IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis
| Autor: | Sarah Winget, Doris A. Phelps, Amanda J. Saraf, Cheryl A. London, Hakan Cam, Xiaokui Mo, Michael Arnold, John M. Hinckley, Hemant K. Bid, Maren Cam, Ryan D. Roberts, Peter J. Houghton, Amy C. Gross, Laura Brandolini |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Lung Neoplasms Combination therapy Adolescent Primary Cell Culture Drug Evaluation Preclinical Bone Neoplasms Bone and Bones Metastasis Receptors Interleukin-8A 03 medical and health sciences Mice Young Adult 0302 clinical medicine Cell Line Tumor Quinoxalines Antineoplastic Combined Chemotherapy Protocols medicine Cytokine Receptor gp130 Animals Humans Interleukin 8 Interleukin 6 Child Lung Tropism Cell Proliferation Osteosarcoma Sulfonamides biology Interleukin-6 Interleukin-8 Cancer General Medicine medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology medicine.anatomical_structure Hydrazines 030220 oncology & carcinogenesis Cancer research biology.protein Follow-Up Studies Research Article |
| Zdroj: | JCI insight. 3(16) |
| ISSN: | 2379-3708 |
| Popis: | Osteosarcoma (OS), a malignant tumor of bone, kills through aggressive metastatic spread almost exclusively to the lung. Mechanisms driving this tropism for lung tissue remain unknown, though likely invoke specific interactions between tumor cells and other cells within the lung metastatic niche. Aberrant overexpression of ΔNp63 in OS cells directly drives production of IL-6 and CXCL8. All these factors were expressed at higher levels in OS lung metastases than in matched primary tumors from the same patients. Expression in cell lines correlated strongly with lung colonization efficiency in murine xenograft models. Lentivirus-mediated expression endowed poorly metastatic OS cells with increased metastatic capacity. Disruption of IL-6 and CXCL8 signaling using genetic or pharmaceutical inhibitors had minimal effects on tumor cell proliferation in vitro or in vivo, but combination treatment inhibited metastasis across multiple models of metastatic OS. Strong interactions occurred between OS cells and both primary bronchial epithelial cells and bronchial smooth muscle cells that drove feed-forward amplification of IL-6 and CXCL8 production. These results identify IL-6 and CXCL8 as primary mediators of OS lung tropism and suggest pleiotropic, redundant mechanisms by which they might effect metastasis. Combination therapy studies demonstrate proof of concept for targeting these tumor-lung interactions to affect metastatic disease. |
| Databáze: | OpenAIRE |
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