Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate ...and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Hepatitis virus infection is a leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Although anti-viral therapies against hepatitis B virus (HBV) and ...hepatitis C virus (HCV) have dramatically progressed during the past decade, the estimated number of people chronically infected with HBV and/or HCV is ~370 million, and hepatitis virus-associated hepatocarcinogenesis is a serious health concern worldwide. Understanding the mechanism of virus-associated carcinogenesis is crucial toward both treatment and prevention, and the recently developed whole genome/exome sequencing analysis using next-generation sequencing technologies has contributed to unveiling the landscape of genetic and epigenetic aberrations in not only tumor tissues but also the background liver tissues underlying chronic liver damage caused by hepatitis virus infection. Several major mechanisms underlie the genetic and epigenetic aberrations in the hepatitis virus-infected liver, such as the generation of reactive oxidative stress, ectopic expression of DNA mutator enzymes, and dysfunction of the DNA repair system. In addition, direct oncogenic effects of hepatitis virus, represented by the integration of HBV-DNA, are observed in infected hepatocytes. Elucidating the whole picture of genetic and epigenetic alterations, as well as the mechanisms of tumorigenesis, will facilitate the development of efficient treatment and prevention strategies for hepatitis virus-associated HCC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Hepatocellular carcinoma (HCC) originates from regenerating liver cells with genetic alterations in chronically inflamed liver. Ductal cells and hepatocytes proliferate for liver regeneration, and ...proliferating ductal cells (PDC) derived from bile ductules have long been considered putative liver stem/progenitor cells and candidate cellular origins of HCC. The potential of PDC as tumor-originating cells, however, remains controversial in contrast to accumulating evidence that HCC originates from hepatocytes. Here, we demonstrate that PDCs expressing the established surface and cancer stem cell marker EpCAM give rise to HCC in inflamed liver. EpCAM-expressing PDCs were specifically labeled in newly developed Epcam
mice and traced in a chemically induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. Lineage-tracing experiments revealed that labeled PDC differentiated into cholangiocytes, but not into hepatocytes, in the chemically damaged liver. Nevertheless, EpCAM-positive PDC with genetic alterations gave rise to HCC after 8 months of chemical administration. PDC-derived HCC showed histologic characteristics of concomitant ductule-like structures resembling human cholangiolocellular carcinoma (CLC) and exhibited serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. The Wnt signaling pathway was specifically upregulated in the CLC components of PDC-derived HCC. Our findings provide direct experimental evidence that EpCAM-expressing PDC could be a cellular origin of HCC, suggesting the existence of stem/progenitor-derived hepatocarcinogenesis.
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Geogenic contaminants, such as arsenic, are often found in soil recovered from coastal areas. These contaminants may leach out when the soil is used as embankment material. Moreover, the leaching of ...such contaminants might be influenced by environmental changes, such as dry-wet cycles, and higher environmental risks due to a larger amount of leaching are anticipated in some cases. In this study, therefore, soil recovered from tsunami deposits was subjected to dry-wet cycles under three different drying conditions to investigate how environmental changes affect the leaching behavior. To evaluate the physical and chemical changes in the soil surface, microscopic/spectroscopic studies were conducted. Batch leaching tests revealed that dry-wet cycles slightly alter the leaching behavior of most elements, such as Fe, Si, Na, Ca, etc. Arsenic leaching was seen to increase in certain dry-wet cycles before decreasing, and microscopic/spectroscopic confirmed that this increase was likely due to pyrite oxidation. These dry-wet cycles can disintegrate pyrite morphology and cause pyrite oxidation, leading to a more acidic leaching condition that accelerates arsenic leaching. After a certain oxidation procedure, the resulting ferric hydroxide may prevent the pyrite surfaces from further oxidation. The Fe oxides and hydroxides can also act as arsenic adsorbents, preventing the increase in arsenic concentration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Global transcriptomic imbalance is a ubiquitous feature associated with cancer, including hepatocellular carcinoma (HCC). Analyses of 1,225 clinical HCC samples revealed that a large numbers of RNA ...binding proteins (RBPs) are dysregulated and that RBP dysregulation is associated with poor prognosis. We further identified that oncogenic activation of a top candidate RBP, negative elongation factor E (NELFE), via somatic copy-number alterations enhanced MYC signaling and promoted HCC progression. Interestingly, NELFE induces a unique tumor transcriptome by selectively regulating MYC-associated genes. Thus, our results revealed NELFE as an oncogenic protein that may contribute to transcriptome imbalance in HCC through the regulation of MYC signaling.
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•mRNA binding proteins (RBPs) are globally dysregulated in HCC•Tumor-associated RBPs are predictive of HCC patient survival•NELFE is oncogenic and enhances MYC signaling•NELFE regulates MYC signaling by binding directly to MYC or its targets
Dang et al. show that a large numbers of RNA binding proteins (RBPs) are dysregulated in hepatocellular carcinoma (HCC) and that NELFE, an RBP, enhances MYC-induced HCC development by regulating the binding of MYC to target promoters and the mRNA stability of several MYC-regulated genes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, ...progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A‐HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC‐prone microenvironment. Here, we have identified and validated an A‐HSC‐specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue‐related, A‐HSC‐specific gene expression is associated with recurrence and poor survival. Analyses of A‐HSC‐specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A‐HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A‐HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation. Conclusion: A‐HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse. (Hepatology 2015;62:481–495
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still ...unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing.
Methods
We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs.
Results
Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including
TP53
and
ARID1A
. In contrast,
TERT
promoter mutations were not detected in any of the RNs examined. Consistently,
TERT
expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of
TERT
expression.
Conclusion
Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using ...molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Three-dimensional cell culture methods are viable in vitro approaches that facilitate the examination of biological features cancer cells present in vivo. In this study, we demonstrate that ...hepatocellular carcinoma (HCC) cells in porous alginate scaffolds can generate organoid-like spheroids that mimic numerous features of glandular epithelium in vivo, such as acinar morphogenesis and apical expression patterns of EpCAM, a hepatic stem/progenitor cell marker highly expressed in a subset of HCC with stemness features. We show that the activation of Wnt/β-catenin signaling, an essential pathway for maintaining HCC stemness, is required for EpCAM(+) HCC spheroid formation as well as the maintenance of the acinous structure. Furthermore, we demonstrate that EpCAM(+) HCC cells cultured as spheroids are more sensitive to TGF/β-induced epithelial-mesenchymal transition with highly tumorigenic and metastatic potential in vivo compared to conventional two-dimensional (2D) culture. In addition, HCC cells in EpCAM(+) spheroids are more resistant to chemotherapeutic agents than 2D-cultured cells. The alginate scaffold-based organotypic culture system is a promising, reliable, and easy system that can be configured into a high throughput fashion for the identification of critical signaling pathways and screening of molecular drug targets specific for HCC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aim
Simple hepatic cysts are typically benign; however, when they are large and symptomatic, therapeutic intervention is required. We previously reported our initial experience with ultrasound ...(US)‐guided polidocanol foam sclerotherapy in three patients with symptomatic giant hepatic cysts. In the present study, we examined the efficacy and safety of polidocanol foam sclerotherapy in a larger number of patients with long‐term follow‐up.
Methods
Between May 2016 and April 2021, 15 patients with symptomatic giant hepatic cysts were referred to our hospital. All patients were prospectively included in the study and underwent US‐guided polidocanol foam sclerotherapy.
Results
The mean maximum diameter and estimated cyst volume were 128.4 mm (77–223 mm) and 922.3 ml (123.2–2797 ml), respectively. Polidocanol foam was successfully administered through an 8.5‐Fr pigtail catheter in all patients. The percentages of cyst diameter/volume after 1–3 months, 3–6 months, 6 months–1 year, 1–2 years, and 2–4 years of sclerotherapy were 66.8%/36.5%, 48.1%/14.8%, 34.1%/6.9%, 28.2%/3.7%, and 26.2%/3.1%, respectively. During the follow‐up period, there were no cases of symptom recurrence or need for additional treatment due to cyst re‐growth. Six patients (40%) had fever, one had nausea, and one had right‐sided chest pain, but none of these adverse events required prolonged hospitalization or readmission.
Conclusions
US‐guided polidocanol foam sclerotherapy may be an effective and safe method for the treatment of symptomatic giant hepatic cysts.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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