Journal
BRITISH JOURNAL OF CANCER
Volume 116, Issue 11, Pages 1425-1435Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2017.116
Keywords
hedgehog; GLI1; angiogenesis; TNBC; NVP-LDE225
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator Grant [IG-15388]
- AIRC Investigator Grant [IG-11420]
- EU Horizon (TRANSCAN-2, project BeFIT)
- Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO)
- Dottorato di Ricerca (PhD) in Terapie Avanzate Biomediche e Chirurgiche
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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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