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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.
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Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.

机译：在小鼠肿瘤模型中，对内源性 IFN-β 有反应的中性粒细胞调节肿瘤血管生成和生长。

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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.
机译：血管生成是恶性肿瘤的标志，因为肿瘤需要形成新的血管才能获得持续生长和转移所必需的氧气和营养物质。然而，导致肿瘤血管化的信号通路尚不完全清楚。在这里，使用可移植的小鼠肿瘤模型，我们已经证明内源性IFN-β通过抑制肿瘤浸润性中性粒细胞中编码促血管生成和归巢因子的基因来抑制肿瘤血管生成。我们确定，与同基因对照小鼠相比，注射 B16F10 黑色素瘤或 MCA205 纤维肉瘤细胞的 IFN-β 缺陷小鼠发育出生长更快的肿瘤，血管发育得更好。这些肿瘤表现出CD11b + Gr1 +中性粒细胞的增强浸润，这些中性粒细胞表达编码促血管生成因子VEGF和MMP9以及归巢受体CXCR4的基因水平升高。它们还表达了更高水平的转录因子 c-myc 和 STAT3，它们是 VEGF、MMP9 和 CXCR4 的已知调节因子。在体外，用低水平的IFN-β治疗这些肿瘤浸润性中性粒细胞可恢复促血管生成因子的表达以控制水平。此外，这些中性粒细胞的消耗抑制了对照组和IFN-β缺陷小鼠的肿瘤生长。因此，我们认为组成型内源性IFN-β是先天性肿瘤监测的重要介质。此外，我们相信我们的数据有助于解释IFN治疗在癌症发展早期阶段的治疗效果。

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