Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.

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.

• Authors: Concetta Di Mauro, Roberta Rosa, Valentina D'Amato, 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
• Journal: British journal of cancer (Br J Cancer) Vol. 116 Issue 11 Pg. 1425-1435 (May 23 2017) ISSN: 1532-1827 [Electronic] England
• PMID: 28441382 (Publication Type: Journal Article)

Chemical References

• Biphenyl Compounds
• GLI1 protein, human
• Hedgehog Proteins
• Membrane Proteins
• Pyridines
• RNA, Messenger
• Thrombospondin 1
• Vascular Endothelial Growth Factor A
• Zinc Finger Protein GLI1
• thrombospondin-1, human
• sonidegib
• Bevacizumab
• Vascular Endothelial Growth Factor Receptor-2
• Paclitaxel

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (pharmacology)
• Biphenyl Compounds (administration & dosage)
• Cell Proliferation (drug effects)
• Coculture Techniques
• Endothelial Cells (drug effects)
• Female
• Gene Silencing
• Hedgehog Proteins (antagonists & inhibitors, metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• MCF-7 Cells
• Membrane Proteins
• Mice
• Mice, Nude
• Middle Aged
• Neoplasm Transplantation
• Neovascularization, Pathologic (drug therapy, metabolism)
• Paclitaxel (administration & dosage)
• Pyridines (administration & dosage)
• RNA, Messenger (metabolism)
• Signal Transduction
• Thrombospondin 1 (genetics, metabolism)
• Tissue Array Analysis
• Transfection
• Triple Negative Breast Neoplasms (chemistry, drug therapy, metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (analysis, genetics, metabolism)
• Young Adult
• Zinc Finger Protein GLI1 (analysis, genetics, metabolism)