Tumor-infiltrating myeloid cells activate Dll4/Notch/TGF-β signaling to drive malignant progression.
Tumor-infiltrating myeloid cells activate Dll4/Notch/TGF-β signaling to drive malignant progression.
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DOI：
10.1158/0008-5472.can-13-3118
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发表时间：
2014-04-01
期刊：
影响因子：
11.2
通讯作者：
Tosato G
中科院分区：
文献类型：
--
作者：
Ohnuki H;Jiang K;Wang D;Salvucci O;Kwak H;Sánchez-Martín D;Maric D;Tosato G
在肿瘤微环境中协调恶性进展的髓系细胞为攻击实体瘤的通用策略提供了靶标。通过对肿瘤微环境的分析，我们探索了肺癌的实验模型，揭示了Dll4/Notch/TGF-β1信号网络将骨髓细胞与癌症进展联系起来。髓系细胞被肿瘤源性细胞因子CCL2和M-CSF吸引到肿瘤微环境中，表达Notch配体Dll4水平升高，从而激活肿瘤细胞中的Notch信号并放大其固有的Notch激活。肿瘤细胞中Dll4/Notch信号的升高放大了TGF-β诱导的pSMAD2/3信号，这是维持TGF-β诱导的肿瘤细胞生长所必需的。相反，Notch阻断可减少TGF-β信号传导，限制肺癌肿瘤进展。为了证实这些发现，我们对人类头颈部鳞状癌临床标本中肿瘤和邻近正常组织的RNAseq结果进行了询问，发现TGF-β/Notch串扰促进了进展。总之，我们描述的髓细胞-癌信号网络揭示了肿瘤微环境和肿瘤生长之间的新机制联系，突出了靶向该网络活跃的肿瘤的新机会。
Myeloid cells that orchestrate malignant progression in the tumor microenvironment offer targets for a generalized strategy to attack solid tumors. Through an analysis of tumor microenvironments, we explored an experimental model of lung cancer that uncovered a network of Dll4/Notch/TGF-β1 signals that links myeloid cells to cancer progression. Myeloid cells attracted to the tumor microenvironment by the tumor-derived cytokines CCL2 and M-CSF expressed increased levels of the Notch ligand Dll4, thereby activating Notch signaling in the tumor cells and amplifying intrinsic Notch activation there. Heightened Dll4/Notch signaling in tumor cells magnified TGF-β-induced pSMAD2/3 signaling and was required to sustain TGF-β-induced tumor cell growth. Conversely, Notch blockade reduced TGF-β signaling and limited lung carcinoma tumor progression. Corroborating these findings, interrogating RNAseq results from tumor and adjacent normal tissue in clinical specimens of human head and neck squamous carcinoma we found evidence that TGF-β/Notch crosstalk contributed to progression. In summary, the myeloid cell-carcinoma signaling network we describe uncovers novel mechanistic links between the tumor microenvironment and tumor growth, highlighting new opportunities to target tumors where this network is active.