Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummary
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-su...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X23000309 |
| _version_ | 1797843884264390656 |
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| author | Li Du Yichun Ji Bing Xin Jiemeng Zhang Li-Chun Lu Christopher K. Glass Gen-Sheng Feng |
| author_facet | Li Du Yichun Ji Bing Xin Jiemeng Zhang Li-Chun Lu Christopher K. Glass Gen-Sheng Feng |
| author_sort | Li Du |
| collection | DOAJ |
| description | 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. Methods: 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. Results: 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. Conclusions: 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). |
| first_indexed | 2024-04-09T17:13:19Z |
| format | Article |
| id | doaj.art-fbf22ff817e64ceaaa6b4a6e3a01135f |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-09T17:13:19Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-fbf22ff817e64ceaaa6b4a6e3a01135f2023-04-20T04:36:43ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2023-01-0115613511369Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummaryLi Du0Yichun Ji1Bing Xin2Jiemeng Zhang3Li-Chun Lu4Christopher K. Glass5Gen-Sheng Feng6Department 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, ChinaDepartment of Pathology, Department of Molecular Biology, Moores Cancer Center, University of California San Diego, La Jolla, CaliforniaDepartment of Pathology, Department of Molecular Biology, Moores Cancer Center, University of California San Diego, La Jolla, CaliforniaDepartment of Pathology, Department of Molecular Biology, Moores Cancer Center, University of California San Diego, La Jolla, CaliforniaDepartment of Pathology, Department of Molecular Biology, Moores Cancer Center, University of California San Diego, La Jolla, California; Department of Oncology, National Taiwan University Hospital, Taipei, TaiwanDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CaliforniaDepartment of Pathology, Department of Molecular Biology, Moores Cancer Center, University of California San Diego, La Jolla, California; Correspondence Address correspondence to: Gen-Sheng Feng, PhD, Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0864.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. Methods: 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. Results: 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. Conclusions: 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).http://www.sciencedirect.com/science/article/pii/S2352345X23000309Hepatocyte/Kupffer Cell CommunicationHepatocarcinogenesisTumor-Associated MacrophagesTumor Microenvironment |
| spellingShingle | Li Du Yichun Ji Bing Xin Jiemeng Zhang Li-Chun Lu Christopher K. Glass Gen-Sheng Feng Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummary Cellular and Molecular Gastroenterology and Hepatology Hepatocyte/Kupffer Cell Communication Hepatocarcinogenesis Tumor-Associated Macrophages Tumor Microenvironment |
| title | Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummary |
| title_full | Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummary |
| title_fullStr | Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummary |
| title_full_unstemmed | Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummary |
| title_short | Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer MacrophagesSummary |
| title_sort | shp2 deficiency in kupffer cells and hepatocytes aggravates hepatocarcinogenesis by recruiting non kupffer macrophagessummary |
| topic | Hepatocyte/Kupffer Cell Communication Hepatocarcinogenesis Tumor-Associated Macrophages Tumor Microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X23000309 |
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