Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We developed and evaluated an in vivo athymic nude mouse model for tumor growth, angiogenesis, metastasis, and antineoplastic drug development. Melanoma cell lines expressing beta-galactosidase encoded by the Escherichia coli lac Z gene have been created by infecting an immortal murine melanocyte cell line with a recombinant retrovirus expressing the v-Ha-ras oncogene and lac Z to generate the MRB (melanoma, ras, beta-galactosidase) cell lines. The amelanotic, phorbol ester-independent, transformed melanoma cell lines developed tumors rapidly when injected subcutaneously into nude mice, as well as experimental lung metastases when injected i.v. into the tail vein. beta-galactosidase-expressing subcutaneous tumors and lung metastases stained blue with X-gal. The melanomas produced in nude mice have been characterized by using various histochemical and immunohistochemical staining methods to detect melanoma- and endothelial-cell-specific markers to determine the extent of neovascularization in MRB nude mouse tumors. Optimal staining of endothelial cells involved in tumor angiogenesis was observed by using ADPase activity and antiangiotensin-converting enzyme antibody staining. Attempts at indirect quantification of metastatic tumor cell number within the lung by either beta-galactosidase enzymatic activity or ELISA immunoreactivity were unsuccessful. However, the MRB cell lines should be useful in screening for and studying the mechanisms of action of antineoplastic, antimetastatic, and angiostatic drugs in vivo in athymic nude mice.
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PMID:Evaluation of a nude mouse tumor model using beta-galactosidase-expressing melanoma cells. 768 92

2-Methoxyestradiol (2ME) is an endogenous metabolite of estradiol (E2) and is known to inhibit tumor angiogenesis. In the present study, the direct effects of 2ME on the vascular endothelial cells were examined. 2ME enhanced apoptosis and beta-galactosidase expression in bovine vascular endothelial cells. A nitric oxide (NO) donor S-nitroso-N-acetyl penicillamin (SNAP) also enhanced beta-galactosidase expression, suggesting a possible role of NO in mediating the action of 2ME. 2ME increased the cellular content of nitric oxide synthase (NOS) and the production of NO. In addition, 2ME altered the membrane localization pattern of NOS. These suggest that the effects of 2ME on apoptosis and senescence of vascular endothelial cells were mediated, at least partly, by NOS and NO.
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PMID:2-Methoxyestradiol, an endogenous metabolite of estrogen, enhances apoptosis and beta-galactosidase expression in vascular endothelial cells. 967 76

Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor-deficient (AT1a-/-) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a-/- mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the beta-galactosidase gene was inserted into the AT1a gene locus in AT1a-/- mice, the site of beta-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a-/- mice, the major site of the beta-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a-/- mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo.
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PMID:Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. 1284 60

Vascular endothelial growth factor (VEGF) is known to play a predominant role in tumor angiogenesis and metastasis formation that is mediated by its interactions with two tyrosine kinase receptors, VEGFRI (Flt-1) and VEGFRII (KDR). Inhibition of VEGF-dependent events in tumor tissues is known to enhance apoptosis and to suppress tumor growth. A novel peptide, SP5.2, which selectively binds Flt-1 and inhibits a broad range of VEGF-mediated events, was identified using a phage-display library screening. The fluorescein-labeled SP5.2 specifically bound to VEGF-stimulated primary human cerebral endothelial cells (HCECs), whereas non-stimulated HCECs, as well as human neuroblastoma cells (ShyY) did not show any interaction with the peptide. SP5.2 prevented proliferation of cultured primary human umbilical vein endothelial cells induced by recombinant human VEGF165 with an IC50 of 5 microm. SP5.2 was also shown to antagonize VEGF- and PLGF-induced, but not basic fibroblast growth factor-induced proliferation of HCECs. In contrast to "scrambled" peptide, SP5.2 was also found to selectively inhibit VEGF-stimulated migration of HCECs. The in vitro analysis of antiangiogenic activity of SP5.2 using a capillary-like tube formation assay showed that VEGF-induced angiogenesis of HCECs grown on Matrigel was completely inhibited in the presence of 10 microm SP5.2. Further studies demonstrated that SP5.2 prevented VEGF-induced permeability increase in HCECs monolayers. To explore whether SP5.2 can be used as a targeting agent, chemical and recombinant conjugates of SP5.2 with reporter proteins (peroxidase and beta-galactosidase) were produced. The resulting products showed significant increases (200-fold for SP5.2-beta-gal and 400-fold for SP5.2-peroxidase) in binding affinity to recombinant Flt-1 compared with the original synthetic SP5.2, suggesting that conjugate with therapeutic activity in nanomolar range could potentially be developed based on SP5.2 structure.
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PMID:A vascular endothelial growth factor high affinity receptor 1-specific peptide with antiangiogenic activity identified using a phage display peptide library. 1295 24

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin (ENG) in HHT1 and activin receptor-like kinase 1 (ACVRL1; ALK1) in HHT2. Although both genes are involved in the transforming growth factor beta signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 (Alk1lacZ) by replacing its exons, including the one that encodes the transmembrane domain, with the beta-galactosidase gene. Using Alk1lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis. We also show that hemodynamic changes, which require vascular remodeling, may regulate Alk1 expression. Our studies suggest the role of Alk1 signaling in arterialization and remodeling of arteries. Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling.
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PMID:Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. 1297 Jan 15

Until recently, it was generally accepted that the vascularization of solid tumors occurred exclusively through the sprouting and co-option from pre-existing blood vessels. Growing evidence now suggests that bone marrow-derived endothelial progenitor cells (EP) circulate in the blood and may play an important role in the formation of new blood vessels in certain tumors. Whether endothelial progenitors participate in the vascularization of brain tumors has not yet been evaluated. In this study, we examined the contribution of EP to tumor angiogenesis in a murine glioma tumor model. Donor bone marrow cells obtained from transgenic mice constitutively expressing beta-galactosidase or GFP either ubiquitously or transcriptionally regulated by an endothelial specific promotor Tie-2 were injected into lethally irradiated adult mice. After bone marrow reconstitution by donor cells, mice were implanted with syngeneic GL261 murine glioma cells. Morphological and confocal 3-dimensional analysis showed that the majority of the engrafted donor marrow cells were expressing hematopoietic and/or microglia markers, but did not appreciably contribute to the tumor vasculature. Implantation of glioma cells genetically engineered to overexpress VEGF produced highly vascularized tumors. However, the number of endothelial progenitors incorporated in the tumor vasculature did not increase. These data strongly suggest that neovascularization in the brain might fundamentally be regulated by the sprouting of pre-existing vessels and implicate that circulating endothelial progenitors do not play a significant role in this process.
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PMID:Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. 1465 62