Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model
Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model
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DOI：
10.1172/jci37223
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Weiss, Siegfried
中科院分区：
文献类型：
--
作者：
Jablonska, Jadwiga;Leschner, Sara;Weiss, Siegfried
血管生成是恶性肿瘤的标志，因为新血管的形成是肿瘤获得其持续生长和转移所必需的氧气和营养物质所必需的。然而，导致肿瘤血管化的信号通路尚未完全了解。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抑制肿瘤血管生成，通过抑制基因编码的促血管生成和归巢因子在肿瘤浸润中性粒细胞。我们确定，与同基因对照小鼠相比，注射B16 F10黑色素瘤或MCA 205纤维肉瘤细胞的IFN-β缺陷小鼠生长更快，血管发育更好。这些肿瘤表现出CD 11b（+）Gr 1（+）中性粒细胞浸润增强，这些中性粒细胞表达高水平的编码促血管生成因子VEGF和MMP 9以及归巢受体CXCR 4的基因。它们还表达了更高水平的转录因子c-myc和STAT 3，它们是VEGF、MMP 9和CXCR 4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，使促血管生成因子的表达恢复到对照水平。此外，这些中性粒细胞的耗竭抑制了对照和IFN-β缺陷小鼠中的肿瘤生长。因此，我们认为，组成性产生的内源性IFN-β是先天性肿瘤监视的重要介质。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。
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.