980 Dec 19

To clarify the reciprocal interaction between human-breast cancer metastatic cells and bone microenvironment, we studied the influence of HGF/Met system on a proposed-prognostic marker of aggressiveness, the beta-catenin/Wnt pathway. For in vitro and in vivo experiments we used 1833-bone metastatic clone, derived from human-MDA-MB231 cells. In osteolytic bone metastases and in metastatic cells, Met was expressed in nuclei and at plasma membrane, and abnormally co-localised at nuclear level with beta-catenin and the tyrosine phosphorylated c-Src kinase. Thus, in 1833 cells nuclear-Met COOH-terminal fragment and beta-catenin-TCF were constitutively activated, possibly by receptor and non-receptor tyrosine kinases. The activity of the gene reporter TOPFLASH (containing multiple TCF/LEF-consensus sites) was measured, as index of beta-catenin functionality. In 1833 cells, human and mouse HGF increased Met and beta-catenin tyrosine phosphorylation and expression in nuclear and perinuclear compartments, beta-catenin nuclear translocation via Kank and TOPFLASH transactivation. Human HGF was autocrine/intracrine in bone metastasis, and mouse HGF originating from the adjacent host-bone marrow, was found inside the metastatic nuclei. Parental MDA-MB231 cell nuclei did not show functional beta-catenin, for TCF-transactivating activity, and the regulation by HGF. Our study highlighted the importance of the metastasis-stroma interaction in human-breast cancer metastatisation and first identified the HGF/nuclear Met/phospho-c-Src/beta-catenin-TCF/Wnt pathway as a potential-therapeutic target to delay establishment/progression of bone metastases by affecting the aggressive phenotype.
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PMID:Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and beta-catenin/Wnt pathways. 2035 Aug 2

Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. We have shown the involvement of the HGF/c-MET system in tumor-bone interaction contributing to human breast cancer metastasis. Therefore, disruption of HGF/c-MET signaling is a potential targeted approach to treating metastatic bone disease. In this study, we evaluated the effects of c-MET inhibition by both an oral, selective, small-molecule c-MET inhibitor, tivantinib, and a specific short hairpin RNA (shRNA) against c-MET in a mouse model of human breast cancer. Tivantinib exhibited dose-dependent antimetastatic activity in vivo, and the 120 mg/kg dose, proven to be suboptimal in reducing subcutaneous tumor growth, induced significant inhibition of metastatic growth of breast cancer cells in bone and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-MET silencing did not affect in vitro proliferation of bone metastatic cells, but significantly reduced their migration, and this effect was further enhanced by tivantinib. Both observations were confirmed in vivo. Indeed, more pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival were achieved by dual c-MET inhibition using both tivantinib and RNA interference strategies. Overall, our findings highlighted the effectiveness of c-MET inhibition in delaying the onset and progression of bone metastases and strongly suggest that targeting c-MET may have promising therapeutic value in the treatment of bone metastases from breast cancer.
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PMID:Breast cancer-derived bone metastasis can be effectively reduced through specific c-MET inhibitor tivantinib (ARQ 197) and shRNA c-MET knockdown. 2202 90

Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients. In addition to established bone-targeted therapies, new drugs such as endothelin A receptor antagonists, MET and VEGFR-2 antagonists or radiopharmaceuticals are in the focus of development. The standard care in prostate cancer patients with bone metastases to prevent skeletal-related events (SRE) are bisphosphonates. Denosumab, a human monoclonal antibody against RANKL, appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases-free survival. In contrast to zoledronic acid, denosumab clearance is not dependent on kidney function and can be administered subcutaneously. Similar rates of toxicity were observed for both substances; however, long-term data for denosumab are limited.
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PMID:[Bone metastasis in prostate cancer]. 2225 72

Cabozantinib/XL184 (Exelexis, Inc.) has demonstrated remarkable responses in kidney cancer. Preclinical results revealed VEGF, KIT and MET inhibition in a variety of solid tumors such as thyroid, ovarian, renal, lung, liver and prostate cancers. A phase II trial demonstrated efficacy in renal cancer with a 28 % objective response rate, stable disease rate of 62 % and median progression free survival of 14.7 months. Predominant toxicities of fatigue and diarrhea were noted. Dramatic responses in bone metastases (three of four patients) make the agent especially valuable for palliation in a disease, where presence of bone metastases is a predictor of worse survival. Cabozantinib is an emerging novel agent with promising activity in advanced kidney cancer. Randomized trials are planned in comparison with standard VEGF inhibitor therapy. Defining the role of MET overexpression would help patient selection and enrich and enhance the future evaluation of this targeted novel agent.
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PMID:Cabozantinib as a novel therapy for renal cell carcinoma. 2329 95

Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and vascular endothelial growth factor receptor (VEGFR) are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and VEGFR-2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date.
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PMID:Targeting MET and vascular endothelial growth factor receptor signaling in castration-resistant prostate cancer. 2333 62


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