Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model

Zhao, Wenxiu; Zhang, Lei; Xu, Yan; Zhang, Zhengqi; Ren, Guangli; Tang, Kai; Kuang, Penghao; Zhao, Bixing; Yin, Zhenyu; Wang, Xiaomin

doi:10.1038/labinvest.2013.139

Cited by 93 publications

(64 citation statements)

References 30 publications

(44 reference statements)

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“…(b) HSCs increase the number of MDSCs in the spleen, BM, and tumor tissues of tumor-bearing mice, which is mediated by the COX2-PGE2-EP4 pathway (107, 109). (c) Moreover, cell-cell contact is also important for the reduced immunosurveillance in the presence of activated HSC Monocytes cocultured with HSC LX-2 cells increased the expression of CD14, CCR2, and CD15 on the cell surface and changed cytokine gene expression from an inflammatory to an immunosuppressive signature, namely, upregulating immunosuppressive cytokines and downregulating inflammatory cytokines (53).…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

Affò

Schwabe

2017

Annu. Rev. Pathol. Mech. Dis.

502

425

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Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix—associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.

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Section: Hepatocellular Carcinomamentioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

Affò

Schwabe

2017

Annu. Rev. Pathol. Mech. Dis.

502

425

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“…However, they are also capable of shaping hepatic immune responses (Thomson & Knolle, 2010). In patients with HCC, activated HSC have been reported to induce an immunosuppressive environment and are associated poor clinical outcome (Ji, et al, 2015; W. Zhao, et al, 2014).…”

Section: Cells Of the Hepatic Tumor Environment And Their Regulatimentioning

confidence: 99%

Tumor regulation of the tissue environment in the liver

Eggert

Greten

2017

Pharmacology & Therapeutics

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The tumor microenvironment (TME) in the liver plays an important role in primary and metastatic liver tumor formation and tumor growth promotion. Cellular and non-cellular components of the TME significantly influence tumor development, growth, metastatic spread, anti-tumor immunity and response to tumor therapy. The cellular components of the TME in the liver not only consist of infiltrating immune cells, but also of liver-resident cells such as liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC), which promote tumor growth by negatively regulating tumor-associated immune responses. In this review, we characterize cells of the TME with pro- and anti-tumor function in primary and metastatic liver tumors. Furthermore, we summarize mechanisms that permit growth of hepatic tumors despite the occurrence of spontaneous anti-tumor immune responses and how novel therapeutic approaches targeting the TME could unleash tumor-specific immune responses to improve survival of liver cancer patients.

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“…12 Briefly, orthotopic liver tumor inoculation surgery was carried out with intrahepatic tunnel implantation of tumor tissues from BALB/C nude mice. Anesthesia was performed by peritoneal injection of 60 mg/ kg of 1% sodium pentobarbital.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the Antitumor Efficacy of RNAi-Mediated Inhibition of CDC20 and Heparanase in an Orthotopic Liver Tumor Model

Liu

Yang-de

Liao

et al. 2015

Cancer Biotherapy and Radiopharmaceuticals

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Over 90% of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage. This study investigated the antitumor efficacy of the inhibition of cell division cycle protein 20 (CDC20) and heparanase (HPSE) expression in Hepa1-6 mouse hepatoma cells. Cell viability was measured by the MTT assay. Cell cycle was analyzed by cytometry. The invasion assay was performed using the Transwell chamber. The orthotopic liver tumor model was established by inoculating the livers of immunocompetent Kunming mice with Hepa1-6 cells. The MTT assay showed that 50 and 100 nM CDC20 siRNA-1 and HPSE siRNA-2 significantly reduced Hepa1-6 cell viability with the combination of CDC20 and HPSE siRNA being the most effective. Silencing of CDC20 or both CDC20 and HPSE expression significantly induced G2/M phase cell cycle arrest in Hepa1-6 HCC cells. Silencing HPSE expression significantly inhibited the invasion ability of Hepa1-6 cells with the combination of CDC20 and HPSE silencing being more effective than HPSE alone. Silencing CDC20 and HPSE expression significantly inhibited HCC tumor growth in the orthotopic liver tumor model, but the combination was most effective. Silencing CDC20 and HPSE expression activated cell apoptosis and autophagy. In conclusion, targeting inhibition of both CDC20 and HPSE expression is an ideal strategy for HCC therapy.

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Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model

Cited by 93 publications

References 30 publications

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

Tumor regulation of the tissue environment in the liver

Evaluation of the Antitumor Efficacy of RNAi-Mediated Inhibition of CDC20 and Heparanase in an Orthotopic Liver Tumor Model

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