A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer
| Autor: | Ugo Pastorino, Nadia Zaffaroni, Orazio Fortunato, Chiara Camisaschi, Giuliana Pollaci, Francesca Giovinazzo, Valeria Cancila, Giulia Bertolini, Massimo Milione, Massimo Moro, Federica Facchinetti, Monica Tortoreto, Giovanni Centonze, Claudia Chiodoni, Stefania Scala, Gabriella Sozzi, Crescenzo D'Alterio, Alessandro De Toma, Giulia Taiè, Luca Roz, Claudio Tripodo, Giuseppe Lo Russo |
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| Přispěvatelé: | Bertolini G., Cancila V., Milione M., Lo Russo G., Fortunato O., Zaffaroni N., Tortoreto M., Centonze G., Chiodoni C., Facchinetti F., Pollaci G., Taie G., Giovinazzo F., Moro M., Camisaschi C., De Toma A., D'Alterio C., Pastorino U., Tripodo C., Scala S., Sozzi G., Roz L. |
| Rok vydání: | 2020 |
| Předmět: |
Male
Receptors CXCR4 Stromal cell Lung Neoplasms Settore MED/08 - Anatomia Patologica Monocytes Metastasis Mice Carcinoma Non-Small-Cell Lung Cell Line Tumor Drug Discovery Genetics Medicine Settore MED/05 - Patologia Clinica Animals Humans Drug Interactions AC133 Antigen Neoplasm Metastasis Lung cancer Molecular Biology Pharmacology Cisplatin CXCR4 antagonist chemotherapy combination therapy inflammatory monocytes lung cancer stem cells metastasis peptide anti-CXCR4 SDF-1/CXCR4 axis business.industry medicine.disease Primary tumor Xenograft Model Antitumor Assays Extravasation Chemokine CXCL12 medicine.anatomical_structure RAW 264.7 Cells A549 Cells Cancer research Neoplastic Stem Cells Molecular Medicine Bone marrow business Peptides medicine.drug |
| Zdroj: | Molecular therapy : the journal of the American Society of Gene Therapy. 29(10) |
| ISSN: | 1525-0024 |
| Popis: | Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133+CXCR4+ metastasis-initiating cells (MICs). Peptide R, a novel CXCR4 inhibitor designed as an SDF-1 mimetic peptide, prevented cisplatin-induced IM expansion, the recruitment of IMs into the lungs, and the promotion of metastasis. At the primary tumor site, cisplatin treatment reduced tumor size while simultaneously inducing tumor release of SDF-1, MIC expansion, and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IMs to distant SDF-1-enriched sites also promoted spontaneous metastases that were prevented by CXCR4 blockade. In clinical specimens from NSCLC patients SDF-1 levels were found to be higher in platinum-treated samples and related to a worse clinical outcome. Our findings reveal that activation of the CXCR4/SDF-1 axis specifically mediates the pro-metastatic effects of cisplatin and suggest CXCR4 blockade as a possible novel combination strategy to control metastatic disease. |
| Databáze: | OpenAIRE |
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