Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers

  • Br J Cancer. 2017 May 23;116(11):1425-1435. doi: 10.1038/bjc.2017.116.
Concetta Di Mauro  1 ,  Roberta Rosa  1 ,  Valentina D'Amato  1 ,  Paola Ciciola  1 ,  Alberto Servetto  1 ,  Roberta Marciano  1 ,  Roberta Clara Orsini  1 ,  Luigi Formisano  1 ,  Sandro De Falco  2 ,  Valeria Cicatiello  2 ,  Maurizio Di Bonito  3 ,  Monica Cantile  3 ,  Francesca Collina  3 ,  Angela Chambery  4 ,  Bianca Maria Veneziani  5 ,  Sabino De Placido  1 ,  Roberto Bianco  1
Affiliations
  • 1. Department of Clinical Medicine and Surgery, University of Naples 'Federico II', Naples, Italy.
  • 2. Angiogenesis Laboratory, Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso', Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
  • 3. Division of Diagnostic Pathology, Department of Diagnostic and Laboratory Pathology, 'Istituto Nazionale Tumori Fondazione Giovanni Pascale-IRCCS', Via Mariano Semmola, Naples, Italy.
  • 4. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy.
  • 5. Department of Molecular Medicine and Medical Biotechnologies, University of Naples 'Federico II', Naples, Italy.
PMID: 28441382 DOI: 10.1038/bjc.2017.116
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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