Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0598934 (tumor growth)
58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth of new blood vessels (angiogenesis), required for all tumor growth, is stimulated by the expression of vascular endothelial growth factor (VEGF). VEGF is up-regulated in all known solid tumors but also in atherosclerosis, diabetic retinopathy, arthritis, and many other conditions. Conventional VEGF isoforms have been universally described as proangiogenic cytokines. Here, we show that an endogenous splice variant, VEGF(165)b, is expressed as protein in normal cells and tissues and is circulating in human plasma. We also present evidence for a sister family of presumably inhibitory splice variants. Moreover, these isoforms are down-regulated in prostate cancer. We also show that VEGF(165)b binds VEGF receptor 2 with the same affinity as VEGF(165) but does not activate it or stimulate downstream signaling pathways. Moreover, it prevents VEGF(165)-mediated VEGF receptor 2 phosphorylation and signaling in cultured cells. Furthermore, we show, with two different in vivo angiogenesis models, that VEGF(165)b is not angiogenic and that it inhibits VEGF(165)-mediated angiogenesis in rabbit cornea and rat mesentery. Finally, we show that VEGF(165)b expressing tumors grow significantly more slowly than VEGF(165)-expressing tumors, indicating that a switch in splicing from VEGF(165) to VEGF(165)b can inhibit tumor growth. These results suggest that regulation of VEGF splicing may be a critical switch from an antiangiogenic to a proangiogenic phenotype.
...
PMID:VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. 1552 Jan 88

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of structurally related cytokines. TWEAK acts on responsive cells via binding to a cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production. It has also been reported that TWEAK can stimulate blood vessel formation in the rat cornea angiogenesis assay, but it is presently unknown whether this cytokine could play a role in the pathological angiogenesis associated with human diseases such as cancer, rheumatoid arthritis, and diabetic retinopathy. In the present study we investigated whether TWEAK was expressed in human tumors and whether it could promote tumor growth and angiogenesis in vivo. TWEAK mRNA expression was detected in many tumor types by cDNA array hybridization analysis, and TWEAK protein expression was confirmed in human colon cancer tissue by immunohistochemistry. As an initial approach to address whether TWEAK might act as a tumor angiogenesis factor, we established several human embryonic kidney cell lines that constitutively secrete a soluble TWEAK protein and examined their growth properties in vitro and in vivo. We found that although TWEAK-overexpressing cells do not have a growth advantage in vitro, they form larger and more highly vascularized tumors in athymic mice when compared with control, vector-transfected cells. This result suggests that the TWEAK-Fn14 signaling system may be a potential regulator of human tumorigenesis.
...
PMID:Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. 1560 60

Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Attempts to optimize a cyclin-dependent kinase-1 (CDK1) inhibitor by using palladium-catalyzed C-C bond, C-N bond formation reactions to assemble diverse biheteroaryl molecules led to the unexpected discovery of a pyrazine-pyridine biheteroaryl as a novel series of potent VEGFR-2 inhibitors. Compound 15, which had IC(50) = 0.084 microM at VEGFR-2, showed very modest selectivity against fibroblast growth factor receptor-2 (IC(50) = 0.21 microM), platelet-derived growth factor receptor (IC(50) = 0.36 microM), and glycogen synthase kinase-3 (IC(50) = 0.478 microM), while it exhibited more than 10-fold selectivity against epidermal growth factor receptor (IC(50) = 1.36 microM) and insulin-R kinase (IC(50) = 1.69 microM). On the other hand, compound 15 exhibited more than 100-fold selectivity against calmodulin kinase 2; casein kinase-1 and -2; CDK1 and -4; mitogen-activated protein kinase; and protein kinase A, Cbeta2, and Cgamma (IC(50) >10 microM). Compound 15 also displayed high inhibitory potency on VEGF-stimulated human umbilical vein endothelial cell (HUVEC) proliferation (IC(50) = 0.005 microM) and good selectivity against cell lines such as HUVEC, human aortic smooth muscle cells, and MRC5 lung fibroblasts. Molecular docking studies were conducted in an attempt to rationalize the unexpected high VEGFR-2 selectivity of 15.
...
PMID:Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors. 1577 33

Transketolase proteins or transketolase enzyme activities have been related to neurodegenerative diseases, diabetes, and cancer. Transketolase enzyme variants and reduced transketolase enzyme activities are present in patients with the neurodegenerative disease Wernicke-Korsakoff syndrome. In Alzheimer's disease patients transketolase protein variants with different isoelectric points or a proteolytic cleavage leading to small transketolase protein isoforms have been identified. In diabetes mellitus patients reduced transketolase enzyme activities have been detected and the lipid-soluble thiamine derivative benfotiamine activates transketolase enzyme reactions, thereby blocking three major pathways of hyperglycemic damage and preventing diabetic retinopathy. In cancer inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis. All the observed phenomena have been interpreted solely on the basis of a single transketolase gene (TKT) encoding a single transketolase enzyme. No mutations have been identified so far in TKT transketolase explaining the altered transketolase proteins or transketolase enzyme activities found in neurodegenerative diseases, diabetes and cancer. We demonstrate the presence of a second transketolase enzyme (TKTL1) in humans. During the evolution of the vertebrate genome, mutations in this transketolase gene (TKTL1) have led to tissue-specific transcripts different in size, which encode an enzymatically active transketolase protein as well as different smaller protein isoforms. The mutations within the TKTL1 gene caused a mutant transketolase enzyme with an altered substrate specificity and reaction modus. Here we characterize the TKTL1 gene and its encoded TKTL1 protein(s) and discuss the medical and clinical implications of this mutated transketolase. We furthermore postulate a novel metabolic concept for the understanding, prevention and therapy of neurodegenerative diseases, diabetes and cancer.
...
PMID:Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. 1599 99

Angiogenesis provides a mechanism by which delivery of oxygen and nutrients is adapted to compliment changes in tissue mass or metabolic activity. However, maladaptive angiogenesis is integral to the process of several diseases common in Western countries, including tumor growth, vascular insufficiency, diabetic retinopathy and rheumatoid arthritis. Understanding the process of capillary growth, including the identification and functional analyses of key pro- and anti-angiogenic factors, provides knowledge that can be applied to improve/reverse these pathological states. Initially, angiogenesis research focused predominantly on vascular endothelial growth factor (VEGF) as a main player in the angiogenesis cascade. It is apparent now that participation of multiple angiogenic factors and signal pathways is critical to enable effective growth and maturation of nascent capillaries. The purpose of this review is to focus on recent progress in identifying angiogenesis signaling pathways that show promise as targets for successful induction or inhibition of capillary growth. The strategies applied to achieve these contradictory tasks are discussed within the framework of our existing fundamental knowledge of angiogenesis signaling cascades, with an emphasis on comparing the employment of distinctive tactics in modulation of these pathways. Innovative developments that are presented include: (1) inducing a pleiotropic response via activation or inhibition of angiogenic transcription factors; (2) modulation of nitric oxide tissue concentration; (3) manipulating the kallikrein-kinin system; (4) use of endothelial progenitor cells as a means to either directly contribute to capillary growth or to be used as a vehicle to deliver "suicide genes" to tumor tissue.
...
PMID:Regulators of angiogenesis and strategies for their therapeutic manipulation. 1630 46

Vascular endothelial growth factor (VEGF)-A, a major regulator for angiogenesis, binds and activates two tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). These receptors regulate physiological as well as pathological angiogenesis. VEGFR2 has strong tyrosine kinase activity, and transduces the major signals for angiogenesis. However, unlike other representative tyrosine kinase receptors which use the Ras pathway, VEGFR2 mostly uses the Phospholipase-Cgamma-Protein kinase-C pathway to activate MAP-kinase and DNA synthesis. VEGFR2 is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR2 itself and the signaling appear to be critical targets for the suppression of these diseases. VEGFR1 plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGF-A, and a positive role in adulthood in a tyrosine kinase-dependent manner. VEGFR1 is expressed not only in endothelial cells but also in macrophage-lineage cells, and promotes tumor growth, metastasis, and inflammation. Furthermore, a soluble form of VEGFR1 was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction. Therefore, VEGFR1 is also an important target in the treatment of human diseases. Recently, the VEGFR2-specific ligand VEGF-E (Orf-VEGF) was extensively characterized. Interestingly, the activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGF-A, suggesting VEGF-E to be a novel material for pro-angiogenic therapy.
...
PMID:Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. 1700 66

The process of postnatal angiogenesis plays a crucial role in pathogenesis of numerous diseases, including but not limited to tumor growth/metastasis, diabetic retinopathy, and in tissue remodeling upon injury. However, the molecular events underlying this complex process are not well understood and numerous issues remain controversial, including the regulatory function of integrin receptors. To analyze the role of integrin phosphorylation and signaling in angiogenesis, we generated knock-in mice that express a mutant beta3 integrin unable to undergo tyrosine phosphorylation. Two distinct models of pathological angiogenesis revealed that neovascularization is impaired in mutant beta3 knock-in mice. In an ex vivo angiogenesis assay, mutant beta3 knock-in endothelial cells did not form complete capillaries in response to vascular endothelial growth factor (VEGF) stimulation. At the cellular level, defective tyrosine phosphorylation in mutant beta3 knock-in cells resulted in impaired adhesion, spreading, and migration of endothelial cells. At the molecular level, VEGF stimulated complex formation between VEGF receptor-2 and beta3 integrin in wild-type but not in mutant beta3 knock-in endothelial cells. Moreover, phosphorylation of VEGF receptor-2 was significantly reduced in cells expressing mutant beta3 compared to wild type, leading to impaired integrin activation in these cells. These findings provide novel mechanistic insights into the role of integrin-VEGF axis in pathological angiogenesis.
...
PMID:Integrin signaling is critical for pathological angiogenesis. 1703 Sep 47

The concept of anti-angiogenesis therapy was introduced by Judah Folkman in 1971 and since then, a plethora of pro- and anti-angiogenic factors have been identified. In the recent years, it has become clear that angiogenesis, the formation of new capillaries from a pre-existing capillary network, is highly regulated by the action of pro- and anti-angiogenic factors. In the healthy adult organism the "angiogenic-switch" is likely turned "Off", i. e. anti-angiogenic factors are likely counteracting the pro-angiogenic factors resulting in a non-angiogenic state. Angiogenesis is encountered during wound healing processes, the female menstrual cycle and endometrial remodeling, as well as during embryonic development and organ growth. In the pathological setting, angiogenesis plays an important role in different diseases like rheumatoid arthritis, psoriasis, macular degeneration, diabetic retinopathy, and tumor growth. In this regard, recent studies have described several endogenous inhibitors of angiogenesis, with a subset derived from extracellular matrix (ECM) proteins. This review will particularly focus on the type IV collagen-derived angiogenesis inhibitors Arresten, Canstatin and Tumstatin.
...
PMID:Type IV collagen-derived angiogenesis inhibitors. 1760 10

Antiangiogenic therapy using drugs and food components is a recognized strategy for the prevention of various angiogenesis-mediated disorders such as tumor growth, diabetic retinopathy, and rheumatoid arthritis. Our preliminary cell culture studies, using both bovine aortic endothelial cells and human umbilical vein endothelial cells (HUVEC) on screening for food-derived antiangiogenic compounds, showed tocotrienol (T3), an unsaturated version of vitamin E, to be a potential angiogenic inhibitor. We therefore investigaged the in vivo antiangiogenic properties of T3 using 2 well-characterized angiogenic models [mouse dorsal air sac (DAS) assay and the chick embryo chorioallantoic membrane (CAM) assay]. In the DAS assay, the increased neovascularization (angiogenesis index, 4.8 +/- 0.6) in tumor cell-implanted mice was suppressed (angiogenesis index, 2.7 +/- 0.6) by dietary supplementation of 10 mg T3-rich oil/d (equivalent to 4.4 mg T3/d). In the CAM assay, T3 (500-1000 microg/egg) inhibited new blood vessel formation on the growing CAM and increased the frequency of avascular zone (36-50%). To evaluate the antiangiogenic mechanism, we conducted cell-culture studies and found that T3 significantly reduced fibroblast growth factor -induced proliferation, migration, and tube formation in HUVEC (P < 0.05), with delta-T3 having the highest activity. Western blot analysis revealed that delta-T3 suppressed the phosphorylation of phosophoinositide-dependent protein kinase (PDK) and Akt, and increased the phosphorylation of apoptosis signal-regulating kinase and p38 in fibroblast growth factor-treated HUVEC, indicating that the antiangiogenic effects of T3 are associated with changes in growth factor-dependent phosphatidylinositol-3 kinase /PDK/Akt signaling as well as induction of apoptosis in endothelial cells. Our findings suggest that T3 has potential as a therapeutic dietary supplement for preventing angiogenic disorders, and therefore future clinical study will be required to evaluate the efficacy and safety of T3.
...
PMID:In vivo angiogenesis is suppressed by unsaturated vitamin E, tocotrienol. 1763 67

Angiogenesis is the formation of new blood vessels from pre-existing vessels to form capillary networks, which, among other diseases, such as diabetic retinopathy and macular degeneration, is particularly important for tumor growth and metastasis. Thus, depriving a tumor of its vascular supply by means of anti-angiogenic agents has been of great interest since its proposal in the 1970s. This review looks at the common angiogenic inhibitors (angiostatin, endostatin, maspin, pigment epithelium-derived factor, bevacizumab and other monoclonal antibodies, and zoledronic acid) and their current status in clinical trials.
...
PMID:Angiogenesis inhibitors and the need for anti-angiogenic therapeutics. 1789 Jun 68


<< Previous 1 2 3 4 5 6 Next >>

---