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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF), a potent cytokine secreted by virtually all cells plays a key role in tumor angiogenesis. Disruption of one VEGF allele in mice has revealed a dramatic lethal effect in early embryogenesis, suggesting a very tight regulation of this gene. This commentary reviews the mechanisms whereby VEGF mRNA is controlled within the tumor environment by hypoxia and the MAP kinase signaling cascades. Using hamster fibroblasts as a cellular model, we demonstrated that the Ras-mediated activation of p42/p44 MAP kinases exerts a prominent action at the transcriptional level. In normoxic conditions, p42/p44 MAPKs activate the VEGF promoter at the proximal (-88/-66) region where Sp 1/AP-2 transcriptional factor complexes are recruited. At low O2 tension, the stabilized and nuclear hypoxia inducible factor- 1alpha (HIF-1alpha) is directly phosphorylated by p42/p44 MAPKs, an action which enhances HIF-1-dependent transcriptional activition of VEGF. In addition, MAPKs activated under various cellular stresses (p38MAPK and JNK), contribute to the increased expression of this angiogenic growth and survival factor by stabilizing the VEGF mRNA.
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PMID:MAP kinases and hypoxia in the control of VEGF expression. 1119 Oct 53

Under low-oxygen conditions, cells develop an adaptive program that leads to the induction of several genes, which are transcriptionally regulated by hypoxia-inducible factor 1 (HIF-1). On the other hand, there are other factors which modulate the HIF-1-mediated induction of some genes by binding to cis-acting motifs present in their promoters. Here, we show that c-Jun functionally cooperates with HIF-1 transcriptional activity in different cell types. Interestingly, a dominant-negative mutant of c-Jun which lacks its transactivation domain partially inhibits HIF-1-mediated transcription. This cooperative effect is not due to an increase in the nuclear amount of the HIF-1alpha subunit, nor does it require direct binding of c-Jun to DNA. c-Jun and HIF-1alpha are able to associate in vivo but not in vitro, suggesting that this interaction involves the participation of additional proteins and/or a posttranslational modification of these factors. In this context, hypoxia induces phosphorylation of c-Jun at Ser(63) in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser(63) and Ser(73) impair its functional cooperation with HIF-1. The functional interplay between c-Jun and HIF-1 provides a novel insight into the regulation of some genes, such as the one for VEGF, which is a key regulator of tumor angiogenesis.
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PMID:c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. 1173 18

IL-8 is an important mediator of leukocyte trafficking and activation, participating in tumor angiogenesis, inflammatory processes and coronary atherosclerosis. Under flow conditions IL-8, in conjunction with MCP-1, triggers the firm adhesion of monocytes to the vascular endothelium. While previous studies have suggested the requirement of NF-kappaB for IL-8 secretion by endothelial cells, we investigated the possibility of IL-8 transactivation under conditions of NF-kappaB suppression. Inhibition of the proteasome by MG-132 or lactacystin completely blocked TNF-alpha-induced IkappaBalpha degradation as well as NF-kappaB activity in human arterial endothelial cells. Surprisingly, basal secretion of IL-8 protein was eight- to tenfold induced by proteasome inhibitors, while MCP-1 expression was, as expected, completely down-regulated. IL-8 was up-regulated at the transcriptional level, and promoter studies proved a more than ninefold induction of transcription factor AP-1 activity to be the cause of increased IL-8 transcription. Mutation of the AP-1 binding site in an IL-8 promoter construct completely abrogated this effect, while mutation of the NF-kappaB motif did not influence IL-8 transactivation by proteasome inhibitors. With DNA binding assays we found a seven- to eightfold induction of phosphorylated c-Jun and hence JNK kinase activity under MG-132 treatment. Induction of JNK kinase appeared independent of the cell type, even in tumor cell lines not responding to proteasome inhibitors. Since neither inactivation of p53 in wild-type p53 cells nor reintroduction of functional p53 into p53(-/-) cells affected MG-132-inducible IL-8 secretion, a direct influence of p53 on IL-8 regulation could be excluded. These results show that proteasome inhibitors can not only lead to functional AP-1 induction by enhanced c-Jun phosphorylation, but also transactivate the IL-8 gene in human endothelial cells despite complete suppression of NF-kappaB activity.
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PMID:Proteasome inhibition leads to NF-kappaB-independent IL-8 transactivation in human endothelial cells through induction of AP-1. 1220 33

The natural hormone 17beta-estradiol (17beta-E2) is known to induce tumor angiogenesis in various target organs by activating positive regulators of angiogenesis. In this study, we show for the first time that in human umbilical vein endothelial cells (HUVECs), 17beta-E2 transiently down-regulates the expression and secretion of a potent negative regulator of angiogenesis, thrombospondin-1 (TSP-1). This inhibitory effect of 17beta-E2 is mediated through nongenomic estrogen receptor (ER)/mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) 1/2 and c-Jun NH(2)-terminal kinase (JNK)/stress-activated protein kinase (SAPK) signaling pathways, because this effect can be abolished by a pure ER antagonist (ICI 182,780) and inhibitors of downstream signaling proteins of MAPK signaling cascades, including MAPK kinase 1/2 and ERK1/2 inhibitor and JNK/SAPK inhibitor. To understand the functional role(s) of TSP-1 during estradiol-induced angiogenesis, we examined the growth and migration of endothelial cells in different experimental environments. Using a recombinant protein, we show that increments of TSP-1 protein concentration in culture medium significantly reduce the migration and proliferation of HUVECs stimulated by 17beta-E2. Together, these studies suggest that TSP-1 can be considered an important negative factor in understanding the increased angiogenesis in response to estrogens.
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PMID:Thombospondin-1 disrupts estrogen-induced endothelial cell proliferation and migration and its expression is suppressed by estradiol. 1503 54

Prostate cancer is the second most common cause of death related to cancer in Western society. 2-Methoxyestradiol (2-ME), an endogenous metabolite of estradiol-17beta, inhibits tumor angiogenesis while also exerting potent cytotoxic effects on various cancer cells. 2-ME has been shown to activate the p38 MAPK and JNK pathways and to induce apoptosis in cells, although the underlying molecular mechanisms for this are unknown. Here we report that the expression of Smad7, an adaptor molecule required to activate p38 MAPK in the transforming growth factor beta signaling pathway, is also required for 2-ME-induced p38 activation and apoptosis in human prostate cancer cells (PC-3U). PC-3U/AS-S7 cells stably transfected with an antisense Smad7 construct, or PC-3U cells transiently transfected with short interfering RNA for Smad7, were protected against 2-ME-induced apoptosis. 2-ME-induced apoptosis was found to involve p38 MAPK and JNK, because simultaneous treatments with 2-ME and a specific p38 inhibitor (SB203580) or an inhibitor of JNK (L-JNK1) prevented 2-ME-induced apoptosis. Most interestingly, Smad7 was shown by both antisense and short interfering RNA techniques to affect levels of beta-catenin, which has been implicated previously in the regulation of apoptosis. Moreover, Smad7 was found to be important for the basal expression of Bim, a pro-apoptotic Bcl-2 family member, and for 2-ME-induced expression of Bim. These results suggest that expression of Smad7 is crucial for 2-ME-induced apoptosis in human prostate cancer cells.
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PMID:2-Methoxyestradiol-induced apoptosis in prostate cancer cells requires Smad7. 1570 59

Vascular endothelial growth factor (VEGF) is associated with tumor angiogenesis and poor prognosis in human colorectal cancer (CRC). VEGF receptor-1 (VEGFR-1 or Flt-1) is a high-affinity receptor for VEGF and is typically considered specific to endothelial cells. Here we report the expression and function of VEGFR-1 in CRC cell lines. VEGFR-1 was expressed in all CRC cell lines studied as determined by RT-PCR, Western blot analysis, FACS, and ELISA. Treatment of the human CRC cell lines HT-29 and SW480 with VEGF-A (a ligand for both VEGFR-1 and -2) or VEGF-B (a ligand specific for VEGFR-1) led to activation of Erk-1/2, SAPK/JNK, and translocation of the p65 subunit of nuclear factor-kappaB into the nucleus. Both VEGF-A and -B led to significant induction of cell motility and invasiveness of CRC cells. Stimulation of cells with VEGF-A or -B also led to larger and more numerous colonies in soft agar. However, activation of VEGFR-1 did not increase CRC cell proliferation. In contrast to the previous paradigm that VEGFRs are not present on tumor cells of epithelial origin, we found that VEGFR-1 is present and functional on CRC cells, and activation by VEGF family ligands can activate processes involved in tumor progression and metastasis.
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PMID:Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. 1573 59

IL-20 belongs to the IL-10 family and is involved in the pathogenesis of keratinocyte hyperproliferation in vivo. Endothelial cells express IL-20 receptors. To explore the function of IL-20 on endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMECs) with human IL-20 and analyzed its effect on endothelial cells. IL-20 induced proliferation of endothelial cells and the activity was specifically blocked by anti-human-IL-20 monoclonal antibody and soluble (s)IL-20 receptor (R)1 and sIL-20R2. An alternatively spliced variant of IL-20 was isolated and also was shown to induce proliferation of HUVECs and HMECs. Treatment of HUVECs with both IL-10 and IL-20 demonstrated that IL-10 antagonized the activity of IL-20 because it diminished IL-20-induced proliferation of HUVECs. IL-20 significantly induced HUVECs migration and vascular tube formation on Matrigel in vitro. In vivo, IL-20 also enhanced tumor angiogenesis. Incubation of IL-20 with HUVECs induced transcripts of bFGF, VEGF, MMP-2, MMP-9, and IL-8. Furthermore, incubation of HUVECs with IL-20 induced phosphorylation of ERK1/2, p38, and JNK. Thus, IL-20 is a pleiotropic cytokine and promotes angiogenesis.
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PMID:Interleukin-20 promotes angiogenesis in a direct and indirect manner. 1651 54

Transforming growth factor beta 1 (TGF-beta1) is a potent tumor suppressor but, paradoxically, TGF-beta1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-beta type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-beta signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinase-inactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-beta-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-beta-mediated cell migration. Collectively, our results show that TGF-beta-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.
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PMID:ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. 1707 48

Fibroblast growth factor (FGF) family signaling mediates cell-to-cell communication in development and organ homeostasis in adults. Of the FGF receptor (FGFR) isotypes, FGFR4 is the sole resident isotype present in mature parenchymal hepatocytes. FGFR1 that is normally associated with activated nonparenchymal cells appears ectopically in hepatoma cells. Ectopic expression and chronic activity of FGFR1 in hepatocytes accelerates diethylnitrosamine (DEN)-initiated hepatocarcinogenesis by driving unrestrained cell proliferation and tumor angiogenesis. Hepatocyte FGFR4 mediates liver's role in systemic cholesterol/bile acid and lipid metabolism and affects proper hepatolobular restoration after damage without effect on cell proliferation. Here we ask whether FGFR4 plays a role in progression of hepatocellular carcinoma (HCC). We report that although spontaneous HCC was not detected in livers of FGFR4-deficient mice, the ablation of FGFR4 accelerated DEN-induced hepatocarcinogenesis. In contrast to FGFR1 that induced a strong mitogenic response and depressed rate of cell death in hepatoma cells, FGFR4 failed to induce a mitogenic response and increased the rate of cell death. FGFR1 but not FGFR4 induced cyclin D1 and repressed p27 expression. Analysis of activation of Erk, JNK, and PI3K-related AKT signaling pathways indicated that in contrast to FGFR1, FGFR4 failed to sustain Erk activation and did not activate AKT. These differences may underlie the opposing effects of FGFR1 and FGFR4. These results suggest that in contrast to ectopic FGFR1 that is a strong promoter of hepatoma, resident FGFR4 that mediates differentiated hepatocyte metabolic functions also serves to suppress hepatoma progression.
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PMID:Resident hepatocyte fibroblast growth factor receptor 4 limits hepatocarcinogenesis. 1900 64

Vascular endothelial growth factor (VEGF) signaling is critical for tumor angiogenesis. However, therapies based on inhibition of VEGF receptors (VEGFRs) have shown modest results for patients with cancer. Surprisingly little is known about mechanisms underlying the regulation of VEGFR1 and VEGFR2 expression, the main targets of these drugs. Here, analysis of tissue microarrays revealed an inversely reciprocal pattern of VEGFR regulation in the endothelium of human squamous-cell carcinomas (high VEGFR1, low VEGFR2), as compared with the endothelium of control tissues (low VEGFR1, high VEGFR2). Mechanistic studies demonstrated that VEGF signals through the Akt/ERK pathway to inhibit constitutive ubiquitination and induce rapid VEGFR1 accumulation in endothelial cells. Surprisingly, VEGFR1 is primarily localized in the nucleus of endothelial cells. In contrast, VEGF signals through the JNK/c-Jun pathway to induce endocytosis, nuclear translocation, and downregulation of VEGFR2 via ubiquitination. VEGFR1 signaling is required for endothelial-cell survival, while VEGFR2 regulates capillary tube formation. Notably, the antiangiogenic effect of bevacizumab (anti-VEGF antibody) requires normalization of VEGFR1 and VEGFR2 levels in human squamous-cell carcinomas vascularized with human blood vessels in immunodeficient mice. Collectively, this work demonstrates that VEGF-induced angiogenesis requires inverse regulation of VEGFR1 and VEGFR2 in tumor-associated endothelial cells.
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PMID:VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. 1983 90


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