NOTCH Signaling via WNT Regulates the Proliferation of Alternative, CCR2-Independent Tumor-Associated Macrophages in Hepatocellular Carcinoma
NOTCH Signaling via WNT Regulates the Proliferation of Alternative, CCR2-Independent Tumor-Associated Macrophages in Hepatocellular Carcinoma
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NOTCH 信号通过 WNT 调节肝细胞癌中替代的、不依赖 CCR2 的肿瘤相关巨噬细胞的增殖
DOI：
10.1158/0008-5472.can-18-1691
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发表时间：
2019-08-15
期刊：
影响因子：
11.2
通讯作者：
Han, Hua
中科院分区：
文献类型：
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作者：
Ye, Yu-Chen;Zhao, Jun-Long;Han, Hua
肿瘤相关巨噬细胞（TAM）在肿瘤的进展和转移中起着关键作用，但不同巨噬细胞群体的贡献和调节仍不清楚。在这里，我们发现Notch信号在调节肝细胞癌（HCC）中不同的TAM亚群中起着不同的作用。通过重组信号结合蛋白J κ（RBPj cKO）的条件性破坏来阻断骨髓特异性NOTCH可显著延迟皮下接种的刘易斯肺癌（LLC）的生长，但加速原位接种的小鼠肝Hepa 1 -6肿瘤的生长。与皮下LLC相比，RBPj cKO显著增加了肝Hepa 1 -6肿瘤中TAM的数量，尽管阻碍了单核细胞衍生的TAM（moTAM）的分化。原位HCC中占主导地位的TAM表现出Kupffer细胞（KC）的特性，因此暂命名为KC样TAM（kclTAM）。RBPj cKO kclTAM的增殖增加甚至在moTAM被遗传阻断的Ccr（-/-）小鼠中也得以维持。NOTCH信号传导阻断通过增强的β-连环蛋白依赖性WNT信号传导加速kclTAM的增殖，这也可能通过c-MYC下调kclTAM的IL 12和上调IL 10表达。此外，骨髓特异性RBPj cKO促进结直肠癌的肝转移，但抑制小鼠的肺转移，表明RBPj cKO促进肿瘤生长的表型是肝脏特异性的。在患者来源的HCC活检中，NOTCH信号与CD 68（+）巨噬细胞中的WNT活化呈负相关，而CD 68（+）巨噬细胞与晚期HCC分期呈正相关。因此，NOTCH阻断阻碍了moTAMs的分化，但上调Wnt/β-catenin信号，以促进增殖和促肿瘤细胞因子产生的kclTAMs，促进HCC进展和肝转移的结直肠cancer.Significance：这些发现突出了NOTCH和WNT信号在调节TAMs在肝细胞癌中的作用。
Tumor-associated macrophages (TAM) play pivotal roles in tumor progression and metastasis, but the contribution and regulation of different macrophage populations remain unclear. Here we show that Notch signaling plays distinct roles in regulating different TAM subsets in hepatocellular carcinoma (HCC). Myeloid-specific NOTCH blockade by conditional disruption of recombination signal binding protein J kappa (RBPj cKO) significantly delayed the growth of subcutaneously inoculated Lewis lung carcinoma (LLC), but accelerated orthotopically inoculated hepatic Hepa1-6 tumors in mice. In contrast to subcutaneous LLC, RBPj cKO significantly increased the number of TAMs in hepatic Hepa1-6 tumors despite impeded differentiation of monocyte-derived TAMs (moTAM). The dominating TAMs in orthotopic HCC manifested properties of Kupffer cells (KC) and hence are tentatively named KC-like TAMs (kclTAM). The increased proliferation of RBPj cKO kclTAMs was maintained even in Ccr(-/-) mice, in which moTAMs were genetically blocked. NOTCH signaling blockade accelerated proliferation of kclTAMs via enhanced beta-catenin-dependent WNT signaling, which also downregulated IL12 and upregulated IL10 expression by kclTAMs likely through c-MYC. In addition, myeloid-specific RBPj cKO facilitated hepatic metastasis of colorectal cancer but suppressed lung metastasis in mice, suggesting that the phenotype of RBPj cKO in promoting tumor growth was liver-specific. In patient-derived HCC biopsies, NOTCH signaling negatively correlated with WNT activation in CD68(+) macrophages, which positively correlated with advanced HCC stages. Therefore, NOTCH blockade impedes the differentiation of moTAMs, but upregulates Wnt/beta-catenin signaling to promote the proliferation and protumor cytokine production of kclTAMs, facilitating HCC progression and hepatic metastasis of colorectal cancer.Significance: These findings highlight the role of NOTCH and WNT signaling in regulating TAMs in hepatocellular carcinoma.