ABSTRACT
Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.
Resumo Os tumores cerebrais são uma das causas mais comuns de mortes relacionadas ao câncer em todo o mundo. A angiogênese tem caráter crítico em gliomas malignos de alto grau, como o glioblastoma multiforme. Objetivo: O objetivo deste estudo foi analisar comparativamente os genes relacionados à angiogênese, VEGFA, VEGFB, KDR, CXCL8, CXCR1 e CXCR2 em GBG vs. GBM para identificar distinções moleculares usando conjuntos de dados disponíveis no The Cancer Genome Atlas (TCGA). Métodos: Os dados de sequenciamento de DNA e expressão de mRNA para 514 pacientes com glioma cerebral de baixo grau (GBG) e 592 pacientes com glioblastoma multiforme (GBM) foram adquiridos do TCGA e as alterações genéticas e os níveis de expressão dos genes selecionados foram analisados. Resultados: Identificamos seis mutações KDR distintas nos pacientes GBG e 18 mutações KDR distintas nos pacientes GBM, incluindo mutações missense e nonsense, exclusão de mudança de quadro e região de emenda alterada. Além disso, VEGFA e CXCL8 foram significativamente super-expressos nos pacientes com GBM. Conclusões: VEGFA e CXCL8 são fatores importantes para a angiogênese, os quais parecem ter um papel significativo durante a tumorigênese. Nossos resultados fornecem evidências adicionais de que o VEGFA e o CXCL8 podem induzir a angiogênese e promover o GBG a progredir no GBM. Esses achados podem ser úteis no desenvolvimento de novas abordagens terapêuticas direcionadas no futuro.
Subject(s)
Humans , Brain Neoplasms/genetics , Glioblastoma/genetics , Carcinogenesis/genetics , Glioma/genetics , Neovascularization, Pathologic/genetics , Reference Values , Gene Expression , Interleukin-8/analysis , Point Mutation/genetics , Glioblastoma/pathology , Receptors, Interleukin-8A/analysis , Receptors, Interleukin-8B/analysis , Vascular Endothelial Growth Factor Receptor-2/analysis , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor B/analysis , Glioma/pathologyABSTRACT
O Líquen Plano Oral (LPO) é uma doença mucocutânea mediada imunologicamente, de etiologia desconhecida, relativamente comum, com prevalências, na população mundial, que variam de 0,22 a 5%. O pênfigo vulgar é uma doença autoimue crônica que pode acometer a mucosa oral sendo o mais comum dos tipos de pênfigo. Entretanto, sua ocorrência é rara, com incidência estimada na população geral de um a cinco casos por milhão de pessoas diagnosticadas a cada ano. O VEGF-A é a proteína angiogênica mais potente tanto na angiogênese normal quanto na patológica. O splicing alternativo do éxon 8 do gene do VEGFA dá origem a duas famílias conhecidas de proteínas isofórmicas, uma desempenhando papel angiogênico, VEGFxxxa, e outra um papel antiangiogênico, VEGFxxxb. Este trabalho se propôs a avaliar a expressão imunoistoquímica do VEGF165 (angiogênico), do VEGF165b (antiangiogênico) em 46 casos de LPO reticular, 23 casos de LPO erosivo e 12 casos de PV, usando como controle 11 casos de hiperplasia fibrosa. Todos os espécimes das lesões e os casos controle foram divididos em e zonas para a análise das marcações, em zona superficial (Z1), média (Z2) e profunda (Z3). Os resultados deste experimento foram submetidos a testes estatístico não-paramétricos com nível de significância de 5%. Comparando apenas as lesões para o marcador anti-VEGF165 foram observadas diferenças significativas apenas nas zonas mais profundas entre as lesões de LPO reticular e PV, e entre as lesões de LPO erosivo e PV. Para o marcador anti-VEGF165b diferenças significativas foram observadas nas zonas médias entre as lesões de LPO reticular e PV; e nas zonas profundas entre LPO erosivo e PV e entre LPO reticular e PV. Avaliando o marcador VEGF165b nos espécimes sem categorizá-los por zonas foram observadas diferenças significativas entre as lesões de LPO reticular e PV. Na análise da correlação entre ambos os marcadores em cada lesão foram observadas correlação positiva fraca e significativa nas zonas média e profunda do LPO reticular e na zona superficial do LPO erosivo. Os resultados do presente estudo sugerem a participação do processo angiogênico na patogênese do LPO e na progressão das lesões de líquen plano oral e pênfigo vulgar, porém outros estudos devem ser realizados a fim de que esses achados, principalmente em relação ao pênfigo vulgar seja fundamentado, uma vez que a presente pesquisa é uma das primeiras que avalia a angiogênese na lesão já estabelecida dessa doença (AU).
Oral Lichen Planus is an immunologically mediated mucocutaneous disease of relatively unknown etiology with prevalences in the world population varying from 0.22 to 5%. Pemphigus vulgaris is a chronic autoimmune disease that may affect the oral mucosa being the most common type of pemphigus. However, its occurrence is rare, with an estimated incidence in the general population of one to five cases per million people diagnosed each year. Angiogenesis plays an important role in tumor growth and in the progression of chronic inflammatory diseases. VEGF-A is the most potent angiogenic protein in both normal and pathological angiogenesis. The alternative splicing of exon 8 VEGF-A gene gives rise to two known families of isoform proteins, one playing angiogenic role, VEGFxxxa, and another an antiangiogenic role, VEGFxxxb. The aim of this study was to evaluate the immunohistochemical expression of VEGF165 (angiogenic), VEGF165b (antiangiogenic) in 46 cases of reticular OLP, 23 cases of erosive OLP and 12 cases of PV, using as control 11 cases of fibrous hyperplasia. All specimens of the lesions and the control cases were divided into zones for the analysis of the immunohistochemical stains, in superficial (Z1), medium (Z2) and deep zones (Z3). The results of this experiment were submitted to non-parametric statistical tests with significance level of 5%. For all immunohistochemical stains the comparison between the lesions with the control group (HF) showed significant differences. Comparing only the lesions to the anti-VEGF165 stains, significant differences were observed only in the deeper zones between the reticular LPO lesions X PV; and between erosive LPO lesions X PV. For the anti-VEGF165b stains, significant differences were observed in medium zones between reticular OLP X PV lesions; and in deep zones between erosive LPO X PV and between reticular LPO and PV. And evaluating VEGF165b stains in specimens without categorizing them by zones was observed a significant difference between reticular LPO and PV lesions. In the analysis of the correlation between both markers in each lesion, a weak and significant positive correlation was observed in medium and deep zones of reticular OLP; and a weak positive correlation in superficial zone of erosive LPO. The present study results suggest angiogenic process participation in the pathogenesis and progression of lesions of oral lichen planus and pemphigus vulgaris. However other studies must be carried out in order that this implication, mainly in relation to pemphigus vulgaris be based once this is one of the first studies to evaluate angiogenesis in the already established lesion of this disease (AU).
Subject(s)
Humans , Male , Female , Immunohistochemistry/methods , Pemphigus/pathology , Lichen Planus, Oral/pathology , Neovascularization, Pathologic/pathology , Epidemiology, Descriptive , Statistics, Nonparametric , Angiogenesis Inhibitors , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor B , Angiogenesis Inducing AgentsABSTRACT
The vascular endothelial growth factor (VEGF) family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF), VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF), play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin) and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.
Subject(s)
Animals , Humans , Angiogenesis Inhibitors , Therapeutic Uses , Antibodies, Monoclonal, Humanized , Therapeutic Uses , Bevacizumab , Lymphangiogenesis , Neoplasms , Drug Therapy , Metabolism , Neovascularization, Pathologic , Metabolism , Placenta Growth Factor , Pregnancy Proteins , Metabolism , Receptors, Vascular Endothelial Growth Factor , Metabolism , Signal Transduction , Vascular Endothelial Growth Factor A , Classification , Metabolism , Vascular Endothelial Growth Factor B , Metabolism , Vascular Endothelial Growth Factor C , Metabolism , Vascular Endothelial Growth Factor D , MetabolismABSTRACT
OBJECTIVE: Supplementation with vitamin E is able to protect bone against free radical-induced elevation of bone-resorbing cytokines. We examined gene expression by microarray analysis during the differentiation of human mesenchymal stem cells treated with vitamin E into osteoblasts in vitro. METHODS: Human bone marrow stem cells were cultured in osteogenic differentiation medium and vitamin E was added. A colorimetric immunoassay for the quantification of cell proliferation was used to measure osteoblast differentiation. Gene expression was analyzed using a microarray technique. We also used a real time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: It was found that vitamin E enhanced cell proliferation when compared to cells cultured in media without vitamin E. We focused on 68 genes which are related to osteogenesis and osteoclastogenesis. Alkaline phosphatase, transforming growth factor-beta 1, fibroblast growth factor receptor 1, matrix metalloproteinase 2, muscle segment homeobox 2, bone morphogenetic protein 1, biglycan, vascular endothelial growth factor B, dentin sialophosphoprotein, cartilage oligomeric matrix protein, runt-related transcription factor 2, fibroblast growth factor receptor 3, and SMAD2 were upregulated > 2-fold compared to the control. Conversely, osteopetrosis-associated transmembrane protein 1, microphthalmia-associated transcription factor, and epidermal growth factor receptor were downregulated > 2-fold compared to the control. Vitamin E produced a 1.5-fold increase in the expression of runt-related transcription factor 2 and transforming growth factor-beta 1 as determined by real time RT-PCR. CONCLUSION: Vitamin E had a positive effect on the gene expressions regarding osteogenic differentiation of mesenchymal stem cells.
Subject(s)
Humans , Alkaline Phosphatase , Biglycan , Bone Marrow , Bone Morphogenetic Protein 1 , Cartilage , Cell Proliferation , Cytokines , Dentin , Durapatite , Extracellular Matrix Proteins , Gene Expression , Genes, Homeobox , Glycoproteins , Immunoassay , Matrix Metalloproteinase 2 , Mesenchymal Stem Cells , Microarray Analysis , Microphthalmia-Associated Transcription Factor , Muscles , Osteoblasts , Osteogenesis , Phosphoproteins , ErbB Receptors , Receptor, Fibroblast Growth Factor, Type 1 , Receptor, Fibroblast Growth Factor, Type 3 , Sialoglycoproteins , Stem Cells , Transcription Factors , Vascular Endothelial Growth Factor B , Vitamin E , VitaminsABSTRACT
O linfoma intravascular é forma rara e agressiva de linfoma não Hodgking, caracterizada por infiltração intravascular multissistêmica e consequente disfunção de múltiplos órgãos e sistemas (SDMOS). São descritos pouco mais de 300 casos em todo o mundo. Este relato descreve a evolução de paciente com insuficiência respiratória pós-biópsia de massa retroperitoneal e colecistectomia. Houve piora progressiva, choque refratário e disfunção de múltiplos órgãos. O linfoma não foi identificado à biópsia de imensa massa retroperitoneal, mas pela revisão da lâmina da colecistectomia, com as células tumorais apresentando características de linfoma encontradas dentro de um vaso da vesícula biliar. O estudo imuno-histoquimico revelou o diagnóstico de linfoma intravascular. Houve evolução para o óbito após ser tentado tratamento com metilpredinisolona e hidrocortisona, sem sucesso.(AU)
Intravascular lymphoma is a rare and aggressive form of non-hodgking characterized by multisystemic intravascular infiltration and consequent dysfunction of multiple organs and systems (DMOS). There are today, just over 300 cases reported in the world. Followed the progress of a patient with respiratory failure after biopsy of retroperitoneal mass + cholecystectomy. The patient developed progressively worsened, refractory shock and subsequent multiple organ dysfunction. Interestingly, the lymphoma was not identified in the biopsy of the huge retroperitoneal mass, but the review of the surgical blade, and the tumor cells with features of lymphoma found in a vessel of the gallbladder. Immunohistochemistry revealed intravascular lymphoma. Tried to treatment with methylprednisolone + hydrocortisone, unsuccessfully, with the evolution of patient to death.(AU)
Subject(s)
Humans , Female , Middle Aged , Lymphoma, Non-Hodgkin , Vascular Endothelial Growth Factor B , Multiple Organ Failure , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/drug therapyABSTRACT
Antecedentes: El factor endotelial de crecimiento vascular (VEGF) y su receptor celular VEGFR-2 ya han sido implicados en la via endotelial principal necesaria para la neovascularización tumoral. Aún así, la importancia del sistema VEGF/VEGFR-2 en angiogenesis en tumores hematológicos como la leucemia mieloide aguda (LMA) no ha sido dilucidado. Pacientes y métodos: Evaluación de 32 pacientes con diagnóstico nuevo y no tratado de LMA, mediante inmunohistoquímica de biopsias de médula osea, se hizo comparación con 10 pacientes control. Resultados: La expresión de VEGF y VEGFR-2 fue significantemente mayor en pacientes con mayor grado de densidad microvascular comparado con aquellos con bajo grado (VEGF: p= 0.024; VEGFR-2: p= 0.040) y también mayor que en los controles (P>0.001), mostrando correlación con la densidad microvascular de médula osea. Los pacientes que alcanzaron una remisión completa después de quimioterapia mostraron niveles bajos normales de VEGFR-2. Conclusión: Se encontró evidencia sobre la aumentada expresión de VEGF/VEGFR-2 en blastos leucémicos, así como la correlación con angiogenesis de pacientes con LMA. Esto sugiere que el sistema VEGF/VEGFR-2 puede ser utilizado como objetivo prometedor en las estrategias de terapia antiangiogénica y antileucémica en LMA...
Subject(s)
Humans , Immunohistochemistry/methods , Leukemia, Myeloid, Acute/complications , Neovascularization, Pathologic/diagnosis , Biopsy/methods , Vascular Endothelial Growth Factor BABSTRACT
0.6, P < .05). 2. In the PlGF gene RT-PCR analysis, PlGF expression was more in tumor tissue than in adjacent normal tissue. Paired-samples analysis determined the difference of PlGF mRNA expression level between the cancer tissue and the normal tissue (Student's t - test, P < .05) These findings suggest that up-regulation of the PlGF gene may play a role in progression and local metastasis in invasive oral squamous cell carcinoma.
Subject(s)
Humans , Carcinoma, Squamous Cell , Endothelium, Vascular , Gene Expression , Inflammation , Intercellular Signaling Peptides and Proteins , Ischemia , Neoplasm Metastasis , Placenta , Pregnancy Proteins , RNA, Messenger , Up-Regulation , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor B , Vascular Endothelial Growth Factor C , Vascular Endothelial Growth Factor DABSTRACT
Vascular endothelial growth factor [VEGF] is the most potent directly acting angiogenic growth factor that plays an important role in inducing tumor-associated angiogenesis. The aim of this study was to evaluate the clinical significance of the circulating VEGF in hepatocelluar carcinoma [HCC] and chronic liver disease [CLD]. The study included 13 with chronic viral hepatitis [CVH], 14 with liver cirrhosis [LC] and 13 with HCC, in addition to 15 age and gender- matched healthy subjects as controls. For each studied subject, detection of hepatitis viral markers, and assessment of liver function tests, alpha-fetoprotein [AFP] and VEGF were performed. Results of the study showed a highly significant [p < 0.001] increase of VEGF in sera of HCC patients as compared to other groups. VEGF serum level was significantly [p < 0.01] associated with portal vein thrombosis, however, it was not significantly associated with tumor size. There was no significant difference between the serum level of VEGF among either LC or CVH group compared to the controls. Moreover, no significant difference was detected between different Child-Pugh classes among LC patients. Furthermore, no correlation was found between serum level of VEGF and AFP, serum albumin, aminotransferases or prothrombin time among the studied groups. In conclusion, serum VEGF can be used as a tumor marker for diagnosis of HCC and as a prognostic marker for tumor invasion