Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model
Jadwiga Jablonska, Sara Leschner, Kathrin Westphal, Stefan Lienenklaus, Siegfried Weiss
Jadwiga Jablonska, Sara Leschner, Kathrin Westphal, Stefan Lienenklaus, Siegfried Weiss
View: Text | PDF | Corrigendum
Research Article Angiogenesis

Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model

Abstract

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-β inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-β–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-β restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-β–deficient mice. We therefore suggest that constitutively produced endogenous IFN-β 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.

Authors

Jadwiga Jablonska, Sara Leschner, Kathrin Westphal, Stefan Lienenklaus, Siegfried Weiss

×

Figure 4

Essential role of IFN-β–responsive CD11b+Gr1+ neutrophils in B16F10 tumor growth and angiogenesis.

Options: View larger image (or click on image) Download as PowerPoint
Essential role of IFN-β–responsive CD11b+Gr1+ neutrophils in B16F10 tumo...
CD11b+Gr1+ cells were depleted by treatment with anti-Gr1 Ab, B16F10 cells injected s.c., and after 14 days, mice were sacrificed and tumors were removed, their weight determined, and cryosections stained for confocal microscopy. (A) Reduced tumor growth in mice depleted of CD11b+Gr1+ cells compared with untreated animals. (B and C) Number of developed vessels is reduced after depletion of Gr1+ cells. (D) Enhanced tumor growth depends strictly on type I IFN-reactive CD11b+Gr1+ neutrophils. Mice injected s.c. with B16F10 cells mixed with neutrophils obtained from tumor-bearing Ifnar1–/– mice (Ifnar–/–+B16) show increased tumor development compared with mice injected with neutrophils obtained from tumor-bearing WT mice (C57BL/6+B16) or B16 alone (B16 control). Experiments were carried out twice with at least 5 animals per group. Data represent mean ± SEM. *P ≤ 0.01. Histology shows representative pictures. At least 20 fields of view were analyzed. (E) B16F10 tumors coinjected with neutrophils obtained from tumor-bearing Ifnar1–/– mice (Ifnar–/–+B16) show a higher content of fully developed vessels (actin+laminin+) compared with B16F10 injected together with neutrophils obtained from tumor-bearing control mice (C57BL/6+B16).