Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway
Abstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. The majority of patients are diagnosed in advanced disease stage. Bone metastasis is the most frequent complication in NSCLC resulting in osteolytic lesions. The perfect balance between bone-res...
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doaj-db6a33130d004cc092b9ee22df28e4be2020-12-08T01:31:35ZengNature Publishing GroupScientific Reports2045-23222017-06-017111410.1038/s41598-017-03460-yAmphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathwaySimona Taverna0Marzia Pucci1Marco Giallombardo2Maria Antonietta Di Bella3Mariacarmela Santarpia4Pablo Reclusa5Ignacio Gil-Bazo6Christian Rolfo7Riccardo Alessandro8Biopathology and Biomedical Methodology, Biology and Genetic section, University of PalermoBiopathology and Biomedical Methodology, Biology and Genetic section, University of PalermoBiopathology and Biomedical Methodology, Biology and Genetic section, University of PalermoBiopathology and Biomedical Methodology, Biology and Genetic section, University of PalermoMedical Oncology Unit, Department of Human Pathology “G. Barresi”, University of MessinaPhase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp UniversityClinica Universidad de Navarra – Center for Applied Medical ResearchPhase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp UniversityBiopathology and Biomedical Methodology, Biology and Genetic section, University of PalermoAbstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. The majority of patients are diagnosed in advanced disease stage. Bone metastasis is the most frequent complication in NSCLC resulting in osteolytic lesions. The perfect balance between bone-resorbing osteoclasts and bone-forming osteoblasts activity is lost in bone metastasis, inducing osteoclastogenesis. In NSCLC, the epidermal growth factor receptor (EGFR) pathway is constitutively activated. EGFR binds Amphiregulin (AREG) that is overexpressed in several cancers such as colon, breast and lung. Its levels in plasma of NSCLC patients correlate with poor prognosis and AREG was recently found as a signaling molecule in exosomes derived from cancer cell lines. Exosomes have a key role in the cell-cell communication and they were recently indicated as important actors in metastatic niche preparation. In the present work, we hypothesize a role of AREG carried by exosomes derived from NSCLC in bone metastasis induction. We observed that NSCLC-exosomes, containing AREG, induce EGFR pathway activation in pre-osteoclasts that in turn causes an increased expression of RANKL. RANKL is able to induce the expression of proteolytic enzymes, well-known markers of osteoclastogenesis, triggering a vicious cycle in osteolytic bone metastasis.https://doi.org/10.1038/s41598-017-03460-y |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Simona Taverna Marzia Pucci Marco Giallombardo Maria Antonietta Di Bella Mariacarmela Santarpia Pablo Reclusa Ignacio Gil-Bazo Christian Rolfo Riccardo Alessandro |
spellingShingle |
Simona Taverna Marzia Pucci Marco Giallombardo Maria Antonietta Di Bella Mariacarmela Santarpia Pablo Reclusa Ignacio Gil-Bazo Christian Rolfo Riccardo Alessandro Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway Scientific Reports |
author_facet |
Simona Taverna Marzia Pucci Marco Giallombardo Maria Antonietta Di Bella Mariacarmela Santarpia Pablo Reclusa Ignacio Gil-Bazo Christian Rolfo Riccardo Alessandro |
author_sort |
Simona Taverna |
title |
Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway |
title_short |
Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway |
title_full |
Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway |
title_fullStr |
Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway |
title_full_unstemmed |
Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway |
title_sort |
amphiregulin contained in nsclc-exosomes induces osteoclast differentiation through the activation of egfr pathway |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-06-01 |
description |
Abstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. The majority of patients are diagnosed in advanced disease stage. Bone metastasis is the most frequent complication in NSCLC resulting in osteolytic lesions. The perfect balance between bone-resorbing osteoclasts and bone-forming osteoblasts activity is lost in bone metastasis, inducing osteoclastogenesis. In NSCLC, the epidermal growth factor receptor (EGFR) pathway is constitutively activated. EGFR binds Amphiregulin (AREG) that is overexpressed in several cancers such as colon, breast and lung. Its levels in plasma of NSCLC patients correlate with poor prognosis and AREG was recently found as a signaling molecule in exosomes derived from cancer cell lines. Exosomes have a key role in the cell-cell communication and they were recently indicated as important actors in metastatic niche preparation. In the present work, we hypothesize a role of AREG carried by exosomes derived from NSCLC in bone metastasis induction. We observed that NSCLC-exosomes, containing AREG, induce EGFR pathway activation in pre-osteoclasts that in turn causes an increased expression of RANKL. RANKL is able to induce the expression of proteolytic enzymes, well-known markers of osteoclastogenesis, triggering a vicious cycle in osteolytic bone metastasis. |
url |
https://doi.org/10.1038/s41598-017-03460-y |
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