EP4 receptor promotes invadopodia and invasion in human breast cancer

Autor: Koen van den Dries, Bojana Gligorijevic, Alessandra Cambi, Felix Tönisen, Louisiane Perrin, Battuya Bayarmagnai
Rok vydání: 2017
Předmět:
0301 basic medicine
Histology
Intravital Microscopy
Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]
Tetrazoles
Breast Neoplasms
Mice
SCID
Biology
Transfection
Article
Dinoprostone
Pathology and Forensic Medicine
Metastasis
03 medical and health sciences
Paracrine signalling
Mice
Cell Line
Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
Epidermal growth factor receptor
Autocrine signalling
Cell Proliferation
Cell Biology
General Medicine
medicine.disease
Pyrrolidinones
Cell biology
ErbB Receptors
Crosstalk (biology)
030104 developmental biology
Invadopodia
Cancer cell
Podosomes
biology.protein
Heterografts
Female
lipids (amino acids
peptides
and proteins)
Signal transduction
Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Receptors
Prostaglandin E
EP4 Subtype
Signal Transduction
Zdroj: European Journal of Cell Biology, 96, 218-226
European Journal of Cell Biology, 96, 2, pp. 218-226
ISSN: 0171-9335
Popis: Item does not contain fulltext The production of Prostaglandin E2 (PGE2) is elevated in human breast cancer cells. The abnormal expression of COX-2, which is involved in the synthesis of PGE2, was recently reported as a critical determinant for invasiveness of human breast cancer cells. Autocrine and paracrine PGE2-mediated stimulation of the PGE2 receptor EP4 transduces multiple signaling pathways leading to diverse patho-physiological effects, including tumor cell invasion and metastasis. It is known that PGE2-induced EP4 activation can transactivate the intracellular signaling pathway of the epidermal growth factor receptor (EGFR). In malignant cancer cells, EGFR pathway activation promotes invadopodia protrusions, which further leads to degradation of the surrounding extracellular matrix (ECM). Despite the known influence of EP4 on the EGFR signaling pathway, the effect of EP4 stimulation on invadopodia formation in human breast cancer was never tested directly. Here we demonstrate the involvement of EP4 in invasion and its effect on invadopodia in breast cancer MDA-MB-231 cells using 2D invadopodia and 3D invasion in vitro assays as well as intravital microscopy. The results show that stimulation with the selective EP4 agonist CAY10598 or PGE2 promotes invadopodia-mediated degradation of the ECM, as well as the invasion of breast cancer cells in in vitro models. The effect on matrix degradation can be abrogated via direct inhibition of EP4 signaling as well as via inhibition of EGFR tyrosine kinase, indicating that EP4-mediated effects on invadopodia-driven degradation are EGFR dependent. Finally, using xenograft mouse models, we show that short-term systemic treatment with CAY10598 results in a >9-fold increase in the number of invadopodia. These findings highlight the importance of further investigation on the role of EP4-EGFR crosstalk in invadopodia formation.
Databáze: OpenAIRE
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