Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of Kaposi's sarcoma (KS) is better understood since the identification of the novel human herpesvirus 8 (HHV8), which can be found in all forms of KS. Viral oncogenesis and cytokine-induced growth, as well as some states of immunocompromise, contribute to its development. Several virally encoded genes--eg, bcl-2, interleukin 6, cyclin D, G-protein-coupled receptor, and interferon regulatory factor--provide key functions on cellular proliferation and survival. Growth promotion of KS is further stimulated by various proinflammatory cytokines and growth factors such as tumour necrosis factor a, interleukin 6, basic fibroblast growth factor, and vascular endothelial growth factor, resulting in a hyperplastic polyclonal lesion with predominant spindle cells derived from lymphoid endothelia. HHV8 has recently been discovered to escape HLA-class-I-restricted antigen presentation to cytotoxic T lymphocytes by increasing endocytosis of MHC class I chains from the cell surface, thus enabling latent infection and immune escape in primary and chronic infection. Multicentric Castleman's disease is a rare lymphoproliferative disorder of the plasma cell type, which has been reported in both HIV-seropositive and HIV-seronegative patients, and which frequently contains HHV8 DNA. Pleural effusion lymphoma, or body-cavity-based lymphoma, belongs to the group of non-Hodgkin B-cell lymphomas characterised by pleural, pericardial, or peritoneal lymphomatous effusions in the absence of a solid tumour mass. Pleural effusion lymphoma has an intermediate immunophenotype lacking B or T lymphocyte antigens and also belongs to the diseases associated with HHV8.
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PMID:Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman's disease, and pleural effusion lymphoma. 1214 97

Glycogen synthase kinase-3beta (GSK3beta) plays important roles in metabolism, embryonic development, and tumorigenesis. Here we investigated the role of GSK3beta signaling in vascular biology by examining its function in endothelial cells (ECs). In EC, the regulatory phosphorylation of GSK3beta was found to be under the control of phosphoinositide 3-kinase-, MAPK-, and protein kinase A-dependent signaling pathways. The transduction of a nonphosphorylatable constitutively active mutant of GSKbeta promoted apoptosis under the conditions of prolonged serum deprivation or the disruption of cell-matrix attachments. Conversely, the transduction of catalytically inactive GSK3beta promoted EC survival under the conditions of cellular stress. Under normal cell culture conditions, the activation of GSK3beta signaling inhibited the migration of EC to vascular endothelial growth factor or basic fibroblast growth factor. Angiogenesis was inhibited by GSK3beta activation in an in vivo Matrigel plug assay, whereas the inhibition of GSK3beta signaling enhanced capillary formation. These data suggest that GSK3beta functions at the nodal point of converging signaling pathways in EC to regulate vessel growth through its control of vascular cell migration and survival.
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PMID:Regulation of angiogenesis by glycogen synthase kinase-3beta. 1216 28

Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV). Latent membrane protein-1 (LMP-1) is an EBV-encoded oncoprotein and is detected in approximately 50-70% of patients with NPC. LMP-1 is thought to play an essential role in tumorigenesis of NPC. In addition to its transforming properties, LMP-1 has been suggested to be associated with promotion of metastasis. Metastasis is a phenomenon composed of multiple sequential cascades. Reduction of tumor cell adhesion, degradation of extracellular matrix, basement membrane, enhancement of cell motility, and promotion of neovascularization are thought to be essential steps. LMP-1 down-regulates expression of E-cadherin, induces matrix metalloproteinase-9 and urokinase type-plasminogen activator through activation of NF-kappaB and AP-1, and enhances cell motility via ets-1 activation. LMP-1 also induces vascular endothelial growth factor through cyclooxygenase-2 activation and interleukin-8 through NF-kappaB activation. Clinical studies suggested the association of these factors with metastatic status of patients with NPC. In this review, the role of LMP-1 in the metastasis of NPC is discussed.
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PMID:Promotion of metastasis in nasopharyngeal carcinoma by Epstein-Barr virus latent membrane protein-1. 1216 95

Pituitary tumorigenesis is a poorly understood process involving dysregulation of the cell cycle, proliferation, and angiogenesis. The novel securin pituitary tumor transforming gene (PTTG) disrupts cell division and stimulates fibroblast growth factor (FGF)-2-mediated angiogenesis. We investigated expression of the angiogenic vascular endothelial growth factor (VEGF) and its receptor KDR/Flk-1 in 103 human pituitary tumors, and we assessed functional relationships between these genes in vitro. Nonfunctioning tumors (n = 81) demonstrated markedly raised VEGF mRNA (3.2-fold, P < 0.05) and protein concentrations, compared with normal pituitaries (n = 10). KDR was also highly induced in nonfunctioning tumors (14-fold, P < 0.001, n = 78) as well as in the whole cohort of pituitary tumors, compared with normal pituitary samples (14-fold, P < 0.0001, n = 100). In vitro, PTTG induced VEGF, but not KDR, expression in fetal neuronal NT2 cells (2.7-fold, P < 0.001, n = 8), MCF-7 breast carcinoma cells (1.9-fold, P = 0.03, n = 10), and choriocarcinoma JEG-3 cells (P = 0.0002, n = 8). A mutated PTTG construct that cannot be phosphorylated showed identical VEGF up-regulation (2.9-fold, P < 0.001, n = 8) in NT2 cells, compared with wild-type PTTG, but a further mutated construct with abrogation of the key protein:protein interaction domain of PTTG resulted in a significant reduction in VEGF stimulation, compared with wild-type (0.37-fold reduction, P < 0.001, n = 8). FGF-2 findings mirrored those of VEGF, although antibody depletion of secreted FGF-2 in the cell medium failed to influence VEGF up-regulation by PTTG. Overall, our findings implicate altered VEGF and KDR signaling in pituitary tumorigenesis, and we propose that PTTG stimulation of FGF-2 and VEGF expression in the presence of up-regulated growth factor receptors may account for angiogenic growth and progression of human pituitary tumors.
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PMID:Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors. 1221 78

Mutational inactivation of BRCA1 confers increased risk for breast cancer. However, the underlying basis for the breast tissue-restricted, tumor-suppressive properties of BRCA1 remains poorly defined. Here, we show that BRCA1 and the estrogen receptor alpha (ER-alpha) modulated vascular endothelial growth factor (VEGF) gene transcription and secretion in breast cancer cells. ER-alpha interacted in vitro and in vivo with BRCA1, and this interaction was mediated by the AF-2 domain of ER-alpha and two domains of BRCA1, the amino-acid residues 1-306 and 428-683. Endogenous interaction of ER-alpha with BRCA1 was observed in normal MCF-10A breast epithelial cells and in breast cancer cells (MCF-7 and T47D), and this interaction was significantly reduced in the presence of estrogen. Furthermore, ER-alpha induced activation of VEGF gene transcription, using human VEGF promoter-luciferase reporter constructs. The AF-2 domain of ER-alpha was also shown to induce VEGF gene transcription activation similar to that obtained with the full-length ER-alpha. However, in the presence of BRCA1, VEGF gene transcription activation and VEGF protein secretion were significantly inhibited in a dose-dependent manner. The BRCA1 domain of 1-683 amino acid residues was required for this inhibition of VEGF gene transcription activation. Three mutated forms of BRCA1 (A1708E, M1775R and Y1853X), that have been identified in familial breast cancers, failed to associate with ER-alpha and to suppress VEGF promoter activity and VEGF protein secretion. Overexpression of wild-type BRCA1 in HCC-1937 breast cancer cells that lack endogenous functional BRCA1 significantly reduced VEGF secretion in these cells. These results demonstrate a novel pathogenic mechanism whereby mutations in BRCA1, via their interaction with ER-alpha, could promote tumorigenesis through the hormonal regulation of mammary epithelial cell proliferation and impaired VEGF function, which may lead to cancer growth and angiogenesis.
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PMID:Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. 1240 15

Antiangiogenesis therapy has become a potentially promising tool to inhibit tumor growth by targeting an essential yet untransformed tissue component. Identifying the factors involved and understanding the mechanisms required for tumor angiogenesis will facilitate efficient and specific targeting. In neurofibromas, tumor growth is facilitated by a genetically and cytologically diverse mixture of cell types, including Schwann cells, fibroblast, mast cells, and neurons where nf-/- Schwann cells are most likely the tumorigenic cell type. The matrix forming nf+/- cells may provide a permissive environment, facilitating tumor development, perhaps by providing landscaping factors such as the angiogenic molecules fibroblast growth factor-2, platelet-derived growth factor, endothelial growth factor, vascular endothelial growth factor, and midkine, which have been detected in neurofibromas. Systemic overexpression of specific factors such as midkine owing to loss of one nf allele might further lower the overall threshold for tumorigenesis and development of a tumor vasculature. Targeting these heparin-binding growth factors might inhibit not only angiogenesis but also proliferation of tumor cells because most of these factors also stimulate proliferation of neurofibroma-derived Schwann cells. We discuss the role of specific secreted molecules for angiogenesis in tumors of neurofibromatosis 1 and possible Approaches for their targeting. Furthermore, results are discussed that demonstrate the efficacy of antiangiogenesis targeting to inhibit growth of neurofibrosarcomas in experimental animal models.
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PMID:Antiangiogenesis in neurofibromatosis 1. 1240 56

Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the 'normal' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that Cyr61 is sufficient to induce MCF-7 cells to grow in the absence of E2. Cyr61-transfected MCF-7 cells (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7 cells transfected with the vector DNA (MCF-7/V) remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ER alpha expression in MCF-7/Cyr61 cells is decreased although still functional. Moreover, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and antiestrogen-resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.
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PMID:Cyr61 promotes breast tumorigenesis and cancer progression. 1244 54

Inducible nitric oxide synthase (iNOS) content is elevated in human lung adenocarcinomas, and lung cancer patients exhale more nitric oxide (NO) than healthy individuals. The mechanism of this association of chronically elevated NO with tumorigenesis has not been defined. We investigated the role of iNOS in murine lung tumorigenesis, a model of human lung adenocarcinoma, using wild-type (+/+) and iNOS (-/-) mice. Genetic disruption of iNOS decreased urethane-induced lung tumor multiplicity by 80% (P < 0.0001). iNOS protein was expressed in lung tumors growing in wild-type mice and bronchiolar Clara cells isolated from normal mouse lungs, but was undetectable in whole lung extracts by immunoblotting. Because NO regulates vascular endothelial growth factor (VEGF) expression in other systems, we examined the effect of iNOS deficiency on VEGF protein concentration in mouse lung tumors. VEGF concentration was 54% lower in lung tumors isolated from iNOS (-/-) mice versus controls, implying that NO modulates angiogenesis in these tumors. Lung tumors also have elevated levels of cyclooxygenase (COX) -1 and COX-2 contents relative to normal lungs, but iNOS deficiency did not change COX expression in the tumors. Chronic inflammation predisposes mice to lung tumorigenesis; accordingly, we examined whether butylated hydroxytoluene-induced chronic lung inflammation was influenced by iNOS deficiency. Butylated hydroxytoluene-induced alveolar macrophage infiltration was unaffected by iNOS (-/-) status, suggesting that although NO is a critical mediator of mouse lung tumorigenesis, it is not essential in this model of lung inflammation. The substantial (80%) reduction in lung tumor multiplicity in iNOS (-/-) mice strongly supports examining iNOS-specific inhibitors as potential lung cancer chemopreventive agents.
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PMID:Genetic ablation of inducible nitric oxide synthase decreases mouse lung tumorigenesis. 1246 Aug 98

Malignant melanoma is the cancer with the most rapid increase in incidence in the United States. Ultraviolet light and deficiency of the p16ink4a gene are known factors that predispose one to the development of malignant melanoma. The signal transduction pathways that underlie the progression of melanoma from their precursors, atypical nevi, are not well understood. We examined activation of the MAP kinase pathway in atypical nevi and melanoma cells and found that this pathway is activated in melanomas. To determine the functional significance of this activation, we introduced constitutively active MAP kinase kinase (MAPKK) into immortalized melanocytes. The introduction of this gene into melanocytes leads to tumorigenesis in nude mice, activation of the angiogenic switch, and increased production of the proangiogenic factor, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Activation of MAP kinase signaling may be an important pathway involved in melanoma transformation. Inhibition of MAP kinase signaling may be useful in the prevention and treatment of melanoma.
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PMID:Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling. 1251 83

Von Hippel-Lindau (VHL) disease is an uncommon, autosomal dominant hereditary multitumor syndrome caused by germline alterations of the VHL gene, which has been cloned recently and identified as a tumor suppressor gene. The major lesions in VHL disease include hemangioblastomas in the central nervous system and retina, clear cell renal cell carcinomas, pheochromocytomas, pancreatic tumors, epididymal cystadenomas, endolymphatic sac tumors, carcinoid tumors, and multiple cysts of the kidney, pancreas, and epididymis. Compared with sporadic ones, the tumors in VHL disease develop at an earlier age and often multifocally. Histologic features of VHL tumors are characterized by their high degree of vascularization and the presence of a clear cell component. Hypervascularization is induced by overexpression of vascular endothelial growth factor (VEGF), and because the principal function of VHL protein is the negative regulation of hypoxia-inducible mRNAs including VEGF mRNA, inactivation of VHL gene plays critical roles in angiogenesis of the VHL tumors. In addition, since VHL protein is also required for the down-regulation of transcription activity of certain genes for the cell growth and cell cycle, inactivation of VHL gene may contribute to tumorigenesis of the VHL tumors. A significant difference in the frequency of types of VHL gene mutation has been noted among the affected families, known as the genotype-phenotype correlations.
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PMID:Von Hippel-Lindau disease. 1253 69


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