| Autor: |
Giulia Bertolini, Orazio Fortunato, Gabriella Sozzi, Chiara Camisaschi, Alessandro De Toma, Francesca Giovinazzo, Monica Tortoreto, Giovanni Centonze, Massimo Moro, Claudio Tripodo, Giuseppe Lo Russo, Luca Roz, Massimo Milione, Nadia Zaffaroni, Stefania Scala, Valeria Cancila, Claudia Chiodoni, Federica Facchinetti, Ugo Pastorino, Crescenzo D'Alterio |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite its ineffectiveness in long-term control of metastasis.Here, we uncover the interconnected pathways subtending cisplatin-induced metastasis promotion.We report that cisplatin treatment of tumor-free mice results in bone-marrow expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) concomitantly with increased levels in the lungs of stromal SDF-1, the CXCR4 ligand. In experimental metastasis assays, cisplatin-induced IM favor tumor cells extravasation and expansion of CD133+CXCR4+ metastasis initiating cells (MICs), facilitating lung metastasis formation. At the primary tumor, cisplatin reduces tumor size but induces tumor release of SDF-1 triggering MICs expansion and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IM at SDF-1-enriched distant sites also promotes spontaneous metastasis. Combination treatment with a CXCR4 inhibitor prevents cisplatin-induced IM/MICs recruitment and interaction thus precluding metastasis overgrowth. Finally, we observe in NSCLC patients’ specimens that SDF-1 levels are higher in platinum-treated samples and correlate with worse outcome.Our findings suggest a possible novel combination therapy based on CXCR4 blockade to control metastatic disease, paradoxically promoted by cisplatin. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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