Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway
Taverna S (1,2), Pucci M (1), Giallombardo M (1), Di Bella MA (1), Santarpia M (3), Reclusa P (4), Gil-Bazo I (5), Rolfo C (6), Alessandro R (7,8).
(1) Biopathology and Biomedical Methodology, Biology and Genetic section, University of Palermo, Palermo, Italy.
(2) Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy.
(3) Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy.
(4) Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp University, Antwerp, Belgium.
(5) Clinica Universidad de Navarra - Center for Applied Medical Research, Pamplona, Spain.
(6) Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp University, Antwerp, Belgium. firstname.lastname@example.org.
(7) Biopathology and Biomedical Methodology, Biology and Genetic section, University of Palermo, Palermo, Italy.
(8) Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy.
Magazine: Scientific Reports
Date: Jan 9, 2017Medical Oncology
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.
CITATION Sci Rep. 2017 Jun 9;7(1):3170. doi: 10.1038/s41598-017-03460-y
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