Gene/Protein Disease Symptom Drug Enzyme Compound
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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) is a mitogen for cultured endothelial cells, and a potent angiogenic factor in vivo. Incubation of 125I-VEGF with human or bovine serum led to the formation of 125I-VEGF containing complexes that had a molecular mass greater than 300 kDa. These complexes were specifically immunoprecipitated with anti-human alpha 2-macroglobulin (alpha 2M) antibodies. Similar high molecular weight complexes were formed when 125I-VEGF was incubated with commercially available alpha 2M. The 125I-VEGF.alpha 2M complexes were resistant to boiling in the presence of SDS. The formation of 125I-VEGF.alpha 2M complexes was inhibited by iodoacetic acid, indicating that free sulfhydryl groups are required for complex assembly. Tryptic digestion of alpha 2M did not affect its VEGF binding ability. Tryptic digestion of 125I-VEGF.alpha 2M complexes on the other hand, resulted in the degradation of bound 125I-VEGF, indicating that alpha 2M does not protect bound 125I-VEGF from proteolytic digestion. The binding of 125I-VEGF to alpha 2M was partially inhibited by an excess of basic fibroblast growth factor. Other growth factors which bind to alpha 2M, such as platelet-derived growth factor and insulin, did not inhibit the binding of 125I-VEGF. The binding of VEGF to alpha 2M inhibited its receptor binding ability, indicating that alpha 2M may function as a VEGF removal and inactivation factor. Heparin and heparan sulfate, but not other glycosaminoglycans such as chondroitin sulfate, efficiently inhibited the binding of 125I-VEGF to alpha 2M. It is possible that heparin-like molecules released from extracellular matrixes could prevent the inactivation of VEGF by alpha 2M resulting in the potentiation of processes such as tumor angiogenesis.
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PMID:Vascular endothelial growth factor is inactivated by binding to alpha 2-macroglobulin and the binding is inhibited by heparin. 768 26

CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert domain-containing receptor) that correlated with the inhibition of the mitogen-activated protein kinase activation, but did not affect the ligand-induced autophosphorylation of the receptors for insulin, insulin-like growth factor-I, or epidermal growth factor. CGP 41251 showed broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs).
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PMID:Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent. 1045 7

The pivotal role of vascular endothelial growth factor (VEGF-A) in the regulation of angiogenesis, in particular in the onset and maintenance of tumor angiogenesis, has been demonstrated repeatedly in experimental model systems and, more recently, in clinical trials. Experimental evidence has also suggested that up-regulated expression of VEGF-A may cooperate with other genetic or epigenetic changes to induce or accelerate tumor progression to invasive and metastatic cancers. Here we report the generation of transgenic mouse lines that express human VEGF-A165 under the control of the rat insulin promoter in the beta cells of pancreatic islets of Langerhans (Rip1VEGF-A). These mice do not exhibit detectable changes in islet development, vascularization, or physiology. Intercrosses of these mice with a transgenic mouse model of pancreatic beta cell carcinogenesis (Rip1Tag2) result in an earlier onset of tumor angiogenesis and with it accelerated tumor growth and mortality. The transition from benign tumors (adenoma) to malignant tumors (carcinoma) is modestly accelerated; however, tumor metastases are not observed. Our findings indicate that in beta-cell tumorigenesis, overexpression of VEGF-A165 accelerates the onset of tumor angiogenesis and with it tumor progression but is not sufficient to induce tumor metastasis.
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PMID:Overexpression of vascular endothelial growth factor-A165 enhances tumor angiogenesis but not metastasis during beta-cell carcinogenesis. 1180 16

The endothelins, a family of potent vasoconstricting peptides, have been implicated in the pathophysiology of advanced prostate cancer. Two endothelin receptors, ET-A and ET-B are found in normal prostate tissue. Malignant prostate cells are notable for the loss of ET-B receptors and increased levels of endothelin-1 [ET-1]; this distortion of the endothelin system may be a significant factor in the progression of prostate cancer. Proposed roles for endothelin in prostate cancer include growth promotion, apoptosis inhibition, bone formation, and stimulation of nociceptive receptors. ET-1 can act alone as a mitogen, but its effects are greatest as a comitogen with a variety of growth factors, including basic fibroblast growth factor, insulin-like growth factors, and platelet derived growth factor. Although their exact functions are unclear, ET-1, in conjunction with vascular endothelial growth factor, appears to play a major role in tumor angiogenesis. By a variety of methods, ET-1 alters the balance of osteoblast and osteoclasts to the favor new bone formation that is characteristic of metastatic disease. Several studies indicate that the refractory pain of metastatic cancer is related to the direct nociceptive effects ET-1. These findings suggest that ET receptors are promising therapeutic targets for pharmacologic intervention. Early clinical trials indicate that the ET-A receptor antagonist used in prostate cancer is reasonably well tolerated with mild but pervasive symptoms related to ET-1's vasoconstrictive effects. Results of ongoing clinical trials are eagerly awaited in order to see if the hypothetical promise of ET antagonism will result in clinical success.
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PMID:Endothelin-1 as a target for therapeutic intervention in prostate cancer. 1209 77

Endothelial progenitor cells (EPCs) are detectable in the blood and bone marrow throughout life. These cells contribute to new blood vessel formation (neovascularization) in physiological states such as wound healing and in pathological states such as tumor angiogenesis. We hypothesized that bone marrow-derived EPCs could play a role in the response to pancreatic islet cell injury. We used a murine model of experimentally induced beta-cell injury followed by transplantation with genetically marked bone marrow cells. Bone marrow-derived cells were detectable throughout the pancreas after transplantation. Whereas the total number of bone marrow-derived cells in the pancreas decreased over time, the frequency of endothelial cells (of both donor and recipient origin) increased after transplantation in the animals in which beta-cell injury had been induced. There was no evidence in this model that bone marrow-derived cells differentiated into insulin-expressing cells. This study provides evidence that bone marrow-derived EPCs are recruited to the pancreas in response to islet injury. EPC-mediated neovascularization of the pancreas could in principle be exploited to facilitate the recovery of non-terminally injured beta-cells or to improve the survival and/or function of islet allografts.
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PMID:Recruitment of bone marrow-derived endothelial cells to sites of pancreatic beta-cell injury. 1469 2

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
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PMID:Pleiotropic functions of plasminogen activator inhibitor-1. 1563 64

CD36 is a multiligand receptor associated with a broad array of physiological processes and involved in markedly diverse disorders, including atherosclerosis, insulin resistance and diabetes, dyslipidemia, tumor angiogenesis, and host defense against Plasmodium falciparum. CD36 deficiency has proved to be common, particularly in ethnic groups such as African Americans and Asians. CD36 is commonly expressed on blasts in acute monocytic leukemia, megakaryoblastic leukemia, and erythroleukemia. The role of CD36 in sickle cell crises and cerebral malaria is debatable. As a receptor for thrombospondin 1, CD36 plays a role in the regulation of angiogenesis, which may be a therapeutic strategy for controlling the dissemination of malignant neoplasms. The future challenge will be to further understand the mechanisms by which CD36 affects these diverse functions and to design therapeutic strategies that can alter the course of the diseases.
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PMID:CD36: a multiligand molecule. 1579 May 50

Transforming growth factor-beta (TGF-beta), a key modulator of endothelial cell apoptosis, must be activated from the latent form (LTGF-beta) to induce biological responses. In the present study, we report activation of TGF-beta by functional and physical co-operation of the mannose-6-phosphate/insulin-like-growth-factor-II receptor (CD222) and the urokinase-type plasminogen activator receptor (CD87). We show that endothelial cells express CD222 and CD87 in a membrane complex and demonstrate that the association of these two receptors is essential for the release of active TGF-beta in the transduced mouse fibroblast used as model cells. By contrast, smooth-muscle cells, which express CD222 and CD87 at similar density to endothelial cells but not in complexed form, do not activate TGF-beta. We also have found that mini-plasminogen is a high-affinity ligand for CD222 and is essential for the activation of TGF-beta by the CD87-CD222 complex to induce apoptosis in endothelial cells. This specific mechanism of TGF-beta-mediated apoptosis in endothelial cells is thus a potential novel target to be considered for treatment of pathological vascular disorders (e.g. tumor angiogenesis).
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PMID:TGF-beta-induced apoptosis in endothelial cells mediated by M6P/IGFII-R and mini-plasminogen. 1617 14

Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) are important regulators of angiogenesis. HIF-1 is composed of HIF-1alpha and HIF-1beta subunits, and regulates VEGF expression at transcriptional level. In this study, we demonstrated that insulin induced H2O2 production and p70S6K1 activation in PC-3 prostate cancer cells. The inhibition of H2O2 production by catalase abolished insulin-induced p70S6K1 activation. H2O2 production is also required for insulin-induced VEGF and HIF-1alpha expression in the cells. Over-expression of p70S6K1 or HIF-1alpha reversed catalase- and rapamycin-inhibited VEGF transcriptional activation. These results suggest that insulin induced HIF-1alpha and VEGF expression through H2O2 production and p70S6K1 activation in prostate cancer cells. In addition, we found that inhibition of p70S6K1 by rapamycin decreased prostate tumor angiogenesis, suggesting that p70S6K1 plays an important role in tumor angiogenesis. These results provide some useful information for prostate cancer therapy in the future.
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PMID:Reactive oxygen species regulate insulin-induced VEGF and HIF-1alpha expression through the activation of p70S6K1 in human prostate cancer cells. 1677 40

Many previous reports have demonstrated that systemic administration of endostatin (ES), a proteolytic cleavage product of collagen type XVIII and an endogenous angiogenesis inhibitor, represses tumor angiogenesis in different preclinical tumor models with varying efficacy. For example, systemic delivery of recombinant ES to rat insulin promoter 1 (Rip1)T-antigen 2 (Tag2)-transgenic mice, a mouse model of pancreatic beta-cell carcinogenesis, has repressed tumor angiogenesis efficiently and with it, tumor growth. Here, we report that the transgenic expression of ES in Rip1ES-transgenic mice only interferes moderately with tumor growth in Rip1Tag2;Rip1ES double-transgenic mice. Tumor incidence is not reduced by the local expression of ES, and tumor outgrowth and progression to tumor malignancy are only retarded slightly. A significant effect of local ES expression on tumor angiogenesis is only apparent during the early stages of tumor development, where less angiogenic hyperplastic lesions are observed. Although efficiently produced and secreted by transgenic beta cells, locally expressed ES appears to be sequestered in the microenvironment, and its systemic levels are not increased. The results indicate that the antiangiogenic functions of ES critically depend on the mode of delivery and the site of expression: although its systemic application represses tumor angiogenesis and tumor growth efficiently, locally expressed ES appears to be less effective, and hence, additional mechanisms of solubilization or activation of latent ES seem to be required. These results have important implications about the modes of delivery used in antiangiogenic, therapeutic strategies, which are based on the antiangiogenic activities of ES.
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PMID:Moderate antiangiogenic activity by local, transgenic expression of endostatin in Rip1Tag2 transgenic mice. 1679 8


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