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.

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. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - 116:11(2017), pp. 1425-1435. [10.1038/bjc.2017.116]

Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers

Servetto, Alberto;Formisano, Luigi;VENEZIANI, BIANCA MARIA;De Placido, Sabino;BIANCO, ROBERTO
2017

Abstract

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.
2017
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. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - 116:11(2017), pp. 1425-1435. [10.1038/bjc.2017.116]
File in questo prodotto:
File Dimensione Formato  
bjc2017116a.pdf

accesso aperto

Tipologia: Versione Editoriale (PDF)
Licenza: Dominio pubblico
Dimensione 1.8 MB
Formato Adobe PDF
1.8 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/671874
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 74
  • ???jsp.display-item.citation.isi??? 72
social impact