Department of Pathology, Department of Molecular Biology, Moores Cancer Center, University of California San Diego, La Jolla, California; Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pathology, Department of Molecular Biology, Moores Cancer Center, University of California San Diego, La Jolla, California.
Cell Mol Gastroenterol Hepatol. 2023;15(6):1351-1369. doi: 10.1016/j.jcmgh.2023.02.011. Epub 2023 Feb 23.
BACKGROUND & AIMS: Complex communications between hepatocytes and Kupffer cells (KCs) are known to drive or suppress hepatocarcinogenesis, with controversial data in the literature. In previous experiments that aimed to decipher hepatocyte/KC interactions, we unexpectedly unveiled a tumor-suppressing effect of polyinosinic-polycytidylic acid, a widely used inducer of MX dynamin like GTPase 1 (Mx1)-cre expression, which questioned a theory of interleukin 1a/6 cytokine circuit in hepatocyte/KC communication. The goal of this study was to clarify the controversy and decipher unique functions of KCs and non-KC macrophages in liver tumorigenesis.
We used the C-type lectin domain family 4 member F (Clec4f)-cre system to delete Src-homology 2 domain-containing tyrosine phosphatase 2 (Shp2)/protein tyrosine phosphatase nonreceptor 11 (Ptpn11) in KCs, and a combination of Clec4f-cre and adeno-associated virus-cre to delete Shp2 in KCs and hepatocytes to investigate the effects on hepatocellular carcinoma development and immune cell compositions/activities.
Ablating Shp2 in KCs generated a tumor-promoting niche, which was exacerbated further by concurrent removal of Shp2 in both KCs and hepatocytes. Shp2 deficiency induced KC apoptosis and decreased its numbers, which induced compensatory recruitment of bone marrow-derived monocytes into liver. These newly recruited monocytes differentiated into non-KC macrophages with tumor-associated macrophage function, leading to aggravated tumor progression through down-regulation of CD8 T cells. Tumor-associated macrophage blockade by anti-chemokine (C-C motif) ligand 2 (CCL2) antibody inhibited hepatocellular carcinoma progression, while depletion of all macrophages had a tumor-promoting effect by increasing myeloid-derived suppressor cells (M-MDSCs) and decreasing CD8 T cells.
Shp2 loss in KCs or hepatocytes generated a protumorigenic microenvironment, which was exacerbated by its removal in both cell types. These results show the complexity of intercellular signaling events in liver tumorigenesis and raises caution on the use of specific Shp2 inhibitor in liver cancer therapy. Transcript profiling: RNA sequencing data are available at Gene Expression Omnibus (GSE222594).
已知肝细胞与库普弗细胞（KCs）之间的复杂通讯会促进或抑制肝癌的发生，但文献中存在争议数据。在旨在阐明肝细胞/KC 相互作用的先前实验中，我们意外地发现聚肌苷酸-聚胞苷酸（一种广泛用于诱导 MX 动力蛋白样 GTP 酶 1（Mx1）-cre 表达的诱导剂）具有抑制肿瘤的作用，这对白细胞介素 1a/6 细胞因子回路在肝细胞/KC 通讯中的理论提出了质疑。本研究的目的是阐明这一争议，并阐明 KCs 和非 KC 巨噬细胞在肝肿瘤发生中的独特功能。
我们使用 C 型凝集素结构域家族 4 成员 F（Clec4f）-cre 系统在 KCs 中缺失 Src 同源性 2 结构域含酪氨酸磷酸酶 2（Shp2）/蛋白酪氨酸磷酸酶非受体 11（Ptpn11），并用 Clec4f-cre 和腺相关病毒-cre 的组合在 KCs 和肝细胞中缺失 Shp2，以研究其对肝细胞癌发展和免疫细胞组成/活性的影响。
在 KCs 中缺失 Shp2 会产生促肿瘤生境，而在 KCs 和肝细胞中同时缺失 Shp2 则会进一步加剧这种情况。Shp2 缺陷诱导 KC 细胞凋亡并减少其数量，从而诱导骨髓来源的单核细胞代偿性募集到肝脏。这些新募集的单核细胞分化为具有肿瘤相关巨噬细胞功能的非 KC 巨噬细胞，通过下调 CD8 T 细胞导致肿瘤进展加剧。抗趋化因子（C-C 基序）配体 2（CCL2）抗体阻断肿瘤相关巨噬细胞可抑制肝细胞癌的进展，而耗尽所有巨噬细胞则通过增加髓源性抑制细胞（M-MDSCs）和减少 CD8 T 细胞而促进肿瘤生长。
KCs 或肝细胞中 Shp2 的缺失会产生促肿瘤发生的微环境，而在这两种细胞类型中缺失 Shp2 会进一步加剧这种环境。这些结果表明了肝细胞癌发生中细胞间信号事件的复杂性，并对在肝癌治疗中使用特定的 Shp2 抑制剂提出了警告。转录谱：RNA 测序数据可在基因表达综合数据库（GSE222594）中获得。
