Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model
Jadwiga Jablonska, … , Stefan Lienenklaus, Siegfried Weiss
Jadwiga Jablonska, … , Stefan Lienenklaus, Siegfried Weiss
Published March 8, 2010
Citation Information: J Clin Invest. 2010;120(4):1151-1164. https://doi.org/10.1172/JCI37223.
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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 2

Increased numbers of lung metastases and enhanced Matrigel angiogenesis in Ifnb1–/– mice.

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Increased numbers of lung metastases and enhanced Matrigel angiogenesis ...
(A–C) Increased formation of metastases in lungs of Ifnb1–/– mice. Ifnb1–/– and control mice were injected i.v. with 4 × 105 B16F10 melanoma cells. Mice were sacrificed after 14 days; lungs were removed and analyzed by counting visible B16F10 colonies and determining the weight of the lungs. (A) Number of visible colonies in lungs of Ifnb–/– and C57BL/6 mice. (B) Weight of lungs isolated from Ifnb1–/– and C57BL/6 mice. (C) Macroscopic comparison of lungs with B16F10 colonies from Ifnb1–/– and C57BL/6 mice. (D) In vivo angiogenesis assay shows higher vessel development in plugs isolated from Ifnb1–/– mice. BD Matrigel was injected s.c. into the abdomen of mice. At day 10, plugs were removed and analyzed for hemoglobin content using Drabkin reagent. Experiments were done twice, with at least 5 animals per group. Data represent mean ± SEM. *P ≤ 0.01.