A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma
A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma
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DOI：
10.1172/jci86443
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发表时间：
2017-05-01
影响因子：
15.9
通讯作者：
Greenfield, Jeffrey
中科院分区：
文献类型：
--
作者：
Huang, Yujie;Rajappa, Prajwal;Greenfield, Jeffrey
肿瘤能够吸收造血细胞以创造合适的微环境来支持恶性生长。在这里，我们已经证明，上调激酶插入结构域受体（KDR），也被称为VEGFR 2，在骨髓细胞亚系是必要的恶性进展的胶质瘤在转基因小鼠模型，并与高级别的肿瘤患者。随着髓源性抑制细胞（MDSC）的积累，髓细胞中KDR表达增加，这与低级别星形细胞瘤向高级别间变性胶质瘤的转化和进展有关。KDR缺陷在小鼠骨髓衍生细胞（BMDCs）抑制髓系分化和减少粒细胞/单核细胞群体。髓源性KDR的耗竭损害了其促血管生成功能，这抑制了低级别至高级别肿瘤恶性进展所必需的血管生成转换。我们还鉴定了DNA结合蛋白2（ID 2）抑制剂作为髓样分化期间KDR活化的关键上游调节剂。BMDC中ID 2的缺乏导致KDR的下调、促血管生成骨髓细胞的抑制和低级别向高级别转变的阻止。肿瘤分泌的TGF-β和粒细胞-巨噬细胞CSF（GM-CSF）增强BMDC中的KDR/ID 2信号传导轴。我们的研究结果表明，KDR/ID 2信号的调制可能会限制肿瘤相关的骨髓细胞，并可能成为一种潜在的治疗策略，以防止转化的癌前胶质瘤。
Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/ monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-beta and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.