1. Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.
- Author
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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, and Bianco, Roberto
- 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. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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