Acquisition of glutamine synthetase expression in human hepatocarcinogenesis

Osada, Takuya; Sakamoto, Michiie; Nagawa, Hirokazu; Yamamoto, Junji; Matsuno, Yoshihiro; Iwamatsu, Akihiro; Muto, Tetsuichiro; Hirohashi, Setsuo

doi:10.1002/(sici)1097-0142(19990215)85:4<819::aid-cncr9>3.0.co;2-e

Cited by 52 publications

(6 citation statements)

References 56 publications

(38 reference statements)

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“…With the positive staining of Hep Par 1 in 75-90% of HCC specimens, Hep Par 1 appears to be a specific protein, which is unique to HCC [116]. Another protein GS was also observed more frequently in HCC samples than non-HCC samples [117], and its expression was shown to be increased in advanced HCC patients and was associated with shorter relapse-free survival [118]. As hypothesized, a pilot study reported that 37 out of 42 (88.1%) HCC patients tested positive for GPC3, Hep Par1, and GS in CTCs, whereas all five non-HCC subjects tested negative.…”

Section: Hepatocyte-specific Markers Of Ctcs In Hccmentioning

confidence: 86%

The Significance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma: Real-Time Monitoring and Moving Targets for Cancer Therapy

Chen

Zhong

Tan

et al. 2020

Cancers

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Hepatocellular carcinoma (HCC) is ranked as the sixth most common cancer around the world. With the emergence of the state-of-the-art modalities lately, such as liver transplantation, image-guided ablation, and chemoembolization, the death rate is still high due to high metastasis rate after therapy. Observation by biannual ultrasonography allows effective diagnosis at an early stage for candidates with no extrahepatic metastasis, but its effectiveness still remains unsatisfactory. Developing a new test with improved effectiveness and specificity is urgently needed for HCC diagnosis, especially for patients after first line therapy. Circulating tumor cells (CTCs) are a small sub-population of tumor cells in human peripheral blood, they release from the primary tumor and invade into the blood circulatory system, thereby residing into the distal tissues and survive. As CTCs have specific and aggressive properties, they can evade from immune defenses, induce gene alterations, and modulate signal transductions. Ultimately, CTCs can manipulate tumor behaviors and patient reactions to anti-tumor treatment. Given the fact that in HCC blood is present around the immediate vicinity of the tumor, which allows thousands of CTCs to release into the blood circulation daily, so CTCs are considered to be the main cause for HCC occurrence, and are also a pivotal factor for HCC prognosis. In this review, we highlight the characteristics and enrichment strategies of CTCs, and focus on the use of CTCs for tumor evaluation and management in patients with HCC.

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Section: Hepatocyte-specific Markers Of Ctcs In Hccmentioning

confidence: 86%

The Significance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma: Real-Time Monitoring and Moving Targets for Cancer Therapy

Chen

Zhong

Tan

et al. 2020

Cancers

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“…In the mammalian liver, GS catalyzes the synthesis of glutamine from glutamate and ammonia, and thus provides a source of energy for tumor cells. Immunohistochemical analysis has shown a stepwise increase of GS expression from precancerous lesions to early and advanced HCC [20]. GS-positive malignant cells are derived from GS-positive hepatocytes, suggesting that GS is a specific marker for tracing cell lineage during the process of hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

The SGLT2 Inhibitor Canagliflozin Prevents Carcinogenesis in a Mouse Model of Diabetes and Non-Alcoholic Steatohepatitis-Related Hepatocarcinogenesis: Association with SGLT2 Expression in Hepatocellular Carcinoma

Jojima

Wakamatsu

Kase

et al. 2019

IJMS

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The aim of the present study is to investigate the effects of canagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, on non-alcoholic steatohepatitis (NASH) and NASH-related hepatocellular carcinoma (HCC) in a mouse model of diabetes and NASH-HCC. First, mice aged five weeks were divided into two groups (vehicle group and canagliflozin group) and were treated for three weeks. Then, mice aged five weeks were divided into three groups of nine animals each: the vehicle group, early canagliflozin group (treated from five to nine weeks), and continuous canagliflozin group (treated from five to 16 weeks). Canagliflozin was administered at a dose of 30 mg/kg in these experiments. In addition, the in vitro effects of canagliflozin were investigated using HepG2 cells, a human HCC cell line. At the age of eight or 16 weeks, the histological non-alcoholic fatty liver disease activity score was lower in the canagliflozin-treated mice than in vehicle-treated mice. There were significantly fewer hepatic tumors in the continuous canagliflozin group than in the vehicle group. Immunohistochemistry showed significantly fewer glutamine synthetase-positive nodules in the continuous canagliflozin group than in the vehicle group. Expression of α-fetoprotein mRNA, a marker of HCC, was downregulated in the continuous canagliflozin group when compared with the vehicle group. At 16 weeks, there was diffuse SGLT1 expression in the hepatic lobules and strong expression by hepatocytes in the vehicle group, while SGLT2 expression was stronger in liver tumors than in the lobules. In the in vitro study, canagliflozin (10 μM) suppressed the proliferation of HepG2 cells. Flow cytometry showed that canagliflozin reduced the percentage of HepG2 cells in the G2/M phase due to arrest in the G1 phase along with decreased expression of cyclin D and Cdk4 proteins, while it increased the percentage of cells in the G0/1 phase. Canagliflozin also induced apoptosis of HepG2 cells via activation of caspase 3. In this mouse model of diabetes and NASH/HCC, canagliflozin showed anti-steatotic and anti-inflammatory effects that attenuated the development of NASH and prevented the progression of NASH to HCC, partly due to the induction of cell cycle arrest and/or apoptosis as well as the reduction of tumor growth through the direct inhibition of SGLT2 in tumor cells.

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“…Activating mutations of the beta-catenin gene and overexpression of gs are frequent pathogenetic events in hcc 52,53 . A stepwise increase in gs immunoreactivity is observed from hgdn to early hcc and thence to advanced hcc 54 . Specificity is increased when immunostaining is diffuse with strong intensity 55 .…”

Section: Pathologymentioning

confidence: 93%

Multidisciplinary Canadian consensus recommendations for the management and treatment of hepatocellular carcinoma

et al. 2011

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Globally, hepatocellular carcinoma (hcc) is the third most common cause of death from cancer, after lung and stomach cancer. The incidence of hcc in Canada is increasing and is expected to continue to increase over the next decade. Given the high mortality rate associated with hcc, steps are required to mitigate the impact of the disease. To address this challenging situation, a panel of 17 hcc experts, representing gastroenterologists, hepatologists, hepatobiliary surgeons, medical oncologists, pathologists, and radiologists from across Canada, convened to provide a framework that, using an evidence-based approach, will assist clinicians in optimizing the management and treatment of hcc. The recommendations, summarized here, were developed based on a rigorous methodology in a pre-specified process that was overseen by the steering committee. Specific topics were identified by the steering committee and delegated to a group of content experts within the expert panel, who then systematically reviewed the literature on that topic and drafted the related content and recommendations. The set of recommendations for each topic were reviewed and assigned a level of evidence and grade according to the levels of evidence set out by the Centre for Evidence-based Medicine, Oxford, United Kingdom. Agreement on the level of evidence for each recommendation was achieved by consensus. Consensus was defined as agreement by a two-thirds majority of the 17 members of the expert panel. Recommendations were subject to iterative review and modification by the expert panel until consensus could be achieved.

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Acquisition of glutamine synthetase expression in human hepatocarcinogenesis

Cited by 52 publications

References 56 publications

The Significance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma: Real-Time Monitoring and Moving Targets for Cancer Therapy

The Significance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma: Real-Time Monitoring and Moving Targets for Cancer Therapy

The SGLT2 Inhibitor Canagliflozin Prevents Carcinogenesis in a Mouse Model of Diabetes and Non-Alcoholic Steatohepatitis-Related Hepatocarcinogenesis: Association with SGLT2 Expression in Hepatocellular Carcinoma

Multidisciplinary Canadian consensus recommendations for the management and treatment of hepatocellular carcinoma

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