Heterogeneity Of Liver Cancer Research Articles

Tumor-Infiltrating B Lymphocytes: Promising Immunotherapeutic Targets for Primary Liver Cancer Treatment.

Hepatocellular carcinoma and cholangiocarcinoma are the fourth most lethal primary cancers worldwide. Therefore, there is an urgent need for therapeutic strategies, including immune cell targeting therapies. The heterogeneity of liver cancer is partially explained by the characteristics of the tumor microenvironment (TME), where adaptive and innate immune system cells are the main components. Pioneering studies of primary liver cancers revealed that tumor-infiltrating immune cells and their dynamic interaction with cancer cells significantly impacted carcinogenesis, playing an important role in cancer immune evasion and responses to immunotherapy treatment. In particular, B cells may play a prominent role and have a controversial function in the TME. In this work, we highlight the effect of B lymphocytes as tumor infiltrates in relation to primary liver cancers and their potential prognostic value. We also present the key pathways underlying B-cell interactions within the TME, as well as the way that a comprehensive characterization of B-cell biology can be exploited to develop novel immune-based therapeutic approaches.

Broad Transcriptomic Impact of Sorafenib and Its Relation to the Antitumoral Properties in Liver Cancer Cells.

Simple SummaryHepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related mortality worldwide. While ablation, resection and orthotopic liver transplantation are indicated at an early stage of the disease, Sorafenib (Sfb) is the current most administrated first-line treatment for advanced HCC, even though its therapeutic benefit is limited due to the appearance of resistance. Deep knowledge on the molecular consequences of Sfb-treatment is essentially required for optimizing novel therapeutic strategies to improve the outcomes for patients with advanced HCC. In this study, we analyzed differential gene expression changes in two well characterized liver cancer cell lines upon a Sfb-treatment, demonstrating that both lines responded similarly to the treatment. Our results provide valuable information on the molecular action of Sfb on diverse cellular fundamental processes such as DNA repair, translation and proteostasis and identify rationalization issues that could provide a different therapeutic perspective to Sfb.Hepatocellular carcinoma (HCC) is one of the most frequent and essentially incurable cancers in its advanced stages. The tyrosine kinase inhibitor Sorafenib (Sfb) remains the globally accepted treatment for advanced HCC. However, the extent of its therapeutic benefit is limited. Sfb exerts antitumor activity through its cytotoxic, anti-proliferative and pro-apoptotic roles in HCC cells. To better understand the molecular mechanisms underlying these effects, we used RNA sequencing to generate comprehensive transcriptome profiles of HepG2 and SNU423, hepatoblastoma- (HB) and HCC-derived cell lines, respectively, following a Sfb treatment at a pharmacological dose. This resulted in similar alterations of gene expression in both cell lines. Genes functionally related to membrane trafficking, stress-responsible and unfolded protein responses, circadian clock and activation of apoptosis were predominantly upregulated, while genes involved in cell growth and cycle, DNA replication and repair, ribosome biogenesis, translation initiation and proteostasis were downregulated. Our results suggest that Sfb causes primary effects on cellular stress that lead to upregulation of selective responses to compensate for its negative effect and restore homeostasis. No significant differences were found specifically affecting each cell line, indicating the robustness of the Sfb mechanism of action despite the heterogeneity of liver cancer. We discuss our results on terms of providing rationalization for possible strategies to improve Sfb clinical outcomes.

DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer

Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) both exhibit notable cancer stem cell (CSC) features. Moreover, the development of both diseases is closely associated with the presence of CSCs. We investigated the role of brain-expressed X-linked protein 1 (BEX1) in regulating the CSC properties of HB and a subtype of HCC with high CSC features (CSC-HCC). Stemness scores were analyzed in 5 murine HCC models. A subpopulation of BEX1-positive cells and BEX1-negative cells were sorted from HCC cell lines, and subjected to transcriptome analysis. The expression and function of BEX1 was examined via western blotting, sphere formation assays, and xenograft tumor models. We identified BEX1 as a novel CSC marker that was required for the self-renewal of liver CSCs. Furthermore, zebularine, a potent DNMT1 inhibitor, can induce the reactivation of BEX1 by removing epigenetic inhibition. Notably, BEX1 was highly expressed in patients with HB and CSC-HCC, but not in patients with non-CSC HCC. Moreover, DNMT1-mediated methylation of the BEX1 promoter resulted in differential BEX1 expression patterns in patients with HB, CSC-HCC, and non-CSC-HCC. Mechanistically, BEX1 interacted with RUNX3 to block its inhibition of β-catenin transcription, which led to the activation of Wnt/β-catenin signaling, and stemness maintenance in both HB and CSC-HCC. In contrast, downregulated BEX1 expression released RUNX3 and inhibited the activation of Wnt/β-catenin signaling in non-CSC-HCC. BEX1, under the regulation of DNMT1, is necessary for the self-renewal and maintenance of liver CSCs through activation of Wnt/β-catenin signaling, rendering BEX1 a potentially valuable therapeutic target in both HB and CSC-HCC. Cancer stem cells (CSCs) contribute to a high rate of cancer recurrence, as well as resistance to conventional therapies. However, the regulatory mechanisms underlying their self-renewal remains elusive. Herein, we have reported that BEX1 plays a key role in regulating CSC properties in different types of liver cancer. Targeting BEX1-mediated Wnt/β-catenin signaling may help to address the high rate of recurrence, and heterogeneity of liver cancer.

The Endless Sources of Hepatocellular Carcinoma Heterogeneity.

Simple SummaryTumor heterogeneity in liver cancer is a major contributor to the high lethality rate found in patients suffering from this disease. The therapeutic outcomes are drastically affected by this heterogeneity, which complicates patient stratification and response prediction. Better understanding of all the factors that can contribute to this heterogeneity will be critical to improve our understanding of liver cancer, in order to optimize the outcome of patients.Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.

Intratumoral heterogeneity and clonal evolution in liver cancer

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

Analysis of Spatial Epidemic Characteristics of Liver Cancer in Small Geographical Area

Background: At present, the spatial studies of liver cancer are too large for observation, or lack systematic spatial epidemics and statistical analyses, so it is difficult to put forward more targeted regional prevention and control measures. This study takes the natural village of Longkou City, Shandong as a small regional research unit, to systematically analyze the spatial structure and spatial heterogeneity of liver cancer in the small region (village as a unit), and provide a scientific basis for the development of regional prevention and control measures for more targeted liver cancer and its related diseases. Methods: Based on the database of the integrated management information system for chronic diseases and death monitoring in Shandong Center for Disease Control and Prevention, the spatial epidemiology and spatial statistics methods were combined in the framework of geographic information system (GIS). Results: The results of spatial distribution showed that there was obvious spatial heterogeneity on liver cancer in Longkou City, and there were many high incidence and high death areas scattered in the distribution. The spatial scanning and space-time scanning results of liver cancer showed that there were relatively fixed high incidence and high death villages in the small area of Longkou City. Conclusion: This study suggests that the liver cancer in Longkou City has a local geographic risk factor, which may have obvious high incidence area, and time factors have a certain influence on the space area of liver cancer. It is necessary to further carry out the geographical weight regression and risk factors analysis, and expand the study model.

Modeling liver cancer and therapy responsiveness using organoids derived from primary mouse liver tumors.

The current understanding of cancer biology and development of effective treatments for cancer remain far from satisfactory. This in turn heavily relies on the availability of easy and robust model systems that resemble the architecture/physiology of the tumors in patients to facilitate research. Cancer research in vitro has mainly been based on the use of immortalized 2D cancer cell lines that deviate in many aspects from the original primary tumors. The recent development of the organoid technology allowing generation of organ-buds in 3D culture from adult stem cells has endowed the possibility of establishing stable culture from primary tumors. Although culturing organoids from liver tumors is thought to be difficult, we now convincingly demonstrate the establishment of organoids from mouse primary liver tumors. We have succeeded in culturing 91 lines from 129 liver tissue/tumors. These organoids can be grown in long-term cultures in vitro. About 20% of these organoids form tumors in immunodeficient mice upon (serial) transplantation, confirming their tumorigenic and self-renewal properties. Interestingly, single cells from the tumor organoids have high efficiency of organoid initiation, and a single organoid derived from a cancer cell is able to initiate a tumor in mice, indicating the enrichment of tumor-initiating cells in the tumor organoids. Furthermore, these organoids recapitulate, to some extent, the heterogeneity of liver cancer in patients, with respect to phenotype, cancer cell composition and treatment response. These model systems shall provide enormous opportunities to advance our research on liver cancer (stem cell) biology, drug development and personalized medicine.

Abstract No. 486 - Percutaneous cholecystostomy: institutional experience and outcomes

Abstract No. 486 - Percutaneous cholecystostomy: institutional experience and outcomes

Composite fatty acid ether amides suppress growth of liver cancer cells in vitro and in an in vivo allograft mouse model

The heterogeneity of liver cancer, in particular hepatocellular carcinoma (HCC), portrays the requirement of multiple targets for both its treatment and prevention. Multifaceted agents, minimally or non-toxic for normal hepatocytes, are required to address the molecular diversity of HCC, including the resistance of putative liver cancer stem cells to chemotherapy. We designed and synthesized two fatty acid ethers of isopropylamino propanol, C16:0-AIP-1 and C18:1-AIP-2 (jointly named AIPs), and evaluated their anti-proliferative effects on the human HCC cell line Huh7 and the murine hepatoma cell line BNL 1MEA.7R.1, both in vitro and in an in vivo allograft mouse model. We found that AIP-1 and AIP-2 inhibited proliferation and caused cell death in both Huh7 and BNL 1MEA.7R.1 cells. Importantly, AIP-1 and AIP-2 were found to block the activation of putative liver cancer stem cells as manifested by suppression of clonal 'carcinosphere' development in growth factor-free and anchorage-free medium. The AIPs exhibited a relatively low toxicity against normal human or rat hepatocytes in primary cultures. In addition, we found that the AIPs utilized multifaceted pathways that mediate both autophagy and apoptosis in HCC, including the inhibition of AKTs and CAMK-1. In immune-competent mice, the AIPs significantly reduced BNL 1MEA.7R.1 cell-driven tumor allograft development, with a higher efficiency than sorafenib. A combination of AIP-1 + AIP-2 was most effective in reducing the tumor allograft incidence. AIPs represent a novel class of simple fatty acid derivatives that are effective against liver tumors via diverse pathways. They show a low toxicity towards normal hepatocytes. The addition of AIPs may represent a new avenue towards the management of chronic liver injury and, ultimately, the prevention and treatment of HCC.