Hedgehog Signalling Pathway Orchestrates Angiogenesis in Triple-negative Breast Cancers

Overview

Journal Br J Cancer

Specialty Oncology

Date 2017 Apr 26

PMID 28441382

Citations 54

Authors

Concetta Di Mauro

Roberta Rosa

Valentina Damato

Paola Ciciola

Alberto Servetto

Roberta Marciano

Roberta Clara Orsini

Luigi Formisano

Sandro De Falco

Valeria Cicatiello

Maurizio di Bonito

Monica Cantile

Francesca Collina

Angela Chambery

Bianca Maria Veneziani

Sabino De Placido

Roberto Bianco

Affiliations

Soon will be listed here.

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.

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