Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine, CXCL12, and its receptor, CXCR4, have recently been shown to play an important role in metastasis of several kinds of carcinoma. It has also been demonstrated that VEGF regulates both the expression of CXCR4 and invasiveness in breast cancer cell lines. We compared the immunohistochemical expression of CXCR4 and VEGF between the primary site and a concordant pulmonary metastatic site in 30 osteosarcoma patients, all of which had undergone thoracotomy. Microvessel density (MVD) as shown by immunostaining of CD34 and proliferative activity with MIB-1 monoclonal antibody was also evaluated. CXCR4 expression (primary, 33.3% positive vs metastatic, 66.6% positive; P = 0.0097) and MVD (primary, 29.86 +/- 6.87/0.26 mm2 vs metastatic, 43.32 +/- 8.65/0.26 mm2; P = 0.0015) in the metastatic site were both significantly increased compared with those in the primary site, whereas no difference between primary and metastatic sites was observed with regard to VEGF expression. There was a significant positive correlation between immunohistochemical CXCR4 and VEGF expression (P = 0.0269). In total population, the MIB-1-labeling index (LI) was significantly higher in tumors, which showed immunoreactivity for VEGF (MIB-1-LI in VEGF-positive tumors, 24.29 +/- 5.4 vs VEGF-negative tumors, 18.33 +/- 4.16; P = 0.034). Furthermore, those patients with VEGF-positive primary tumors had a significantly worse prognosis compared with the patients with VEGF-negative primary tumors (P = 0.0053). Our results suggested that CXCR4 expression was associated with metastatic progression, and immunohistochemical VEGF expression in the primary site had predictive value for the osteosarcoma patients, who developed lung metastasis.
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PMID:CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: analysis within a group of patients, all of whom developed lung metastasis. 1652 67

About one third of osteosarcoma patients develop lung metastasis refractory to chemotherapy. Recent studies indicate that biological response modifiers activating the patient's immune system may help controlling minimal residual disease via pathways distinct from those used by cytotoxic drugs, and therefore prove effective against tumor resistance. Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic lipophilic glycopeptide capable of activating monocytes and macrophages to a tumoricidal state. When intercalated in multilamellar liposomes (L-MTP-PE) and injected intravenously, it targets lung, liver, and spleen macrophages. Therapeutic activity of L-MTP-PE was demonstrated in several preclinical models of experimental lung metastasis and in clinical trials in dogs with osteosarcoma. Although macrophage activation was shown to be directly involved in the in vivo anti-metastatic activity of this molecule, cytokine and chemokine secretion by activated macrophages could induce recruitment and stimulation of other immune cells, which may in turn indirectly contribute to the anti-tumor effect. L-MTP-PE has undergone clinical development in humans. In early trials, most side effects of L-MTP-PE were minimal. L-MTP-PE showed signs of efficacy in treatment of patients with recurrent osteosarcoma and the encouraging results from phase II studies led to a phase III trial conducted by the Children's Oncology Group in patients with newly diagnosed high-grade osteosarcoma. Patients were treated with or without L-MTP-PE in combination with multi-drug chemotherapy in adjuvant setting; significantly higher overall survival and disease-free survival were observed in the group receiving L-MTP-PE.
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PMID:Liposomal muramyl tripeptide phosphatidylethanolamine: Targeting and activating macrophages for adjuvant treatment of osteosarcoma. 1652 42

The hepatitis C virus (HCV) non-structural (NS) 3/4A protein complex inhibits the retinoic acid inducible gene I (RIG-I) pathway by proteolytically cleaving mitochondria-associated CARD-containing adaptor protein Cardif, and this leads to reduced production of beta interferon (IFN-beta). This study examined the expression of CCL5 (regulated upon activation, normal T-cell expressed and secreted, or RANTES), CXCL8 (interleukin 8) and CXCL10 (IFN-gamma-activated protein 10, or IP-10) chemokine genes in osteosarcoma cell lines that inducibly expressed NS3/4A, NS4B, core-E1-E2-p7 and the entire HCV polyprotein. Sendai virus (SeV)-induced production of IFN-beta, CCL5, CXCL8 and CXCL10 was downregulated by the NS3/4A protein complex and by the full-length HCV polyprotein. Expression of NS3/4A and the HCV polyprotein reduced the binding of interferon regulatory factors (IRFs) 1 and 3 and, to a lesser extent, nuclear factor (NF)-kappaB (p65/p50) to their respective binding elements on the CXCL10 promoter during SeV infection. Furthermore, binding of IRF1 and IRF3 to the interferon-stimulated response element-like element, and of c-Jun and phosphorylated c-Jun to the activator protein 1 element of the CXCL8 promoter, was reduced when NS3/4A and the HCV polyprotein were expressed. In cell lines expressing NS3/4A and the HCV polyprotein, the subcellular localization of mitochondria was changed, and this was kinetically associated with the partial degradation of endogenous Cardif. These results indicate that NS3/4A alone or as part of the HCV polyprotein disturbs the expression of IRF1- and IRF3-regulated genes, as well as affecting mitogen-activated protein kinase kinase- and NF-kappaB-regulated genes.
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PMID:Hepatitis C virus proteins interfere with the activation of chemokine gene promoters and downregulate chemokine gene expression. 1819 74

Potassium channels, the most diverse superfamily of ion channels, have recently emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large conductance Ca(2+)-activated K(+) channels, often referred to as BK channels, are at the crossroads of several tumor-associated processes such as cell proliferation, survival, secretion and migration. Despite the high BK channel expression in osteosarcoma (OS), their function has not yet been investigated in this malignant bone pathology. Here, using stable RNA interference to reduce the expression of hSlo, the human pore-forming alpha-subunit of the BK channel, in human Cal72 OS cells, we show that BK channels play a functional role in carcinogenesis. Our results reveal for the first time that BK channels exhibit antitumoral properties in OS in vivo and affect the tumor microenvironment through the modulation of both chemokine expression and leukocyte infiltration.
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PMID:Silencing of hSlo potassium channels in human osteosarcoma cells promotes tumorigenesis. 1840 72

Six allosteric HIV-1 entry inhibitor modulators of the chemokine (C-C motif) receptor 5 (CCR5) receptor are compared for their potency as inhibitors of HIV-1 entry [infection of human osteosarcoma (HOS) cells and peripheral blood mononuclear cells (PBMC)] and antagonists of chemokine (C-C motif) ligand 3-like 1 [CCL3L1]-mediated internalization of CCR5. This latter activity has been identified as a beneficial action of CCL3L1 in prolonging survival after HIV-1 infection ( Science 307: 1434-1440, 2005 ). The allosteric nature of these modulators was further confirmed with the finding of a 58-fold (HOS cells) and 282-fold (PBMC) difference in relative potency for blockade of CCL3L1-mediated internalization versus HIV-1 entry. For the CCR5 modulators, statistically significant differences in this ratio were found for maraviroc, vicriviroc, aplaviroc, Sch-C, TAK652, and TAK779. For instance, although TAK652 is 13-fold more potent as an HIV-1 inhibitor (over blockade of CCL3L1-mediated CCR5 internalization), this ratio of potency is reversed for Sch-C (22-fold more potent for CCR5-mediated internalization over HIV-1 entry). Quantitative analyses of the insurmountable antagonism of CCR5 internalization by these ligands suggest that all of them reduce the efficacy of CCL3L1 for CCR5 internalization. The relatively small magnitude of dextral displacement accompanying the depression of maximal responses for aplaviroc, maraviroc and vicriviroc suggests that these modulators have minimal effects on CCL3L1 affinity, although possible receptor reserve effects obscure complete interpretation of this effect. These data are discussed in terms of the possible benefits of sparing natural CCR5 chemokine function in HIV-1 entry inhibition treatment for AIDS involving allosteric inhibitors.
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PMID:The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property? 1906 29

Osteosarcoma is characterized by a high malignant and metastatic potential. The chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor, CXCR4, play a crucial role in adhesion and migration of human cancer cells. Integrins are the major adhesive molecules in mammalian cells, and has been associated with metastasis of cancer cells. Here, we found that human osteosarcoma cell lines had significant expression of SDF-1 and CXCR4 (SDF-1 receptor). Treatment of osteosarcoma cells with SDF-1alpha increased the migration and cell surface expression of alphavbeta3 integrin. CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited the SDF-1alpha-induced increase the migration and integrin expression of osteosarcoma cells. Pretreated of osteosarcoma cells with MAPK kinase (MEK) inhibitor PD98059 inhibited the SDF-1alpha-mediated migration and integrin expression. Stimulation of cells with SDF-1alpha increased the phosphorylation of MEK and extracellular signal-regulating kinase (ERK). In addition, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited SDF-1alpha-mediated cell migration and integrin up-regulation. Stimulation of cells with SDF-1alpha induced IkappaB kinase (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the SDF-1alpha-mediated increasing kappaB-luciferase activity was inhibited by AMD3100, PD98059, PDTC and TPCK or MEK1, ERK2, IKKalpha and IKKbeta mutants. Taken together, these results suggest that the SDF-1alpha acts through CXCR4 to activate MEK and ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of alphavbeta3 integrins and contributing the migration of human osteosarcoma cells.
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PMID:Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-kappaB-dependent pathways. 1949 72

The tumor suppressor gene HIC1 (Hypermethylated in Cancer 1) that is epigenetically silenced in many human tumors and is essential for mammalian development encodes a sequence-specific transcriptional repressor. The few genes that have been reported to be directly regulated by HIC1 include ATOH1, FGFBP1, SIRT1, and E2F1. HIC1 is thus involved in the complex regulatory loops modulating p53-dependent and E2F1-dependent cell survival and stress responses. We performed genome-wide expression profiling analyses to identify new HIC1 target genes, using HIC1-deficient U2OS human osteosarcoma cells infected with adenoviruses expressing either HIC1 or GFP as a negative control. These studies identified several putative direct target genes, including CXCR7, a G-protein-coupled receptor recently identified as a scavenger receptor for the chemokine SDF-1/CXCL12. CXCR7 is highly expressed in human breast, lung, and prostate cancers. Using quantitative reverse transcription-PCR analyses, we demonstrated that CXCR7 was repressed in U2OS cells overexpressing HIC1. Inversely, inactivation of endogenous HIC1 by RNA interference in normal human WI38 fibroblasts results in up-regulation of CXCR7 and SIRT1. In silico analyses followed by deletion studies and luciferase reporter assays identified a functional and phylogenetically conserved HIC1-responsive element in the human CXCR7 promoter. Moreover, chromatin immunoprecipitation (ChIP) and ChIP upon ChIP experiments demonstrated that endogenous HIC1 proteins are bound together with the C-terminal binding protein corepressor to the CXCR7 and SIRT1 promoters in WI38 cells. Taken together, our results implicate the tumor suppressor HIC1 in the transcriptional regulation of the chemokine receptor CXCR7, a key player in the promotion of tumorigenesis in a wide variety of cell types.
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PMID:Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1). 1952 23

The mouse polyoma virus induces a broad array of solid tumors in mice of many inbred strains. In most strains tumors grow rapidly but fail to metastasize. An exception has been found in the Czech-II/Ei mouse in which bone tumors metastasize regularly to the lung. These tumors resemble human osteosarcoma in their propensity for pulmonary metastasis. Cell lines established from these metastatic tumors have been compared with ones from non-metastatic osteosarcomas arising in C3H/BiDa mice. Osteopontin, a chemokine implicated in migration and metastasis, is known to be transcriptionally induced by the viral middle T antigen. Czech-II/Ei and C3H/BiDa tumor cells expressed middle T and secreted osteopontin at comparable levels as the major chemoattractant. The tumor cell lines migrated equally well in response to recombinant osteopontin as the sole attractant. An important difference emerged in assays for invasion in which tumor cells from Czech-II/Ei mice were able to invade across an extracellular matrix barrier while those from C3H/BiDa mice were unable to invade. Invasive behavior was linked to elevated levels of the metalloproteinase MMP-2 and of the transcription factor NFAT. Inhibition of either MMP-2 or NFAT inhibited invasion by Czech-II/Ei osteosarcoma cells. The metastatic phenotype is dominant in F1 mice. Osteosarcoma cell lines from F1 mice expressed intermediate levels of MMP-2 and NFAT and were invasive. Osteosarcomas in Czech-II/Ei mice retain functional p53. This virus-host model of metastasis differs from engineered models targeting p53 or pRb and provides a system for investigating the genetic and molecular basis of bone tumor metastasis in the absence of p53 loss.
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PMID:Polyoma virus-induced osteosarcomas in inbred strains of mice: host determinants of metastasis. 2010 4

The lung is one target organ to which solid tumors frequently metastasize. Given the systemic adverse effects of currently available treatments, developing effective strategies of drug/gene delivery directly to the lungs is therefore needed. Aerosol delivery is a non-invasive gene transfer approach to target the airways. Here, we sought to evaluate the potential to deliver a fractalkine (FKN)-encoding plasmid formulated with the tetrafunctional amphiphilic block copolymer 704 through aerosolization in two models of pulmonary metastases. FKN is a chemokine recently described as a good candidate to stimulate a strong antitumor immune response in various forms of cancers. Here, we have assessed the effect of single and repeated aerosolizations of FKN-encoding plasmid formulated with 704 on the development of experimental lung metastases of mouse colon carcinoma and osteosarcoma. For this purpose, we have designed FKN-Fc sequences encoding an optimized version of the chemokine. Repeated intratracheal administrations of 704/FKN-Fc markedly inhibited growth of experimental lung metastases of CT-26 and K7M2 cells. Our results showed that tetrafunctional amphiphilic block copolymer 704 is a highly efficient synthetic vector for mediating local and safe gene transfer into the lung. In addition, FKN-Fc gene therapy of pulmonary nodules may provide a promising immunotherapeutic approach.
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PMID:Effect of fractalkine-Fc delivery in experimental lung metastasis using DNA/704 nanospheres. 2186 19

Hematogenous spread determines the outcome of osteosarcoma (OS) patients, but the pathogenesis of developing metastatic disease is still unclear. Chemokines are critical regulators of cell trafficking and adhesion, and have been reported to be aberrantly expressed and to correlate with an unfavorable prognosis and metastatic spread in several malignant tumors. The chemokine receptors CXCR4 and CXCR7 together with their common ligand CXCL12 form one of the most important chemokine axes in this context. To investigate a potential role of these chemokines in OSs, we analyzed their expression in a series of 223 well-characterized and pretherapeutic OS samples. Interestingly, we found the expression of CXCL12 and CXCR4 to correlate with a better long-term outcome and with a lower prevalence of metastases. These findings suggest a distinct role of CXCR4/CXCR7/CXCL12 signaling in the tumors of bone, as has also been previously described in acute leukemia. As many malignant tumors metastasize to bone, and tumor cells are thought to be directed to bone in response to CXCL12, OS cells expressing both CXCL12 and the corresponding receptors might be detained at their site of origin. The disruption of CXCR4/CXCR7/CXCL12 signaling could therefore be crucial in OSs for the migration of tumor cells from bone into circulation and for developing systemic disease.
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PMID:Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. 2217 90


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