Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.

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New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

Journal of Personalized Medicine ◽

10.3390/jpm11030219 ◽

2021 ◽

Vol 11 (3) ◽

pp. 219

Author(s):

Ya-Ling Yang ◽

Yen-Hsiang Chang ◽

Chia-Jung Li ◽

Ying-Hsien Huang ◽

Ming-Chao Tsai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Crucial Role ◽

Human Cancer ◽

Metabolic Adaptation ◽

Advanced Hcc ◽

Diagnosis And Prognosis ◽

Competitive Endogenous Rnas ◽

Growing Body

Hepatocellular carcinoma (HCC) remains one of the most lethal human cancer globally. For advanced HCC, curable plan for advanced HCC is yet to be established, and the prognosis remains poor. The detail mechanisms underlying the progression of HCC tumorigenicity and the corruption of tumor microenvironment (TME) is complex and inconclusive. A growing body of studies demonstrate microRNAs (miRs) are important regulators in the tumorigenicity and TME development. Notably, mounting evidences indicate miR-29a play a crucial role in exerting hepatoprotective effect on various types of stress and involved in the progression of HCC, which elucidates their potential theragnostic implications. In this review, we reviewed the advanced insights into the detail mechanisms by which miR-29a dictates carcinogenesis, epigenetic program, and metabolic adaptation, and implicated in the sponging activity of competitive endogenous RNAs (ceRNA) and the TME components in the scenario of HCC. Furthermore, we highlighted its clinical significance in diagnosis and prognosis, as well as the emerging therapeutics centered on the activation of miR-29a.

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Multiple Roles of Autophagy in the Sorafenib Resistance of Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000485285 ◽

2017 ◽

Vol 44 (2) ◽

pp. 716-727 ◽

Cited By ~ 40

Author(s):

Ting Sun ◽

Hongchun Liu ◽

Liang Ming

Keyword(s):

Hepatocellular Carcinoma ◽

Current Knowledge ◽

Acquired Resistance ◽

Multiple Roles ◽

Multikinase Inhibitor ◽

Advanced Hcc ◽

Cellular Autophagy ◽

Advanced Stages ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and prognosis remains unsatisfactory since the disease is often diagnosed at the advanced stages. Currently, the multikinase inhibitor sorafenib is the only drug approved for the treatment of advanced HCC. However, primary or acquired resistance to sorafenib develops, generating a roadblock in HCC therapy. Autophagy is an intracellular lysosomal pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. Current understanding of the role of autophagy in the progression of cancer and the response to cancer therapy remains controversial. Sorafenib is able to induce autophagy in HCC, but the effect of autophagy is indistinct. Some studies established that sorafenib-induced autophagy serves as a pro-survival response. However, other studies found that sorafenib-induced autophagy improves the lethality of sorafenib against HCC cells. The mechanisms underlying autophagy and sorafenib resistance remain elusive. The purpose of this review is to summarize the progress of research focused on autophagy and sorafenib resistance and to update current knowledge of how cellular autophagy impacts sorafenib sensitivity in HCC treatment.

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Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22158011 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8011

Author(s):

Hyo-Jung Cho ◽

Jae-Youn Cheong

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Inflammation ◽

Cd8 T Cells ◽

Immune Cells ◽

Adaptive Immune ◽

B Virus

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.

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The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages

BioMed Research International ◽

10.1155/2013/187204 ◽

2013 ◽

Vol 2013 ◽

pp. 1-15 ◽

Cited By ~ 189

Author(s):

Daria Capece ◽

Mariafausta Fischietti ◽

Daniela Verzella ◽

Agata Gaggiano ◽

Germana Cicciarelli ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factors ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Signaling Pathways ◽

Matrix Metalloproteases ◽

Pivotal Role ◽

M2 Macrophage ◽

Tumor Associated Macrophages

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human cancers worldwide. HCC is an example of inflammation-related cancer and represents a paradigm of the relation occurring between tumor microenvironment and tumor development. Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltrate of tumors and play a pivotal role in tumor progression of inflammation-related cancer, including HCC. Several studies indicate that, in the tumor microenvironment, TAMs acquire an M2-polarized phenotype and promote angiogenesis, metastasis, and suppression of adaptive immunity through the expression of cytokines, chemokines, growth factors, and matrix metalloproteases. Indeed, an established M2 macrophage population has been associated with poor prognosis in HCC. The molecular links that connect cancer cells and TAMs are not completely known, but recent studies have demonstrated that NF-κB, STAT-3, and HIF-1 signaling pathways play key roles in this crosstalk. In this paper, we discuss the current knowledge about the role of TAMs in HCC development, highlighting the role of TAM-derived cytokines, chemokines, and growth factors in the initiation and progression of liver cancer and outlining the signaling pathways involved in the interplay between cancer cells and TAMs.

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Genetic and Epigenetic Events Generate Multiple Pathways in Colorectal Cancer Progression

Pathology Research International ◽

10.1155/2012/509348 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 55

Author(s):

Massimo Pancione ◽

Andrea Remo ◽

Vittorio Colantuoni

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Cancer Biology ◽

Current Knowledge ◽

Alternative Pathway ◽

Epigenetic Events ◽

Cells Of Origin ◽

Common Causes ◽

Colorectal Cancer Progression

Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment.

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Learning the Roles of the Hepatic Adaptive Immune System in Hepatocellular Carcinoma—Nature's Guide for Successful Cancer Immunotherapy

Seminars in Liver Disease ◽

10.1055/s-0037-1606255 ◽

2017 ◽

Vol 37 (03) ◽

pp. 210-218 ◽

Cited By ~ 2

Author(s):

Mathias Heikenwälder ◽

Eli Pikarsky

Keyword(s):

Hepatocellular Carcinoma ◽

Immune System ◽

Immune Cells ◽

Protective Immunity ◽

Adaptive Immune System ◽

Hepatic Parenchyma ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Pathophysiological Role

AbstractThe different roles of the adaptive immune system in cancer are beginning to unfold. The dramatic responses to immune check point drugs in some tumors generated an accelerated need for understanding the complex set of interactions between tumor and immune cells. In view of the major pathophysiological role of immune cells in hepatocellular carcinoma, it is not surprising that malignant hepatocytes interact extensively with adaptive immune cells, resulting in both protumor immunopathology and antitumor protective immunity. Identifying potential responders to drugs that target the adaptive immune system, monitoring their immune response to the tumor, and devising the best treatment combinations depends on understanding the complex set of interactions taking place within the tumor and in the adjacent hepatic parenchyma.

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Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections

Thrombosis and Haemostasis ◽

10.1160/th09-05-0323 ◽

2009 ◽

Vol 102 (12) ◽

pp. 1103-1109 ◽

Cited By ~ 49

Author(s):

Julia Eitel ◽

Karolin Meixenberger ◽

Norbert Suttorp ◽

Bastian Opitz

Keyword(s):

Endothelial Cells ◽

Current Knowledge ◽

Adaptive Immune Response ◽

Vascular Diseases ◽

Innate Immune ◽

Toll Like Receptors ◽

Surface Molecules ◽

Adaptive Immune ◽

Systemic Infections

SummaryBacteraemia and viraemia are characterised by pathogens entering the bloodstream. Endothelial cells are among the first cells coming into contact with the microbes and also some endogenous molecules which are released by tissue damage. As part of the innate immune system, endothelial cells respond to these contacts by producing inflammatory mediators and expressing surface molecules. The initial sensing of microbial and endogenous danger-associated molecules is mediated by so-called pattern recognition receptors (PRRs). PRRs can be classified in different protein families such as the Toll-like receptors, the NODlike receptors and the RIG-I-like receptors. By activating inflammatory gene transcription and posttranslational processing, PRRs control the immediate innate immune reaction and also the subsequent adaptive immune response. Here we describe the current knowledge of extra-and intracellular PRRs in endothelial cells and their potential role in sepsis and vascular diseases.

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The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia

International Journal of Molecular Sciences ◽

10.3390/ijms22041565 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1565

Author(s):

Aldona Kasprzak

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Systemic Inflammation ◽

Cancer Cachexia ◽

Current Knowledge ◽

Colorectal Cancer Cells ◽

Factor Α ◽

Cellular Components

Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50–61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.

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The Role of Non-Gaussian Models of Diffusion Weighted MRI in Hepatocellular Carcinoma: A Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm10122641 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2641

Author(s):

Liberatore Tramontano ◽

Carlo Cavaliere ◽

Marco Salvatore ◽

Valentina Brancato

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Current Knowledge ◽

Exponential Model ◽

Response To Treatment ◽

Diffusion Kurtosis Imaging ◽

Diffusion Weighted ◽

Non Gaussian ◽

Diffusion Kurtosis

The importance of Diffusion Weighted Imaging (DWI) in hepatocellular carcinoma (HCC) has been widely handled in the literature. Due to the mono-exponential model limitations, several studies recently investigated the role of non-Gaussian DWI models in HCC. However, their results are variable and inconsistent. Therefore, the aim of this systematic review is to summarize current knowledge on non-Gaussian DWI techniques in HCC. A systematic search of the literature, including PubMed, Google Scholar, MEDLINE, and ScienceDirect databases, was performed to identify original articles since 2010 that evaluated the role of non-Gaussian DWI models for HCC diagnosis, grading, response to treatment, and prognosis. Studies were grouped and summarized according to the non-Gaussian DWI models investigated. We focused on the most used non-Gaussian DWI models (Intravoxel Incoherent Motion (IVIM), Diffusion Kurtosis Imaging (DKI), and Stretched Exponential—SE). The quality of included studies was evaluated by using QUADAS-2 and QUIPS tools. Forty-three articles were included, with IVIM and DKI being the most investigated models. Although the role of non-Gaussian DWI models in clinical settings has not fully been established, our findings showed that their parameters may potentially play a role in HCC. Further studies are required to identify a standardized DWI acquisition protocol for HCC diagnosis, grading, response to treatment, and prognosis.

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WNT and β-Catenin in Cancer: Genes and Therapy

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-030419-033628 ◽

2020 ◽

Vol 4 (1) ◽

pp. 177-196 ◽

Cited By ~ 5

Author(s):

Rene Jackstadt ◽

Michael Charles Hodder ◽

Owen James Sansom

Keyword(s):

Tumor Microenvironment ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Pathway ◽

Therapeutic Strategy ◽

Wnt Signaling Pathway ◽

Therapeutic Strategies ◽

Tissue Homeostasis ◽

Cancer Genes

The WNT pathway is a pleiotropic signaling pathway that controls developmental processes, tissue homeostasis, and cancer. The WNT pathway is commonly mutated in many cancers, leading to widespread research into the role of WNT signaling in carcinogenesis. Understanding which cancers are reliant upon WNT activation and which components of the WNT signaling pathway are mutated is paramount to advancing therapeutic strategies. In addition, building holistic insights into the role of WNT signaling in not only tumor cells but also the tumor microenvironment is a vital area of research and may be a promising therapeutic strategy in multiple immunologically inert cancers. Novel compounds aimed at modulating the WNT signaling pathway using diverse mechanisms are currently under investigation in preclinical/early clinical studies. Here, we review how the WNT pathway is activated in multiple cancers and discuss current strategies to target aberrant WNT signaling.

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