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1.
Cancers (Basel) ; 11(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331081

RESUMO

The term WNT (wingless-type MMTV integration site family) signaling comprises a complex molecular pathway consisting of ligands, receptors, coreceptors, signal transducers and transcriptional modulators with crucial functions during embryonic development, including all aspects of proliferation, morphogenesis and differentiation. Its involvement in cancer biology is well documented. Even though WNT signaling has been divided into mainly three distinct branches in the past, increasing evidence shows that some molecular hubs can act in various branches by exchanging interaction partners. Here we discuss developmental and clinical aspects of WNT signaling in neuroblastoma (NB), an embryonic tumor with an extremely broad clinical spectrum, ranging from spontaneous differentiation to fatal outcome. We discuss implications of WNT molecules in NB onset, progression, and relapse due to chemoresistance. In the light of the still too high number of NB deaths, new pathways must be considered.

2.
BMC Cancer ; 8: 92, 2008 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-18400094

RESUMO

BACKGROUND: Prospero-related homeobox 1 (Prox1) transcription factor was described as a tumor-suppressor gene in liver tumors. In contrast, Prox1 knock out in murine embryos drastically reduces proliferation of hepatoblasts. METHODS: We have studied the expression of Prox1 in normal liver, liver cirrhosis and peritumoral liver samples in comparison to hepatocellular (HCC) and cholangiocellular carcinoma (CCC) at mRNA, protein and functional levels. RESULTS: Prox1 was found in hepatocytes of normal liver, while normal bile duct epithelial cells were negative. However, Prox1+ cells, which co-expressed biliary epithelial makers and showed ductular morphology, could be detected within fibrotic septa of cirrhotic livers, and in both HCC and CCC. Two Prox1 mRNA isoforms (2.9 kb and 7.9 kb) were identified with a prevalence of the longer isoform in several HCC samples and the shorter in most CCC samples. Evidence was provided that Myc-associated zinc finger protein (MAZ) might significantly contribute to the gene expression of Prox1 in HCC, while neo-expression of Prox1 in CCC remains to be resolved. A point mutation in the prospero domain of Prox1 was found in one HCC sample. CONCLUSION: Our study shows dysregulation of Prox1 in liver cirrhosis, HCC and CCC, such as neo-expression in cells with biliary epithelial phenotype in liver cirrhosis, and in CCC. Altered Prox1 mRNA expression is partly regulated by MAZ, and mutation of the prospero domain in HCC indicates an involvement for Prox1 during tumor progression.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/genética , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/genética , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Humanos , Imuno-Histoquímica , Fígado/metabolismo , Cirrose Hepática/genética , RNA Mensageiro/metabolismo
3.
Int J Oncol ; 32(1): 235-40, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18097563

RESUMO

Neuroblastoma is the most frequent solid malignancy of children. The most reliable prognostic factor in neuroblastoma is the amplification status of the MYCN oncogene, but exceptions from this rule have been observed. Recently we have demonstrated that keratoepithelin (BIGH3, TGFBI) expression significantly reduces proliferation and invasion of neuroblastomas in vitro and in vivo. In these experiments, we also observed that tissue factor pathway inhibitor 2 (TFPI2, PP5, MSPI), a potent inhibitor of matrix-metalloproteinases, is most prominently up-regulated. As MYCN-amplified neuroblastomas are highly invasive, we sought to determine the interaction between MYCN, keratoepithelin and TFPI2. In this study we provide initial evidence that i) keratoepithelin expression in neuroblastoma inversely correlates with MYCN expression; ii) TFPI2 expression in neuroblastoma also correlates inversely with MYCN expression but positively with keratoepithelin expression and iii) keratoepithelin induces elevated TFPI2 transcript levels in neuroblastoma cells without alterations of MYCN expression.


Assuntos
Proteínas da Matriz Extracelular/fisiologia , Glicoproteínas/fisiologia , Neuroblastoma/patologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Oncogenes , Fator de Crescimento Transformador beta/fisiologia , Linhagem Celular Tumoral , Amplificação de Genes , Glicoproteínas/genética , Humanos , Proteína Proto-Oncogênica N-Myc , Invasividade Neoplásica , Proteínas Nucleares/fisiologia , Proteínas Oncogênicas/fisiologia
4.
Histochem Cell Biol ; 126(5): 549-62, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16770575

RESUMO

The aim of this study was to analyse the changes of Prospero-related homeobox 1 (Prox1) gene expression in rat liver under different experimental conditions of liver injury, regeneration and acute phase reaction, and to correlate it with that of markers for hepatoblasts, hepatocytes, cholangiocytes and oval cells. Gene expression was studied at RNA level by RT-PCR, and at protein level by immunohistochemistry. At embryonal stage of rat liver development (embryonal days (ED) 14-16) hepatoblasts were found to be Prox1(+)/Cytokeratin (CK) 19(+) and alpha-fetoprotein (AFP)(+), at this stage Prox1(-)/CK19(+)/AFP(-) small cells (early cholangiocytes?) were identified. In fetal liver (ED 18-22) hepatoblasts were Prox1(+)/CK19(-)/AFP(+). CK7(+) cholangiocytes were detected at this stage, and they were Prox1(-)/AFP(-). In the adult liver hepatocytes were Prox1(+)/CK19(-)/CK7(-)/AFP(-), cholangiocytes were CK19(+) and/or CK7(+) and AFP(-)/Prox1(-). In models of liver damage and regeneration Prox1 remained a stable marker of hepatocytes. After 2-acetyl-aminofluorene treatment with partial hepatectomy (AAF/PH) the amount of Prox1 specific transcripts was low in the liver, when CK19 and AFP gene expression was high, and at no time point AFP(+)/CK19(+ )"oval cells" were found to be Prox1(+). However, a few Prox1(+)/CK19(+) and a few Prox1(+)/CK7(+ )cells were identified in the liver of AAF/PH-animals, which may represent precursors of hepatocytes, or a precancerous state.


Assuntos
Hepatócitos/metabolismo , Proteínas de Homeodomínio/metabolismo , Regeneração Hepática/fisiologia , Fígado/embriologia , Proteínas Supressoras de Tumor/metabolismo , 2-Acetilaminofluoreno , Reação de Fase Aguda/metabolismo , Animais , Ductos Biliares/metabolismo , Biomarcadores/metabolismo , Intoxicação por Tetracloreto de Carbono/patologia , Doença Hepática Induzida por Substâncias e Drogas , Células Epiteliais/metabolismo , Feminino , Imuno-Histoquímica , Queratina-19/biossíntese , Queratina-7/biossíntese , Fígado/patologia , Hepatopatias/metabolismo , Masculino , Gravidez , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , alfa-Fetoproteínas/biossíntese
5.
Carcinogenesis ; 26(12): 2105-15, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16051641

RESUMO

Neuroblastoma is the most frequent extracranial solid malignancy of childhood with a high mortality in advanced tumour stages. The hallmark of neuroblastoma is its clinical and biological heterogeneity. The molecular mechanisms leading to favourable or unfavourable tumour behaviour are still speculative. However, amplification of the oncogene MYCN and expression of the neurotrophin receptor TrkB are known to contribute to a highly malignant phenotype. To define the mechanisms through which TrkB may mediate neuroblastoma progression, we stably expressed this receptor in the neuroblastoma cell lines SH-SY5Y and SK-N-AS. The transfectants, but not the controls, had an increased invasive potency both, in vitro and in vivo, as demonstrated by Matrigel-invasion and chorioallantoic membrane assays, respectively. The retinoic acid-induced TrkB expression in parental SH-SY5Y cells was also associated with enhanced cell invasiveness. The TrkB mediated invasiveness involved the upregulation of the hepatocyte growth factor (HGF) and its receptor c-Met, resulting in an autocrine loop. Inhibition of HGF activity by anti-HGF neutralizing antibodies or disabling the function of c-Met by small interfering RNA suppressed the TrkB-induced invasiveness. The enhanced TrkB expression was associated with a significant increase in the secretion of various matrix-degrading proteases. Immunostaining and real-time RT-PCR analysis of tumour specimens demonstrated coordinated expression of TrkB and HGF/c-Met in experimental and primary neuroblastomas. We conclude that TrkB expression in neuroblastoma cells results in an increase in their invasive capability via upregulated expression of HGF/c-Met and enhanced activity of proteolytic networks.


Assuntos
Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor trkB/metabolismo , Animais , Embrião de Galinha , Membrana Corioalantoide/metabolismo , Colágeno/metabolismo , Combinação de Medicamentos , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Fator de Crescimento de Hepatócito/imunologia , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Laminina/metabolismo , Invasividade Neoplásica , Neovascularização Patológica , Neuroblastoma/metabolismo , Fosforilação , Proteoglicanas/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Codorniz , RNA Interferente Pequeno/farmacologia , Receptor trkB/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Tretinoína/farmacologia , Células Tumorais Cultivadas
6.
Cancer Res ; 64(17): 6109-18, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15342394

RESUMO

Neuroblastoma is the most frequent solid childhood malignancy. Despite aggressive therapy, mortality is high due to rapid tumor progression to advanced stages. The molecules and mechanisms underlying poor prognosis are not well understood. Here, we report that cultured human neuroblastoma cells express the hepatocyte growth factor (HGF) and its receptor c-Met. Binding of HGF to c-Met triggers receptor autophosphorylation, indicating functional relevance of this interaction. HGF activates several downstream effectors of c-Met such as the mitogen-activated protein kinases extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 and phospholipase C-gamma, whereas signal transducer and activator of transcription 3 is constitutively activated in neuroblastoma cells expressing c-Met. In addition, HGF is able to stimulate expression and proteolytic activity of matrix metalloproteinase-2 and tissue-type plasminogen activator in neuroblastoma cells, thereby promoting degradation of extracellular matrix components. We show that HGF stimulates invasion of neuroblastoma cells in vitro and in vivo, and it promotes the formation of angiogenic neuroblastomas in vivo. These processes can be blocked by specific inhibitors of the mitogen-activated protein kinase cascade, by inhibitors of phospholipase C-gamma, and also by the expression of a dominant negative signal transducer and activator of transcription 3 mutant. Our data provide the first evidence that the HGF/c-Met pathway is essential for invasiveness and malignant progression of human neuroblastomas. They further suggest that specific inhibitors of this pathway may be suitable as therapeutic agents to improve clinical outcome of neuroblastomas.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Fator de Crescimento de Hepatócito/biossíntese , Humanos , Sistema de Sinalização das MAP Quinases , Metaloproteinase 2 da Matriz/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neuroblastoma/irrigação sanguínea , Neuroblastoma/genética , Fosforilação , Proteínas Proto-Oncogênicas c-met/biossíntese , Fator de Transcrição STAT3 , Ativador de Plasminogênio Tecidual/metabolismo , Transativadores/biossíntese , Transativadores/genética , Transativadores/metabolismo , Transfecção
7.
Dev Dyn ; 230(1): 23-33, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15108306

RESUMO

Biological activities of vascular endothelial growth factor (VEGF) have been studied extensively in endothelial cells (ECs), but few data are available regarding its effects on pericytes. In murine embryoid body cultures, VEGF-induced expression of desmin and alpha-smooth muscle actin (alpha-SMA) in CD-31+ cells. The number of CD-31+/desmin+ vascular chords increased with VEGF treatment time and peaked during a differentiation window between 6 and 9 days after plating. In vivo, VEGF-induced elongation and migration of desmin-positive pericytes and coverage of angiogenic capillaries, as revealed by analysis of Sambucus nigra lectin-stained vascular beds of the chick chorioallantoic membrane. VEGF also caused significant decrease of intercapillary spaces, an indicator for intussusceptive vascular growth. These VEGF-mediated effects point at a more intricate interaction between ECs and pericytes cells than previously demonstrated and suggest that pericytes may be derived from EC progenitors in vitro and not only stabilize capillaries but also participate in vascular remodeling in vivo.


Assuntos
Células Endoteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Neovascularização Patológica , Neovascularização Fisiológica , Pericitos/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Capilares/metabolismo , Capilares/ultraestrutura , Diferenciação Celular , Divisão Celular , Embrião de Galinha , Desmina/biossíntese , Células Endoteliais/citologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Camundongos , Microcirculação , Microscopia Confocal , Microscopia Eletrônica , Pericitos/química , Fatores de Tempo
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