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)

Cancer cells promote angiogenesis early in tumorigenesis because cancer cells require oxygen and nutrients for their survival they need to be supported by blood vessels. The angiogenic switch is driven by several proangiogenic factors, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), basic fibroblast growth factor (bFGF) and others. These proangiogenic factors are released from not only cancer cells but also various stromal cells by various stimulations, mutations or inflammation. From our experimental results using human lung cancer cell lines, survival factors in each cancer cell line are different. This makes cancer therapy difficult. Various angiogenesis inhibitors have been developed to block tumor angiogenesis. However we need to think how and when to use angiogenesis inhibitors together with conventional chemotherapeutic agents.
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PMID:[Screening of antiangiogenic compound]. 1511 93

Recent reports have suggested that phosphatidylinositol 3-kinase/Akt signaling can induce angiogenesis and tumor growth by activating the hypoxia-inducible factor-1 (HIF-1). However, the absence of specific biochemical inhibitors of HIF-1 signaling has prevented a direct test of the requirement for HIF-1 activity in Akt-dependent tumorigenesis. To genetically test the relationship between HIF-1 and Akt, activated Akt was expressed in a hepatoma cell line lacking HIF-1. Akt expression was associated with a dramatic increase in tumor size, despite the absence of HIF-1. Tumor size was not further increased in cells with reconstituted HIF-1 activity, indicating that the effects of Akt on tumorigenesis were not limited by the absence of HIF-1. Increased tumor size in Akt-expressing, HIF-deficient cells was associated with vascular endothelial growth factor secretion and tumor vascularization. In addition to vascular endothelial growth factor production, Akt also conferred a cell-autonomous competitive advantage to tumor cells in an in vivo competition experiment. Thus, Akt has potent, HIF-1-independent oncogenic and angiogenic activities.
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PMID:Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. 1515 Jan 4

A small synthetic library of cyclohexapeptidomimetic calixarenes was prepared to identify disrupters of vascular endothelial growth factor (VEGF) binding to its receptor that inhibits angiogenesis. From this library, we discovered GFA-116, which potently inhibits (125)I-VEGF binding to Flk-1 in Flk-1-overexpressing NIH 3T3 cells and human prostate tumor cells with an IC(50) of 750 nM. This inhibition is highly selective for VEGF in that (125)I- platelet-derived growth factor binding to its receptor is not affected. GFA-116 inhibits VEGF-stimulated Flk-1 tyrosine phosphorylation and subsequent activation of Erk1/2 mitogen-activated protein kinases. Furthermore, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor-dependent stimulation of Erk1/2 phosphorylation are not affected at concentrations as high as 10 microM. In vitro, GFA-116 inhibits angiogenesis as measured by inhibition of migration and formation of capillary-like structures by human endothelial cells as well as suppression of microvessel outgrowth in rat aortic rings and rat cornea angiogenesis. In vivo, GFA-116 (50 mpk/day) inhibits tumor growth and angiogenesis as measured by CD31 staining of A-549 human lung tumors in nude mice. Furthermore, GFA-116 is also effective at inhibiting tumor growth and metastasis to the lung of B16-F10 melanoma cells injected into immunocompetent mice. Taken together, these results demonstrate that a synthetic molecule capable of disrupting the binding of VEGF to its receptor selectively inhibits VEGF-dependent signaling and suppresses angiogenesis and tumorigenesis.
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PMID:Blocking angiogenesis and tumorigenesis with GFA-116, a synthetic molecule that inhibits binding of vascular endothelial growth factor to its receptor. 1515 Jan 16

Estrogen is involved in breast tumorigenesis, but the precise mechanisms for its oncogenic and angiogenic actions are poorly understood. Angiogenesis is regulated, in part, by these critical components: vascular endothelial growth factor (VEGF) and its two receptors (VEGFR-1 and VEGFR-2). VEGFR-2 is a positive angiogenic signal transducer, whereas VEGFR-1, especially its soluble form (soluble VEGFR-1), is a negative regulator of VEGF availability. We found that breast epithelial cells express soluble VEGFR-1 and hypothesized that because estrogen can regulate expression of members of the VEGF family, it might stimulate angiogenesis in breast cancer by decreasing expression of soluble VEGFR-1. Soluble VEGFR-1 expression decreased in estrogen receptor (ER)-positive but not in ER-negative breast cancer cell lines treated with estrogen. Pretreatment of the cells with the ER antagonist ICI 182,780 blocked the effect. The estrogen-mediated decrease in soluble VEGFR-1 expression was accompanied by a statistically significant increase in angiogenesis in vivo. Our data suggest that inhibition of soluble VEGFR-1 expression represents a novel mechanism--an estrogen-driven angiogenic switch--possibly responsible for breast carcinoma progression.
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PMID:An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1. 1517 72

Oral administration of tea (Camellia sinensis) has been shown to inhibit the formation and growth of several tumor types in animal models. The present study investigated the effects of treatment with different concentrations of green tea on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice. Two days after a single dose of NNK (100 mg/kg body weight, i.p.), the mice were given 0.1, 0.2, 0.4, and 0.6% green tea solution (1, 2, 4, and 6 g of tea solids, respectively, dissolved in 1 l of water), 0.02% caffeine, or water as the sole source of drinking fluid until the termination of the experiment. Only the treatment with 0.6% tea preparation significantly reduced lung tumor multiplicity (mean +/- SE, 6.07 +/- 0.77 vs. 8.60 +/- 0.50 tumors per mouse, P = 0.018). Treatment with 0.6% tea also inhibited angiogenesis, as indicated by the lower microvessel density (number of blood vessels/mm2) based on immunostaining for the von Willebrand factor antigen (81.9 +/- 9.5 vs. 129.4 +/- 8.2, P = 0.0018) and anti-CD31 antibody staining (465.3 +/- 61.4 vs. 657.1 +/- 43.6, P = 0.0012). Significantly lower vascular endothelial growth factor immunostaining scores were also observed in the 0.6% tea-treated group (0.98 +/- 0.17 vs. 1.43 +/- 0.07, P = 0.006). The apoptosis index was significantly higher in lung adenomas from 0.6% tea-treated mice based on morphological analysis of cell apoptosis (2.51 +/- 0.18% vs. 1.57 +/- 0.11%, P = 0.00005), and the result was further confirmed using the TUNEL method. Inhibition of angiogenesis and the induction of apoptosis by green tea may be closely related to the inhibition of pulmonary carcinogenesis.
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PMID:Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in A/J mice by oral administration of green tea. 1520 77

We previously performed gene expression profiling in a multistep squamous cell carcinoma (SCC) progression model, and identified growth-regulated oncogene-1 (Gro-1/KC) as a factor that contributes to enhanced angiogenesis, tumorigenesis and metastasis. In the present study, we explored molecular pathways coactivated with Gro-1/KC, and identified a transcript that encodes c-Met, the receptor for hepatocyte growth factor/scatter factor (HGF). Northern, Western blot, and immunohistochemical analyses confirm that expression of c-Met mRNA and protein is increased with SCC progression. In vitro, HGF preferentially promoted scattering in the metastatic LY-1 and LY-2 lines, and enhanced angiogenesis factors Gro-1/KC and vascular endothelial growth factor (VEGF) production by all tumor cell lines. In vivo, tumor growth and lung metastasis were promoted by transfection and overexpression of HGF cDNA in metastatic LY-1 cells. Our data indicate that metastatic SCC cells that overexpress c-Met exhibit angiogenesis factor expression and enhanced scattering in response to HGF in vitro, and tumorigenesis and metastasis in response to HGF in the tumor microenvironment in vivo.
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PMID:Metastatic squamous cell carcinoma cells that overexpress c-Met exhibit enhanced angiogenesis factor expression, scattering and metastasis in response to hepatocyte growth factor. 1522 Oct 9

Immunosuppressive factors, such as vascular endothelial growth factor, transforming growth factor-beta, prostaglandin E2, interleukin (IL)-10, and IL-6, are made frequently by cancer cells. These factors, along with others, can inhibit the development and function of tumor-reactive effector T cells and the clinical results of cancer vaccines. Production of these factors by tumor cells is associated with disease progression and may represent an active immune surveillance escape mechanism. However, a number of factors appear to be made directly in response to signaling molecules, such as RAS, AKT, and signal transducer and activator of transcription 3, which are activated as a result of genetic events that occur during oncogenesis. Methods to overcome the negative effects of immunosuppressive factors, which are "hard wired" into gene programs of cancer cells, might then improve the results of cancer vaccines. For example, specific blocking antibodies, which recognize such factors, or kinase inhibitors, which block the signaling pathways that lead to their production, could potentially be used as vaccine adjuvants. The effects of immunosuppressive factors may also be "turned off" by cytokines with tumor suppressor properties. The enhanced clinical and immunological effects of melanoma vaccines observed after the administration of high doses of interferon-alpha2b provide a "proof of principle" in human patients, that agents which counter the gene programs of cancer cells, causing them to intrinsically resist tumor-reactive T cells, may improve significantly the efficacy of cancer vaccines.
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PMID:Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells. 1527 80

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to stimulate the growth of a variety of cells in an autocrine or paracrine manner. Although HB-EGF is widely expressed in tumors compared with normal tissue, its contribution to tumorigenicity is unknown. HB-EGF can be produced as a membrane-anchored form (pro-HB-EGF) and later processed to a soluble form (s-HB-EGF), although a significant amount of pro-HB-EGF remains uncleaved on the cell surface. To understand the roles of two forms of HB-EGF in promoting tumor growth, we have studied the effects of HB-EGF expression in the process of tumorigenesis using in vitro and in vivo systems. We demonstrate here that in EJ human bladder cancer cells containing a tetracycline-regulatable s-HB-EGF or pro-HB-EGF expression system, s-HB-EGF expression increased their transformed phenotypes, including growth rate, colony-forming ability, and activation of cyclin D1 promoter, as well as induction of vascular endothelial growth factor in vitro. Moreover, s-HB-EGF or wild-type HB-EGF induced the expression and activities of the metalloproteases, MMP-9 and MMP-3, leading to enhanced cell migration. In vivo studies also demonstrated that tumor cells expressing s-HB-EGF or wild-type HB-EGF significantly enhanced tumorigenic potential in athymic nude mice and exerted an angiogenic effect, increasing the density and size of tumor blood vessels. However, cells expressing solely pro-HB-EGF did not exhibit any significant tumorigenic potential. These findings establish s-HB-EGF as a potent inducer of tumor growth and angiogenesis and suggest that therapeutic intervention aimed at the inhibition of s-HB-EGF functions may be useful in cancer treatment.
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PMID:HB-EGF is a potent inducer of tumor growth and angiogenesis. 1528 34

The oncoprotein Tax of human T-cell leukemia virus type I (HTLV-1) is the major mediator of viral pathogenesis in infected individuals. Expression of Tax under the regulation of the human granzyme B promoter in mice results in a lymphoproliferative disorder resembling adult T-cell leukemia/lymphoma (ATL). Tax expression is associated with the production of high levels interferon-gamma (IFN-gamma) in HTLV-1-infected CD4(+) cells and Tax-transgenic tumors. We examined the role of IFN-gamma in tumorigenesis, by mating Tax-transgenic mice with a gene-specific knockout for IFN-gamma. IFN-gamma(-/-) Tax(+)-transgenic mice show accelerated tumor onset (median, 4 versus 6 months), dissemination (median, 5 versus 7 months), and death (median, 7 versus 10 months), compared with IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Pathologic and immunophenotypic characteristics of tumors from all genotypes are indistinguishable, except for enhanced interleukin 2 receptor-beta (IL-2Rbeta) and suppressed intercellular adhesion molecule-1 (ICAM-1) expression on tumors from IFN-gamma(-/-) Tax(+) transgenic mice. IFN-gamma(-/-) tumors demonstrate enhanced CD31 (platelet-endothelial CAM-1 [PECAM-1]) staining compared with those from IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Angiogenesis-specific cDNA microarray analysis identified 4 mediators of angiogenic growth differentially expressed in tumors from Tax(+)IFN-gamma(-/-) mice compared with Tax(+)IFN-gamma(+/+) littermates. As confirmed by reverse transcription-polymerase chain reaction (RT-PCR), loss of IFN-gamma results in down-regulation of tumor necrosis factor-alpha (TNF-alpha) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) while up-regulating expression of vascular endothelial growth factor (VEGF) and tenascin C. These results provide insight into a possible mechanism by which IFN-gamma contributes to host resistance against HTLV-induced tumors through an angiostatic effect.
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PMID:Enhanced tumorigenesis in HTLV-1 tax-transgenic mice deficient in interferon-gamma. 1529 59

Our previous study shows that cigarette smoking can promote inflammation-associated adenoma formation in the mouse colon, but the underlying mechanism remains unknown. Several studies suggest that there is a link between 5-lipoxygenase (5-LOX) and carcinogenesis in humans and animals. In the present study, we aims to investigate whether the promoting action of cigarette smoke on inflammation-associated colon cancer formation is associated with 5-LOX activation in mice. Results showed that exposure to the mainstream smoke of unfiltered cigarettes enhanced the 5-LOX protein expression in the inflammation-associated colonic adenomas. It was accompanied with an up-regulation of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF). Both are the key angiogenic factors for tumorigenesis. 5-LOX inhibitors decreased the incidence of colonic adenoma formation and reduced angiogenesis, MMP-2 activity and VEGF protein expression in the colons of these animals. Taken together, these results strongly suggest that cigarette smoke can induce 5-LOX expression which plays an important role in activation of MMP-2 and VEGF to induce angiogenic process and promotion of inflammation-associated adenoma formation in mice.
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PMID:Contributory role of 5-lipoxygenase and its association with angiogenesis in the promotion of inflammation-associated colonic tumorigenesis by cigarette smoking. 1536 93


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