Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression

Eggert, Tobias; Wolter, Katharina; Ji, Juling; Ma, Chi; Yevsa, Tetyana; Klotz, Sabrina; Medina-Echeverz, José; Longerich, Thomas; Forgues, Marshonna; Reisinger, Florian; Heikenwälder, Mathias; Wang, Xin Wei; Zender, Lars; Greten, Tim F.

doi:10.1016/j.ccell.2016.09.003

Cited by 422 publications

(440 citation statements)

References 40 publications

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“…HCC constitutes one of the most common causes of cancer-related death worldwide [19]. However, the mechanism associated with the development and progression of HCC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

Liu

Rao

Lou

et al. 2017

Cell Physiol Biochem

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Background/Aims: The tripartite motif containing (TRIM) family plays crucial roles in tumor development and progression. However, little is known about the function and mechanism of TRIM11 in hepatocellular carcinoma (HCC). Methods: The expression levels of TRIM11 were examined by real-time PCR, Western blot and Immunohistochemical (IHC) staining. TRIM11 knockdown cells were produced by lentivirus infection, and functional assays, such as MTT, colony formation assay, migration and invasion assays and a xenograft tumor model were used to investigate the role of TRIM11 in HCC. We also determined the effect of TRIM11 on p53 signaling and its downstream molecules. Results: We found that TRIM11 mRNA and protein levels were significantly increased in HCC tissues as compared with normal tissues; increased levels correlated with poor patient survival. By loss-and gain-of-function investigations, knockdown of TRIM11 suppressed cell proliferation, migration, invasion in vitro and tumor growth in vivo. Moreover, TRIM11 negatively regulated p53 expression. Knockdown of p53 abrogated the in vitro and in vivo biological functions of TRIM11 shRNA in HCC cells. Conclusions: These data show that TRIM11 exerts its oncogenic effect in HCC by downregulating p53 both in vitro and in vivo. Our data provide new insights into the pathogenesis of HCC and indicate that TRIM11 may serve as a new therapeutic target for HCC treatment.

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“…HCC constitutes one of the most common causes of cancer-related death worldwide [19]. However, the mechanism associated with the development and progression of HCC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

Liu

Rao

Lou

et al. 2017

Cell Physiol Biochem

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“…Recent studies showed that CCL2 is secreted from oncogene-induced senescent hepatocytes to recruit CCR2+ immature myeloid cells that clear premalignant senescent cells [49, 50] but promote growth of established HCC through inhibition of antitumor T and NK cells [48, 49]. CCL2 can also be produced by resident liver cells as hepatic stellate cells, which have been shown to generate a recurrence-favorable environment by facilitating HCC cell migration upon interaction with monocytes [51].…”

Section: Discussionmentioning

confidence: 99%

Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence

et al. 2018

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Background: The antitumor immune response may play a major role in the clinical outcome of hepatocellular carcinoma (HCC). We characterized the liver immune microenvironment by direct hybridization of RNA extracted from HCC and nontumorous tissues. Methods: RNA was extracted from frozen liver tissue samples of HCC (T; n = 30) and nontumorous tissues (NT; n = 33) obtained from 38 patients. Matched samples were available for 25 patients. The immune gene expression profile was analyzed with the nCounter GX Human Immunology v2 system (NanoString Technologies), which detects the expression levels of 579 immune response-related genes simultaneously. Results: Since the immune gene expression profile of T and NT tissues was significantly different, the prognostic relevance of the liver immune microenvironment was evaluated in the T and NT samples separately. Unsupervised clustering detected two main clusters of immune gene expression both in T and in NT liver samples. In both cases, the expression clusters identified groups of patients with a significantly different median time to HCC recurrence (TTR) but similar overall survival. Based on T tissue, two groups with median TTR of 19 and 127 months, respectively, were detected (p < 0.005). Expression of genes related to T-cell activation was associated with longer TTR. The analysis of NT tissue discriminated subsets of patients with median TTR of 22 and 68 months (p < 0.05). In contrast to T tissue, a predominant inflammatory immune environment was associated with shorter TTR. Conclusions: Immune gene expression profiles predictive of TTR could be identified both in HCC and in adjacent cirrhotic tissues. Longer TTR was associated with overexpression in T tissue and downregulation in NT tissue of the immune response and of inflammation-related genes.

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“…cellular senescence, that has primarily been linked to cancer suppression, can surprisingly also promote growth of neighboring tumor cells in the liver (Eggert, et al, 2016). Senescent hepatocytes accumulate in inflamed livers through activation of oncogenic pathways or DNA damage (Jurk, et al, 2014; Mudbhary, et al, 2014).…”

Section: Effect Of the Tumor Microenvironment On Primary Liver Canmentioning

confidence: 99%

“…However, if full-blown tumor cells arise in livers with senescent hepatocytes, e.g. through bypassing the senescence program or additional senescence-inhibiting oncogenic mutations (Mudbhary, et al, 2014), the nascent tumors secrete factors to impede maturation of senescence-induced monocyte precursors, causing accumulation of immunosuppressive immature myeloid cells that inhibit anti-tumor NK cell responses (Eggert, et al, 2016). The accumulation of these senescence-induced immature myeloid cells is mediated by CCR2.…”

Section: Effect Of the Tumor Microenvironment On Primary Liver Canmentioning

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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Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression

Cited by 422 publications

References 40 publications

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence

Tumor regulation of the tissue environment in the liver

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