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Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.
Di Mauro, Concetta; Rosa, Roberta; D'Amato, Valentina; Ciciola, Paola; Servetto, Alberto; Marciano, Roberta; Orsini, Roberta Clara; Formisano, Luigi; De Falco, Sandro; Cicatiello, Valeria; Di Bonito, Maurizio; Cantile, Monica; Collina, Francesca; Chambery, Angela; Veneziani, Bianca Maria; De Placido, Sabino; Bianco, Roberto.
Afiliación
  • Di Mauro C; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • Rosa R; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • D'Amato V; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • Ciciola P; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • Servetto A; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • Marciano R; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • Orsini RC; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • Formisano L; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • De Falco S; Angiogenesis Laboratory, Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso', Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
  • Cicatiello V; Angiogenesis Laboratory, Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso', Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
  • Di Bonito M; Division of Diagnostic Pathology, Department of Diagnostic and Laboratory Pathology, 'Istituto Nazionale Tumori Fondazione Giovanni Pascale-IRCCS', Via Mariano Semmola, Naples, Italy.
  • Cantile M; Division of Diagnostic Pathology, Department of Diagnostic and Laboratory Pathology, 'Istituto Nazionale Tumori Fondazione Giovanni Pascale-IRCCS', Via Mariano Semmola, Naples, Italy.
  • Collina F; Division of Diagnostic Pathology, Department of Diagnostic and Laboratory Pathology, 'Istituto Nazionale Tumori Fondazione Giovanni Pascale-IRCCS', Via Mariano Semmola, Naples, Italy.
  • Chambery A; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy.
  • Veneziani BM; Department of Molecular Medicine and Medical Biotechnologies, University of Naples 'Federico II', Naples, Italy.
  • De Placido S; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • Bianco R; Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
Br J Cancer ; 116(11): 1425-1435, 2017 May 23.
Article en En | MEDLINE | ID: mdl-28441382
BACKGROUND: Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. METHODS: Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice. RESULTS: Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation. CONCLUSIONS: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.
Asunto(s)
Proteínas Hedgehog/metabolismo; Neovascularización Patológica/metabolismo; Transducción de Señal; Neoplasias de la Mama Triple Negativas/metabolismo; Proteína con Dedos de Zinc GLI1/genética; Proteína con Dedos de Zinc GLI1/metabolismo; Adulto; Anciano; Anciano de 80 o más Años; Animales; Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico; Bevacizumab/farmacología; Compuestos de Bifenilo/administración & dosificación; Proliferación Celular/efectos de los fármacos; Técnicas de Cocultivo; Células Endoteliales/efectos de los fármacos; Femenino; Silenciador del Gen; Proteínas Hedgehog/antagonistas & inhibidores; Células Endoteliales de la Vena Umbilical Humana; Humanos; Células MCF-7; Proteínas de la Membrana; Ratones; Ratones Desnudos; Persona de Mediana Edad; Trasplante de Neoplasias; Neovascularización Patológica/tratamiento farmacológico; Paclitaxel/administración & dosificación; Piridinas/administración & dosificación; ARN Mensajero/metabolismo; Trombospondina 1/genética; Trombospondina 1/metabolismo; Análisis de Matrices Tisulares; Transfección; Neoplasias de la Mama Triple Negativas/química; Neoplasias de la Mama Triple Negativas/tratamiento farmacológico; Factor A de Crecimiento Endotelial Vascular/metabolismo; Receptor 2 de Factores de Crecimiento Endotelial Vascular/análisis; Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética; Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo; Adulto Joven; Proteína con Dedos de Zinc GLI1/análisis
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Hedgehog / Neoplasias de la Mama Triple Negativas / Proteína con Dedos de Zinc GLI1 / Neovascularización Patológica Tipo de estudio: Prognostic_studies Límite: Aged80 Idioma: En Revista: Br J Cancer Año: 2017 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Hedgehog / Neoplasias de la Mama Triple Negativas / Proteína con Dedos de Zinc GLI1 / Neovascularización Patológica Tipo de estudio: Prognostic_studies Límite: Aged80 Idioma: En Revista: Br J Cancer Año: 2017 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido