Peritumoral monocytes induce cancer cell autophagy to facilitate the progression of human hepatocellular carcinoma

Chen, Dongping; Wang, Ning; Li, Xuefeng; Yuan, Wei; Lao, Xiang-Ming; Wang, Juncheng; Wu, Yan; Zheng, Limin

doi:10.1080/15548627.2018.1474994

Cited by 55 publications

(40 citation statements)

References 55 publications

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“…Subsequent IHC staining for LC3 (Fig. A), a marker for autophagy, revealed similar levels of LC3 between VETC + and VETC – HCCs (Figure B). Compared to VETC – patients, VETC + patients achieved significantly more OS benefit from sorafenib therapy in both low LC3 (VETC + vs. VETC – : HR = 0.498 vs. 1.005; P interaction < 0.001; Fig.…”

Section: Resultsmentioning

confidence: 73%

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma

Fang

Shang

et al. 2019

Hepatology

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Sorafenib is the most recommended first‐line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC‐mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+/VETC–) was investigated. Kaplan‐Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio [HR] = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC‐ patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+, but not VETC–, patients. Further mechanistic investigations showed that VETC+ and VETC– HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal‐regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC‐pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC– irrespective of levels of pERK/EC‐pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC– HCCs may not result from activation of Raf/mitogen‐activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+, but not VETC–, patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.

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Section: Resultsmentioning

confidence: 73%

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma

Fang

Shang

et al. 2019

Hepatology

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“…Immunoblotting was performed as previously described. 32 Protein was extracted using a protein extraction kit (Thermo Fisher, Cat#89900) according to the manufacturer's instructions. SDS-PAGE was used to separate an equal amount of cellular proteins.…”

Section: Immunoblottingmentioning

confidence: 99%

“…17,[24][25][26][27][28][29][30] For example, our previous studies showed that tumoractivated monocytes (Mos)/Mφs secrete cytokines, such as TNFα, IL-1β and IL-6, to enhance tumor cell autophagy and angiogenesis in HCC. 31,32 Given the critical role of Mos/Mφs in regulating tumor progression, we speculated that it would, in turn, influence the phagocytic signaling on tumor cells, thus resulting in impaired phagocytic clearance of the tumor.…”

Section: Introductionmentioning

confidence: 99%

Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients

Chen

Zheng

et al. 2019

OncoImmunology

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CD47 is known to be involved in phagocyte-mediated tumor clearance; however, its expression, clinical significance, and regulatory mechanism in hepatocellular carcinoma (HCC) remain poorly understood. In the present study, we found that upregulation of CD47 expression on tumor cells was correlated with poor overall survival and recurrence-free survival in patients with HCC. Abundance of macrophages (Mφs) infiltration was found in CD47 + tumor tissues. Mechanistic studies revealed that IL-6 derived from tumorinfiltrating Mφs could upregulate CD47 expression on hepatoma cells through activation of the STAT3 pathway. Neutralization of CD47 or disruption of the IL-6-STAT3 axis reduced the ability of tumor cells to escape phagocytosis. Moreover, CD47 blockade could enhance Mφ-mediated phagocytosis in the presence of chemotherapeutic drugs, and HCC patients with lower CD47 expression were more likely to benefit from adjuvant transcatheter arterial chemoembolization (TACE) treatment. These findings revealed that Mφderived IL-6 was responsible for CD47 expression on hepatoma cells, which might be served as a potential prognostic marker and a predictor for patients who might benefit from adjuvant TACE treatment.

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“…In addition, the invasion of peripheral areas by HCC tumors has been associated with higher levels of autophagy in HCC cancer cells [10]. Autophagy promotes HCC cell proliferation through the induction intracellular ATP via mitochondrial oxidative phosphorylation [11].…”

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confidence: 99%

Identification of an Autophagy-Related Gene Signature that Can Improve Prognosis of Hepatocellular Carcinoma Patients

Huo

Huang

et al. 2020

Preprint

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Background: Autophagy is a programmed cell degradation mechanism that has been associated with several physiological and pathophysiological processes, including malignancy. Improper induction of autophagy has been proposed to play a pivotal role in the progression of hepatocellular carcinoma (HCC).Methods: Univariate Cox regression analysis of overall survival (OS) was performed to identify risk-associated autophagy-related genes (ARGs) in HCC data set from The Cancer Genome Atlas (TCGA). Multivariate cox regression was then performed to develop a risk prediction model for the prognosis of 370 HCC patients. The multi-target receiver operating characteristic (ROC) curve was used to determine the model’s accuracy. Besides, the relationship between drug sensitivity and ARGs expression was also examined. Results: A total of 62 differentially expressed ARGs were identified in HCC patients. Univariate and multivariate regression identified five risk-associated ARGs ( HDAC1, RHEB , ATIC, SPNS1 and SQSTM1 ) that were correlated with OS in HCC patients. Of importance, the risk-associated ARGs were independent risk factor s in the multivariate risk model including clinical parameters such as malignant stage (HR=1.433, 95% CI=1.293-1.589, P<0.001). In addition, the area under curve for the prognostic risk model was 0.747, which indicates the high accuracy of the model in prediction of HCC outcomes. Interestingly, the risk-associated ARGs were also correlated with drug sensitivity in HCC cell lines.Conclusions: We developed a novel prognostic risk model by integrating the molecular signature and clinical parameters of HCC, which can effectively predict the outcomes of HCC patients.

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Peritumoral monocytes induce cancer cell autophagy to facilitate the progression of human hepatocellular carcinoma

Cited by 55 publications

References 55 publications

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma

Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients

Identification of an Autophagy-Related Gene Signature that Can Improve Prognosis of Hepatocellular Carcinoma Patients

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