PMID- 28600504 OWN - NLM STAT- MEDLINE DCOM- 20181228 LR - 20181228 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 7 IP - 1 DP - 2017 Jun 9 TI - Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway. PG - 3170 LID - 10.1038/s41598-017-03460-y [doi] LID - 3170 AB - 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. FAU - Taverna, Simona AU - Taverna S AD - Biopathology and Biomedical Methodology, Biology and Genetic section, University of Palermo, Palermo, Italy. AD - Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy. FAU - Pucci, Marzia AU - Pucci M AD - Biopathology and Biomedical Methodology, Biology and Genetic section, University of Palermo, Palermo, Italy. FAU - Giallombardo, Marco AU - Giallombardo M AD - Biopathology and Biomedical Methodology, Biology and Genetic section, University of Palermo, Palermo, Italy. FAU - Di Bella, Maria Antonietta AU - Di Bella MA AD - Biopathology and Biomedical Methodology, Biology and Genetic section, University of Palermo, Palermo, Italy. FAU - Santarpia, Mariacarmela AU - Santarpia M AD - Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy. FAU - Reclusa, Pablo AU - Reclusa P AD - Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp University, Antwerp, Belgium. FAU - Gil-Bazo, Ignacio AU - Gil-Bazo I AD - Clinica Universidad de Navarra - Center for Applied Medical Research, Pamplona, Spain. FAU - Rolfo, Christian AU - Rolfo C AUID- ORCID: 0000-0002-5109-0267 AD - Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp University, Antwerp, Belgium. christian.rolfo@uza.be. FAU - Alessandro, Riccardo AU - Alessandro R AD - Biopathology and Biomedical Methodology, Biology and Genetic section, University of Palermo, Palermo, Italy. riccardo.alessandro@unipa.it. AD - Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy. riccardo.alessandro@unipa.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170609 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (RANK Ligand) RN - 0 (RNA, Small Interfering) RN - 0 (TNFSF11 protein, human) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Amphiregulin/*genetics/metabolism MH - Animals MH - Biological Transport MH - Bone Neoplasms/*genetics/metabolism/secondary MH - Carcinoma, Non-Small-Cell Lung/*genetics/metabolism/pathology MH - Cell Differentiation MH - Cell Line, Tumor MH - Coculture Techniques MH - ErbB Receptors/genetics/metabolism MH - Exosomes/chemistry/pathology MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/*genetics/metabolism/pathology MH - Mice MH - Osteoclasts/*metabolism/pathology MH - Primary Cell Culture MH - RANK Ligand/genetics/metabolism MH - RAW 264.7 Cells MH - RNA, Small Interfering/genetics/metabolism PMC - PMC5466625 COIS- The authors declare that they have no competing interests. EDAT- 2017/06/11 06:00 MHDA- 2018/12/29 06:00 PMCR- 2017/06/09 CRDT- 2017/06/11 06:00 PHST- 2017/02/21 00:00 [received] PHST- 2017/04/26 00:00 [accepted] PHST- 2017/06/11 06:00 [entrez] PHST- 2017/06/11 06:00 [pubmed] PHST- 2018/12/29 06:00 [medline] PHST- 2017/06/09 00:00 [pmc-release] AID - 10.1038/s41598-017-03460-y [pii] AID - 3460 [pii] AID - 10.1038/s41598-017-03460-y [doi] PST - epublish SO - Sci Rep. 2017 Jun 9;7(1):3170. doi: 10.1038/s41598-017-03460-y.