Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway

Maria Antonietta Di Bella, Simona Taverna, Riccardo Alessandro, Marzia Pucci, Marco Giallombardo, Pablo Reclusa Asiain, Mariacarmela Santarpia, Ignacio Gil-Bazo, Simona Taverna, Pablo Reclusa, Christian Rolfo, Riccardo Alessandro

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3170-
Number of pages14
JournalScientific Reports
Volume7
Publication statusPublished - 2017

All Science Journal Classification (ASJC) codes

  • General

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