IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis

JCI Insight. 2018 Aug 23;3(16):e99791. doi: 10.1172/jci.insight.99791.


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.

Keywords: Cancer; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / pathology*
  • Bone and Bones / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Child
  • Cytokine Receptor gp130 / antagonists & inhibitors
  • Cytokine Receptor gp130 / metabolism
  • Drug Evaluation, Preclinical
  • Follow-Up Studies
  • Humans
  • Hydrazines / pharmacology
  • Hydrazines / therapeutic use
  • Interleukin-6 / metabolism*
  • Interleukin-8 / metabolism*
  • Lung / pathology
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Male
  • Mice
  • Osteosarcoma / drug therapy
  • Osteosarcoma / prevention & control
  • Osteosarcoma / secondary
  • Primary Cell Culture
  • Quinoxalines / pharmacology
  • Quinoxalines / therapeutic use
  • Receptors, Interleukin-8A / antagonists & inhibitors
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Xenograft Model Antitumor Assays
  • Young Adult


  • 2'-((4'-trifluoromethanesulfonyloxy)phenyl)-N-methanesulfonylpropionamide
  • CXCL8 protein, human
  • Hydrazines
  • IL6 protein, human
  • IL6ST protein, human
  • Interleukin-6
  • Interleukin-8
  • N'-(7-fluoroH-pyrrolo(1,2-a)quinoxalin-4-yl)pyrazine-2-carbohydrazide
  • Quinoxalines
  • Receptors, Interleukin-8A
  • Sulfonamides
  • Cytokine Receptor gp130