Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis is essential for tumor progression and metastasis, however, the angiogenesis regulators that are biologically relevant for human melanoma are still unknown. In this study, we analyzed the expression of the potent angiogenic factor angiogenin (ANG) in human melanoma in vitro and in vivo. Four different human melanoma cell lines and two normal melanocytes were kept either under normoxic or hypoxic conditions. After 24 h of hypoxic culture conditions, ANG was up-regulated in the melanoma cell lines but not in normal melanocytes. Induction levels correlated with the metastatic potential of the cell lines. These data were confirmed by Northern blot analysis. In contrast, induction of vascular endothelial growth factor by hypoxia was equally strong in the examined highly aggressive melanoma cell lines and in one nonaggressive cell line. Other angiogenic factors tested as well as the melanoma growth stimulatory activity (Gro-alpha) showed no up-regulation. Thus, in the present study, hypoxia-induced up-regulation in melanoma cells was only observed for ANG and vascular endothelial growth factor. Immunohistochemical studies showed that 8 of 10 melanomas and all 15 metastases were positive for ANG, particularly in the vicinity of small vessels, whereas all benign nevi were negative. Reverse transcription-PCR detected only weak ANG mRNA in nevi but strong signals in primary melanomas and metastases. In conclusion, we demonstrate for the first time enhanced expression of ANG in highly metastatic cell lines as well as in melanomas and metastases in vivo, suggesting that ANG expression is associated with the metastatic potential.
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PMID:Hypoxia-induced up-regulation of angiogenin in human malignant melanoma. 1019 32

To investigate the possible role of mast cells (MC) in the angiogenic process in cutaneous melanoma, we examined tissue samples from 35 adult patients with primary malignant melanoma and compared with 20 intradermal benign nevi. MC were identified by anti-tryptase, microvessels by anti-CD34, and vascular endothelial growth factor (VEGF) expression by standard immunohistochemical methods. Tryptase-positive MC expressing VEGF were identified by double immunostaining. The numbers of MC and microvessels around the tumor were determined by the point counting method. MC density was significantly greater in melanoma compared with benign nevi (197.6 +/- 19.4 v 95.7 +/- 5.0/mm2, P < .001). Vascular density was also significantly higher in melanoma than in benign lesions (3.6-fold, P < .001). Double immunostaining showed the presence of VEGF in the cytoplasm of tryptase-positive peritumoral MC. The percentage of this MC-subtype was significantly higher in melanoma than in nevus tissues (71.9 +/- 2.4% v 30.6 +/- 2.5%, P < .001). A strong significant correlation was shown between the number of VEGF+ MC and microvessel density (r = .811, P < .001). MC count and VEGF+ MC count, as well as microvessel density were significantly higher in aggressive (metastasizing) melanomas (P < .001). Our results suggest that peritumoral accumulation of MC and the subsequent release of potent angiogenic factor such as VEGF may thus represent a tumor-host interaction that may favor progression of this tumor.
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PMID:Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. 1098 56

The optimal vector, regulatory sequences, and method of delivery of angiogenic gene therapy are of considerable interest. The Spalax ehrenbergi superspecies live in subterranean burrows at low oxygen tensions and its tissues are highly vascularized. We tested whether continuous perimuscular administration of Spalax vascular endothelial growth factor (VEGF) DNA could increase tissue perfusion in a murine hindlimb ischemia model. Placebo or VEGF +/- internal ribosome entry site (IRES) was continuously administrated perimuscularly in the ischemic zone by using an infusion pump. None of the mice in the VEGF-treated group (>50 microg) developed visible necrosis vs. 33% of the placebo group. Microscopic necrosis was observed only in the placebo group. Spalax VEGF muscular infiltration resulted in a faster and more complete restoration of blood flow. The restoration of blood flow by VEGF was dose-dependent and more robust and rapid when using the VEGF-IRES elements. The flow restoration using continuous perimuscular infiltration was faster than single i.m. injections. Vessel density was higher in the VEGF and VEGF-IRES (-) groups compared with the placebo. Continuous perimuscular administration of angiogenic gene therapy offers a new approach to restore blood flow to an ischemic limb. Incorporation of an IRES element may assist in the expression of transgenes delivered to ischemic tissues. Further studies are needed to determine whether VEGF from the subterranean mole rat Spalax VEGF is superior to VEGF from other species. If so, 40 million years of Spalax evolution underground, including adaptive hypoxia tolerance, may prove important to human angiogenic gene therapy.
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PMID:Restoration of blood flow by using continuous perimuscular infiltration of plasmid DNA encoding subterranean mole rat Spalax ehrenbergi VEGF. 1267 67

Cutaneous ossification may occur in association with a variety of cutaneous neoplasms and inflammatory conditions, such as pilomatricomas, basal cell carcinomas, nevi, chondroid syringomas, venous stasis, and scars. However, it has rarely been reported in pyogenic granuloma, a relatively common benign vascular tumor of the skin and mucous membranes. We herein presented a rare case of cutaneous pyogenic granuloma with ectopic ossification on the big toe of a 37-year-old man, with high recurrence despite repeated CO2 laser ablations. We propose the hypothesis that vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) play pathologic roles in the development of ectopic bone formation in pyogenic granuloma.
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PMID:Metaplastic ossification in a cutaneous pyogenic granuloma: a case report. 1518 28

A peptide analog, 4-fluorobenzoyl-RR-(L-3-(2-naphthyl)alanine)-CYEK-(L-citrulline)-PYR-(L-citrulline)-CR, covalently linked to a phospholipid, was used for targeting a lipid-based gene delivery vehicle to CXCR4(+)-cells. Characterization of transfection activity was done in vitro using a transformed rat glioma cell line (RG2) that expresses CXCR4. The substitution of the targeting lipid at increasing mole percentages in the place of helper lipids yielded a progressive increase in reporter gene expression, reaching a maximum of 2.5 times the control value at 20 mol% of ligand. The substitution of helper lipids with cysteine-derivatized phospholipid analog or phosphatidylethanolamine resulted in a progressive decrease in transfection activity, with complete inactivation of the complex occurring at 20 mol%. A DNA dose-response with 10 mol% of lipopeptide reduced the effective DNA dose at least fivefold with regard to the number of transfected cells and >20-fold with regard to the amount of gene expression. Gene transfer to rat endothelial cells was studied in the context of an arterial organ culture. Mesenteric arteries were cannulated and maintained in culture for up to 4 days. CXCR4 cell-surface expression on endothelial cells was induced after overnight incubation with vascular endothelial growth factor (VEGF). Gene transfer studies showed that only the peptide-targeted lipoplexes transfected the endothelium, and only after CXCR4 had been induced with VEGF. These results demonstrate that non-viral transfection complexes can be targeted to cells expressing CXCR4, and that gene transfer is dependent upon cell surface receptor expression levels.
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PMID:Development of peptide-targeted lipoplexes to CXCR4-expressing rat glioma cells and rat proliferating endothelial cells. 1819 20

Vascular endothelial growth factors (VEGFs) have a leading role among variety of angiogenic factors. Together with their receptors, they play an important role in endothelial cell proliferation and/or elongation, migration and vascular morphogenesis. In order to determine their possible role in malignant melanoma progression, VEGF (representing VEGFA), VEGF-C and VEGFR-1, -2, -3 immunohistochemical expression on formalin-fixed, paraffin-embedded tissue sections were evaluated. A total of 196 tissue samples consisting of 130 malignant melanomas (MM) with various vertical depth of invasion, 15 metastatic melanomas, and 66 nevi including dysplastic nevi and melanocytic nevi were analysed. Production of both VEGFs were common in benign melanocytic tumors while MM exhibited significant upregulation of VEGF (p<0.0027) and VEGF-C (p<0.0001). The proteins were also detected within stromal cells surrounding tumors, particularly in fibrocytes/ fibroblasts, macrophages and endothelial cells. They also exhibited significant increase in malignant lesions (p<0.0001). VEGFRs were localized in tumor, as well in stromal cells. Although expression of VEGF receptors was significantly higher in MM versus nevi (p<0.002 for VEGFR-1, p<0.004 for VEGFR-2 and p<0.0001 for VEGFR-3), a considerable percentage of MM were negative. There were no correlations between sentinel node positivity and all investigated proteins. When clinical outcome was evaluated, progression of the disease positively correlated with VEGF (p<0,007) and VEGF-C (p<0,008) expression VEGF (p<0.001) and VEGF-C (p<0.0001) positively correlated with nestin expression in the capillary endothelium, which was used for angiogenesis detection. Our work demonstrated that upregulation of VEGFs is associated with progression of malignant melanomas. The protein expression in the tumor microenvironment highlights their importance in malignant stromal phenotype which may serve as a potential target for the anticancer therapy.
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PMID:The role of vascular endothelial growth factors and their receptors in malignant melanomas. 1850 36

Angiogenesis is a key process needed for the growth and survival of solid tumors. Anti-angiogenesis may arrest the tumor growth and keep check on cancer metastasis. Developing antiangiogenic agents have remained a significant hope in the mainstream of anticancer research. The free radical implications in the initiation of cancers are well established. In the present studies, simple flavone and flavones with hydroxyl substitution in 'A' and 'C' ring at 3, 5, 6, and 7 were studied for antiangiogenic activities using chorioallantoic membrane (CAM) model and kinetics of DPPH (2,2-diphenyl-1-picryl hydrazine) and superoxide anion radical (SOR) scavenging activities. The docking of selected flavones with specific angiogenic targets such as vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF-1alpha) and vascular endothelial growth factor receptor-2 (VEGFR2) from human origin was carried out to focus the possible underlying mechanism of anti-angiogenesis. The result of the present studies shows that the 3-hydroxy substitution of the flavone was found to be the most promising lead for antiangiogenic activity in CAM model. The same was true for DPPH reduction with greater velocity as compared to other hydroxyl substitutions. However the 7- and 6-hydroxy substitution were observed to be more favourable for SOR scavenging activities as compared to other hydroxyl substitutions. The docking experiments shows that the VEGFR2 seems to be a structurally compatible target for tight binding of the flavones especially with 3-hydroxy substitution (-9.78 kcal/mole) as compared to VEGF (-8.47 kcal/mole) and HIF-1alpha (-8.99 kcal/mole). The quantum chemical descriptors of the test flavones related to free radical scavenging and other biological activities were calculated using computational tools. The data is discussed in the light of structure-activity relationship.
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PMID:Effect of hydroxyl substitution of flavone on angiogenesis and free radical scavenging activities: a structure-activity relationship studies using computational tools. 1987 90

Angiogenesis is required for progression and metastasis of melanoma. Analysis of angiogenic molecules in benign and malignant tissues may allow identification of markers useful for prediction of sensitivity to antiangiogenic agents. We hypothesized that differential expression of vascular endothelial growth factor (VEGF) and its receptors VEGF-R1, VEGF-R2, and VEGF-R3 would be higher in melanomas than nevi and higher in advanced melanoma. Using automated quantitative analysis, we quantified VEGF, -R1, -R2 and -R3 expression in melanoma tissue microarrays composed of 540 nevi and 468 melanoma specimens (198 primaries, 270 metastases). VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 expression was significantly higher in melanomas than nevi by unpaired t tests (P < .0001). VEGF-R2 expression was higher in metastatic specimens (P < .0001), but VEGF-R3 expression was higher in primaries (P < .0001). VEGF was coexpressed with all 3 receptors when assessed by Spearman's rank correlation. VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 expression is higher in melanomas than nevi. Higher expression of VEGF-R2 was found in metastases versus primaries, supporting the idea that selection for an angiogenic phenotype in metastatic melanoma is conferred via up-regulation of VEGF-R2. However, higher expression of VEGF-R3 was seen on primary lesions, potentially implicating this receptor in initiation of lymphatic tumor spread. Clinical trials using antiangiogenic agents in melanoma should include correlative assays of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 as biomarkers of response to therapy, preferably using quantitative methods such as automated quantitative analysis. Such assessments could assist with evaluation of these molecules as therapeutic targets in melanoma, ultimately facilitating improved selection of patients for treatment.
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PMID:Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays. 2000 43

Angiogenesis is critical in melanoma progression and metastasis and relies on the synthesis and release of proangiogenic molecules such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factors (FGFs). S100A13 is a small calcium-binding protein that facilitates the release of FGF-1, the prototype of the FGF family. S100A13 is upregulated in astrocytic gliomas, in which it correlates with VEGF-A expression, microvessel density and tumor grading, and promotes a more aggressive, invasive phenotype in lung cancer-derived cell lines. To investigate the involvement of S100A13 in human cutaneous melanoma, we analyzed a series of 87 cutaneous melanocytic lesions: 14 common acquired melanocytic nevi, 14 atypical, so-called 'dysplastic' nevi, 45 melanomas (17 radial growth phase and 28 vertical growth phase) and 14 melanoma metastases. Main clinical and pathological features, including histotype, Breslow thickness, Clark's level and outcome were recorded. Microvessel density was determined with CD105/endoglin staining. Semiquantitative determination of S100A13, FGF-1 and VEGF-A protein expression was obtained by immunostaining. Quantification of S100A13 mRNA was achieved by real-time PCR. We found that S100A13 was expressed in melanocytic lesions; compared with benign nevi, S100A13 protein expression was significantly upregulated in melanomas (P=0.024), in which it correlated positively with the intensity of VEGF-A staining (P=0.041) and microvessel density (P=0.007). The level of expression of S100A13 mRNA also significantly increased with progression of disease, from radial growth phase (0.7+/-0.7) to vertical growth phase (3.6+/-3.1) to metastases (7.0+/-7.0) (P<0.001). Furthermore, S100A13 mRNA correlated positively with VEGF-A (P=0.023), TNM stage (P=0.05), risk of relapse (P=0.014) and status at follow-up (P=0.024). In conclusion, S100A13 is expressed in melanocytic lesions when the angiogenic switch occurs and it may cooperate with VEGF-A in supporting the formation of new blood vessels, favoring the shift from radial to vertical tumor growth. Therefore, S100A13 may represent a new angiogenic and prognostic marker in melanoma.
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PMID:S100A13 is a new angiogenic marker in human melanoma. 2020 80

Spitz nevi are small dome-shaped nodules that sometimes arise in areas of preexisting hyperpigmentation, such as a speckled lentiginous nevus (nevus spilus), where they present a diagnostic dilemma. We report clinical, histopathological, and molecular findings of two cases of multiple Spitz nevi arising in a speckled lentiginous nevus. We used immunohistochemistry to assess expression of Ki-67, epidermal growth factor receptor, vascular endothelial growth factor, and RelA in two cases of Spitz nevi arising in a speckled lentiginous nevus. We observed rare staining for the proliferative marker Ki-67, but positive staining for the growth and antiapoptotic factors epidermal growth factor receptor, vascular endothelial growth factor, and RelA. Characterization of the molecular phenotype of Spitz nevi arising in speckled lentiginous nevi may provide a useful adjunct to long-term monitoring in this rare but difficult clinical presentation.
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PMID:Spitz nevi arising in speckled lentiginous nevus: clinical, histologic, and molecular evaluation of two cases. 2275 80


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