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

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the human, malformations of lymphatic vessels can be observed as lymphangiectasia, lymphangioma and lymphangiomatosis, with a prevalence of 1.2-2.8 per thousand. Their aetiology is unknown and a causal therapy does not exist. We investigated the origin of lymphatic endothelial cells (LECs) in avian and murine embryos, and compared the molecular profile of LECs from normal and malformed lymphatics of children. In avian embryos, Prox1+ lymphangioblasts are located in the confluence of the cranial and caudal cardinal veins, where the jugular lymph sac (JLS) forms. Cell lineage studies show that the JLS is of venous origin. In contrast, the lymphatics of the dermis are derived from mesenchymal lymphangioblasts located in the dermatomes, suggesting a dual origin of LECs in avian embryos. The same may hold true for murine embryos, where Lyve1+ LEC precursors are found in the cardinal veins, and in the mesenchyme. The mesenchymal cells express the pan-leukocyte marker CD45, indicating a cell type with lymphendothelial and leukocyte characteristics. In the human, such cells might give rise to Kaposi's sarcoma. Microarray analyses of LECs from lymphangiomas of children show a large number of regulated genes, such as VEGFR3. Our studies show that lymphvasculogenesis and lymphangiogenesis occur simultaneously in the embryo, and suggest a function for VEGFR3 in lymphangiomas.
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PMID:Embryonic development and malformation of lymphatic vessels. 1830 Apr 25

Osteoclasts are bone-resorbing cells, but they also secrete and respond to cytokines. Here, we test the hypothesis that osteoclasts secrete the lymphatic growth factor, VEGF-C, to increase their resorptive activity. Osteoclasts and osteoclast precursors were generated by culturing splenocytes with macrophage colony-stimulating factor and RANKL from wild-type, NF-kappaBp50(-/-)/p52(-/-), and Src(-/-) mice. Expression of VEGFs was measured by real time reverse transcription-PCR, Western blotting, and immunostaining. The effect of VEGF-C signaling on osteoclast function was determined by osteoclastogenesis and pit assays. RANKL increased the expression of VEGF-C but not of other VEGFs in osteoclasts and their precursors. RANKL-induced VEGF-C expression was reduced in NF-kappaBp50(-/-)/p52(-/-) precursors or wild-type cells treated with an NF-kappaB inhibitor. VEGF-C directly stimulated RANKL-mediated bone resorption, which was reduced by the VEGF-C-specific receptor blocker, VEGFR3:Fc. Osteoclasts express VEGFR3, and VEGF-C stimulated Src phosphorylation in osteoclasts. VEGF-C-mediated bone resorption was abolished in Src(-/-) osteoclasts or cells treated with an Src inhibitor. We conclude that RANKL stimulates osteoclasts and their precursors to release VEGF-C through an NF-kappaB-dependent mechanism, indicating that VEGF-C is a new RANKL target gene in osteoclasts and functions as an autocrine factor regulating osteoclast activity.
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PMID:VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. 1835 70

Lymphatic vessels exist in adventitia in the atherosclerotic coronary artery and play an important role in the inflammatory and immune response. After adventitia removal, the carotid wall of rat model showed significantly increased ratio of intimal to medial area (I/M ratio), the number of adventitial lymphatic vessels (Ad-LV) and microvessels (Ad-MV), and macrophage index and expression of VEGF-C, VEGFR-3, PDGF-B and PDGFR-beta. The I/M ratio was significantly correlated with Ad-LV and macrophage index but not Ad-MV. These results suggest that adventitial lymphangiogenesis is stimulated by growth factors released by inflammatory cells in vasculature after adventitia removal, and these neogenetic lymph vessels in turn promote intimal inflammation and hyperplasia, probably via delivery and activation of inflammatory cells.
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PMID:Lymphangiogenesis promotes inflammation and neointimal hyperplasia after adventitia removal in the rat carotid artery. 1838 81

Metastasis is the principal cause of cancer mortality, with the lymphatic system being the first route of tumor dissemination. The glycoproteins VEGF-C and VEGF-D are members of the vascular endothelial growth factor (VEGF) family, whose role has been recently recognized as lymphatic system regulators during embryogenesis and in pathological processes such as inflammation, lymphatic system disorders and malignant tumor metastasis. They are ligands for the VEGFR-3 receptor on the membrane of the lymphatic endothelial cell, resulting in dilatation of existing lymphatic vessels as well as in vegetation of new ones (lymphangiogenesis). Their determination is feasible in the circulating blood by immunoabsorption and in the tissue specimen by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Experimental and clinicopathological studies have linked the VEGF-C, VEGF-D/VEGFR3 axis to lymphatic spread as well as to the clinical outcome in several human solid tumors. The majority of these data are derived from surgical specimens and malignant cell series, rendering their clinical application questionable, due to subjectivity factors and post-treatment quantification. In an effort to overcome these drawbacks, an alternative method of immunodetection of the circulating levels of these molecules has been used in studies on gastric, esophageal and colorectal cancer. Their results denote that quantification of VEGF-C and VEGF-D in blood samples could serve as lymph node metastasis predictive biomarkers and contribute to preoperative staging of gastrointestinal malignancies.
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PMID:Circulating lymphangiogenic growth factors in gastrointestinal solid tumors, could they be of any clinical significance? 1846 54

The phenotypic entities of primary lymphedema vary in age of onset, site of edema, associated features, inheritance patterns, and underlying genetic cause. Determining the representative phenotype for different types of genetically determined primary lymphedema has been successfully achieved with Milroy's disease and the lymphedema-distichiasis syndrome. Here we describe and illustrate their well-delineated phenotypes. Phenotype characterization facilitates the identification of causative genes, as has been demonstrated with VEGFR3 and FOXC2, in Milroy's disease and lymphedema-distichiasis respectively. Other forms of primary lymphedema are discussed.
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PMID:Phenotypic characterization of primary lymphedema. 1851 67

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.
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PMID:Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. 1859 12

Vascular benign lesions are the most common non-hematological splenic primary tumors. Although rare they may sometimes pose problems in differential diagnosis, because of their morphologic heterogeneity. We present vascular lesions of the spleen, which were found in archive of the Chair of Pathomorphology. Immunohistochemistry including CD34, CD31, factor VIII, CD8, CD21, CD68, lysosyme, GLUT-1, D2-40, VEGFR3, SMA, Ki67 were performed. 8 benign vascular lesions were identified, including two hamartomas, two lesions representing sclerosing angiomatoid nodular transformation (SANT) and four hemangiomas. We present briefly the spectrum of vascular lesions occurring in the spleen and discuss differential diagnosis and nosological status of selected lesions.
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PMID:From hamartoma to splenic hemangioma. 1865 69

The human VEGF family consists of VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). The VEGF family of receptors consists of three protein-tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3) and two non-protein kinase co-receptors (neuropilin-1 and neuropilin-2). These components participate in new blood vessel formation from angioblasts (vasculogenesis) and new blood vessel formation from pre-existing vasculature (angiogenesis). Interaction between VEGFR1 and VEGFR2 or VEGFR2 and VEGFR3 alters receptor tyrosine phosphorylation.
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PMID:VEGF receptor protein-tyrosine kinases: structure and regulation. 1868 Jul 22

This study aimed to define the co-expression pattern of target receptor tyrosine kinases (RTKs) in human esophageal adenocarcinoma and squamous cell cancer. The co-expression pattern of vascular endothelial growth factor receptor (VEGFR)1-3, platelet-derived growth factor receptor (PDGFR)alpha/beta and epidermal growth factor receptor 1 (EGFR1) was analyzed by RT-PCR in 50 human esophageal cancers (35 adenocarcinomas and 15 squamous cell cancers). In addition, IHC staining was applied for the confirmation of the expression and analysis of RTK localisation. The adenocarcinoma samples revealed VEGFR1 (97%), VEGFR2 (94%), VEGFR3 (77%), PDGFRalpha (91%), PDGFRbeta (85%) and EGFR1 (97%) expression at different intensities. Ninety-four percent of the esophageal adenocarcinomas expressed at least four out of six RTKs. Similarly, squamous cell cancers revealed VEGFR1 (100%), VEGFR2 (100%), VEGFR3 (53%), PDGFRalpha (100%), PDGFRbeta (87%) and EGFR1 (100%) expression at different intensities. All esophageal squamous cell carcinomas expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRalpha and EGFR1 was expressed by tumor cells, PDGFRbeta was restricted to stromal cells, which also depicted a PDGFRalpha expression. Our results revealed a high rate of RTK co-expression in esophageal adenocarcinoma and squamous cell cancer and may encourage application of multi-target RTK inhibitors within a multimodal concept as a promising novel approach for innovative treatment strategies.
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PMID:Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer. 1881 25

The mechanism of lymphangiogenesis is poorly understood, and controversy exists whether it is part of the inflammatory response to tissue injury. Utilizing markers specific to lymphatics, we aimed to study if lymphangiogenesis plays a role in the tissue response of mucoceles. Twenty-three extravasated mucoceles were selected. They were grouped by using widely accepted histologic criteria of wound healing into early-, intermediate-, and late-phase lesions. To identify lymphatic vessels we used lymphatic endothelium-specific antibodies (VEGFR3, Prospero-related homeobox gene-1 [Prox-1], and D2-40). To assess the proportion of lymphatic channels to all lesional vessels we used the panendothelial marker CD31. The presence, distribution, and proportion of lymphatic channels were assessed and compared among the groups. To investigate the involvement of lymphangiogenic signals, the expression of VEGFC was determined. To assess for proliferative activity of lymphatic endothelial cells we utilized Ki-67 antibody. Early-phase lesions (n = 6) were characterized by the presence of centrally located mucicarmine-positive material (mucin pools) with numerous inflammatory cells dominated by mucin-laden CD163-positive macrophages. Only scattered peripheral thin-walled large and small vessels were seen in the stroma surrounding the central mucin pool. Less than half of these vessels were of lymphatic nature as determined by Prox-1, VEGFR3, and D2-40 positivity. The histology of the intermediate-phase lesions (n = 6) was dominated by numerous lymphatics of varying size, not seen in the early phase. The histology of late-phase lesions (n = 11) resembled a "pseudo-cyst," with dense granulation tissue containing rare macrophages and rare lymphatic vessels. Although VEGFC was present in all phases, the highest expression was in the early phase. Low-grade proliferative lymphatic endothelium was noted in the intermediate lesions with a Ki-67 index of 4%. Early lymphangiogenesis and late lymphatic vessel regression were observed during mucocele evolution. The abundant newly formed ectatic lymphatic vessels seen in the intermediate phase may play a role in the clearance of extravasated material (mucin, edema, and lymph fluid) and in the initiation of the young fibroblast-rich granulation tissue. Mucocele appears to be an excellent human model for studying the factors that play a role in new lymphangiogenesis and regression.
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PMID:Mucocele: a human model for lymphangiogenesis. 1893 25


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