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
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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

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Figure 1

Enhanced tumor growth and angiogenesis in Ifnb1–/– mice.

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Enhanced tumor growth and angiogenesis in Ifnb1–/– mice. (A) Growth ...
(A) Growth and size of tumors are significantly higher in Ifnb1–/– mice. B16F10 melanoma cells were injected s.c. into the abdomen of C57BL/6 or Ifnb1–/– mice, and tumor growth was monitored. At day 14, mice were sacrificed and tumor weight and diameter were measured. Experiments were done with at least 5 animals per group and repeated at least 3 times with similar results. Data represent mean ± SEM. *P ≤ 0.01. (B) The number, the area, and the perimeter of vessels in tumors isolated from Ifnb1–/– mice are significantly higher than in C57BL/6 mice. For histological analysis, material was collected as described in A. 10 μm cryosections were prepared and stained for laminin and actin (SMA). Fully developed vessels (laminin+actin+) were counted and the size of vessels calculated using ImageJ software. Histograms represent data from at least 3 independent experiments with at least 3 mice per group. More than 20 fields of view were analyzed in each experiment. Data represent mean ± SEM. *P ≤ 0.01. (C) B16F10 tumors grown in Ifnb1–/– mice exhibit a higher content of fully developed vessels (laminin+actin+). Histological analysis was done with material collected as described in A, with 10 μm cryosections prepared and stained for laminin (red) and actin (green). Scale bars: 200 μm and 50 μm, respectively. Photographs represent data from at least 3 independent experiments, with at least 3 mice per group.