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.
Highlights
The majority of patients are diagnosed in advanced disease stage
Its levels in plasma of Non-small cell lung cancer (NSCLC) patients correlate with poor prognosis[9] and was recently found as a signaling molecule in exosomes derived from cancer cell lines[10]
epidermal growth factor receptor (EGFR) is bound and activated by a family of seven peptide growth factors among which we focused on Amphiregulin; we observed that CRL-2868 exosomes were enriched in AREG with respect to parental cells (Fig. 1c)
Summary
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Its levels in plasma of NSCLC patients correlate with poor prognosis[9] and was recently found as a signaling molecule in exosomes derived from cancer cell lines[10]. This bone destructive process induces a “vicious cycle” in which growth factors released by the osteoclasts are able to stimulate tumor growth and molecules released by cancer cells in turn enhance the osteoclast differentiation. Our research group demonstrated that exosomes released by multiple myeloma cells are involved in osteoclasts differentiation These exosomes induced the differentiation of murine RAW 264.7 and human primary preosteoclasts in osteoclasts, increasing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix. We observed that NSCLC-exosomes, containing AREG, induced EGFR pathway activation that in turn caused osteoclasts differentiation. AREG knockdown, neutralizing antibodies for AREG and the co-treatment with NSCLC-exosomes and Erlotinib reverted the osteoclast differentiation induced by exosomes
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