Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.
Angiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-beta inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-beta-deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-beta restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-beta-deficient mice. We therefore suggest that constitutively produced endogenous IFN-beta is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development.
Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany. jja@gbf.de
Jadwiga
J
Jablonska
Sara
S
Leschner
Kathrin
K
Westphal
Stefan
S
Lienenklaus
Siegfried
S
Weiss
D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D005260:Female; D016259:Genes, myc; D016899:Interferon-beta / Q000502:physiology*; D007694:Killer Cells, Natural / Q000502:physiology; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000209:etiology*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology*; D011836:Radiation Tolerance; D050796:STAT3 Transcription Factor / Q000235:genetics
D039481:CD11b Antigen; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016899:Interferon-beta