International Journal of Molecular Sciences

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Open AccessEditorial

Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies

by Daniela Gabbia and Sara De Martin

Int. J. Mol. Sci. 2024, 25(8), 4188; https://doi.org/10.3390/ijms25084188 - 10 Apr 2024

Cited by 3 | Viewed by 1639

Abstract

Hepatocellular carcinoma (HCC), the most common primary liver cancer, accounts for 830,180 related deaths worldwide in 2020, according to GLOBOCAN, representing the fourth leading cause of cancer-related death, with a five-year survival rate of about 18% for advanced stage, and the second leading [...] Read more.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, accounts for 830,180 related deaths worldwide in 2020, according to GLOBOCAN, representing the fourth leading cause of cancer-related death, with a five-year survival rate of about 18% for advanced stage, and the second leading cause in men of cancer-related mortality worldwide [...] Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

Research

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16 pages, 3063 KiB

Open AccessArticle

Efficacy of Lenvatinib Combined with Transcatheter Intra-Arterial Therapies for Patients with Advanced-Stage of Hepatocellular Carcinoma: A Propensity Score Matching

by Shigeo Shimose, Hideki Iwamoto, Takashi Niizeki, Masatoshi Tanaka, Tomotake Shirono, Etsuko Moriyama, Yu Noda, Masahito Nakano, Hideya Suga, Ryoko Kuromatsu, Takuji Torimura, Hironori Koga and Takumi Kawaguchi

Int. J. Mol. Sci. 2023, 24(18), 13715; https://doi.org/10.3390/ijms241813715 - 5 Sep 2023

Cited by 5 | Viewed by 1737

Abstract

This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized [...] Read more.

This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized into the LEN combined with TIT group (n = 30) or the LEN monotherapy group (n = 85). After PSM, 38 patients (LEN + TIT group, n = 19; LEN monotherapy group, n = 19) were analyzed. The median overall survival (OS) in the LEN + TIT group was significantly higher than that in the LEN monotherapy group (median survival time (MST): 28.1 months vs. 11.6 months, p = 0.014). The OS in the LEN combined with transcatheter arterial chemoembolization and LEN combined with hepatic arterial infusion chemotherapy groups was significantly higher than that in the LEN monotherapy group (MST 20.0 vs. 11.6 months, 30.2 vs. 11.6 months, p = 0.048, and p = 0.029, respectively). Independent factors associated with OS were alpha-fetoprotein and LEN combined with TIT. The indications for LEN combined with TIT were age <75 years and modified albumin bilirubin (m-ALBI) grade 1. We concluded that LEN combined with TIT may improve prognosis compared with LEN monotherapy in patients with advanced-stage HCC. Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

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16 pages, 2504 KiB

Open AccessArticle

Studies on the Role of Compartmentalized Profiles of Cytokines in the Risk of Hepatocellular Carcinoma

by Silvano Fasolato, Paola Del Bianco, Sandro Malacrida, Adriana Mattiolo, Enrico Gringeri, Paolo Angeli, Patrizia Pontisso and Maria Luisa Calabrò

Int. J. Mol. Sci. 2023, 24(17), 13432; https://doi.org/10.3390/ijms241713432 - 30 Aug 2023

Cited by 2 | Viewed by 1476

Abstract

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is frequently diagnosed late due to the absence of symptoms during early disease, thus heavily affecting the overall survival of these patients. Soluble immunological factors persistently produced during cirrhosis have been recognized as [...] Read more.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is frequently diagnosed late due to the absence of symptoms during early disease, thus heavily affecting the overall survival of these patients. Soluble immunological factors persistently produced during cirrhosis have been recognized as promoters of chronic inflammation and neoplastic transformation. The aim of this pilot study was to evaluate the predictive value of the cytokine profiles for HCC development. A Luminex xMAP approach was used for the quantification of 45 proteins in plasma and ascitic fluids of 44 cirrhotic patients without or with HCC of different etiologies. The association with patient survival was also evaluated. Univariate analyses revealed that very low levels of interleukin 5 (IL-5) (<15.86 pg/mL) in ascites and IL-15 (<12.40 pg/mL) in plasma were able to predict HCC onset with an accuracy of 81.8% and a sensitivity of 95.2%. Univariate analyses also showed that HCC, hepatitis B virus/hepatitis C virus infections, low levels of IL-5 and granulocyte-macrophage colony-stimulating factor in ascitic fluids, and high levels of eotaxin-1, hepatocyte growth factor and stromal-cell-derived factor 1α in plasma samples were factors potentially associated with a poor prognosis and decreased survival. Our results suggest a potential protective role of some immune modulators that may act in the peritoneal cavity to counteract disease progression leading to HCC development. Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

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15 pages, 18157 KiB

Open AccessArticle

Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice

by Jessica Krzistetzko, Cyrill Géraud, Christof Dormann, Anna Riedel and Thomas Leibing

Int. J. Mol. Sci. 2023, 24(13), 10969; https://doi.org/10.3390/ijms241310969 - 30 Jun 2023

Cited by 5 | Viewed by 1941

Abstract

Liver sinusoidal endothelial cells (LSECs) control clearance of Transforming growth factor, beta-induced, 68kDa (TGFBi) and Periostin (POSTN) through scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2). Stabilin inhibition can ameliorate atherosclerosis in mouse models, while Stabilin-double-knockout leads to glomerulofibrosis. Fibrotic organ damage may pose [...] Read more.

Liver sinusoidal endothelial cells (LSECs) control clearance of Transforming growth factor, beta-induced, 68kDa (TGFBi) and Periostin (POSTN) through scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2). Stabilin inhibition can ameliorate atherosclerosis in mouse models, while Stabilin-double-knockout leads to glomerulofibrosis. Fibrotic organ damage may pose a limiting factor in future anti-Stabilin therapies. While Stab1-deficient (Stab1−/−) mice were shown to exhibit higher liver fibrosis levels upon challenges, fibrosis susceptibility has not been studied in Stab2-deficient (Stab2−/−) mice. Wildtype (WT), Stab1−/− and Stab2−/− mice were fed experimental diets, and local ligand abundance, hepatic fibrosis, and ligand plasma levels were measured. Hepatic fibrosis was increased in both Stab1−/− and Stab2−/− at baseline. A pro-fibrotic short Methionine-Choline-deficient (MCD) diet induced slightly increased liver fibrosis in Stab1−/− and Stab2−/− mice. A Choline-deficient L-amino acid-defined (CDAA) diet induced liver fibrosis of similar distribution and extent in all genotypes (WT, Stab1−/− and Stab2−/−). A hepatic abundance of Stabilin ligand TGFBi correlated very highly with liver fibrosis levels. In contrast, plasma levels of TGFBi were increased only in Stab2−/− mice after the CDAA diet but not the MCD diet, indicating the differential effects of these diets. Here we show that a single Stabilin deficiency of either Stab1 or Stab2 induces mildly increased collagen depositions under homeostatic conditions. Upon experimental dietary challenge, the local abundance of Stabilin ligand TGFBi was differentially altered in Stabilin-deficient mice, indicating differentially affected LSEC scavenger functions. Since anti-Stabilin-directed therapies are in clinical evaluation for the treatment of diseases, these findings bear relevance to treatment with novel anti-Stabilin agents. Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

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Review

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17 pages, 1036 KiB

Open AccessReview

Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma

by Annarosa Floreani, Daniela Gabbia and Sara De Martin

Int. J. Mol. Sci. 2024, 25(4), 2194; https://doi.org/10.3390/ijms25042194 - 12 Feb 2024

Cited by 5 | Viewed by 2247

Abstract

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, [...] Read more.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms. Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

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15 pages, 1112 KiB

Open AccessReview

Insights into Hepatocellular Carcinoma in Patients with Thalassemia: From Pathophysiology to Novel Therapies

by Pei-Chin Lin, Wan-Yi Hsu, Po-Yi Lee, Shih-Hsien Hsu and Shyh-Shin Chiou

Int. J. Mol. Sci. 2023, 24(16), 12654; https://doi.org/10.3390/ijms241612654 - 10 Aug 2023

Cited by 2 | Viewed by 2330

Abstract

Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing incidence in Northern Europe and North America due to immigration. Iron overloading is one of the major long-term complications in patients with thalassemia [...] Read more.

Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing incidence in Northern Europe and North America due to immigration. Iron overloading is one of the major long-term complications in patients with thalassemia and can lead to organ damage and carcinogenesis. Hepatocellular carcinoma (HCC) is one of the most common malignancies in both transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The incidence of HCC in patients with thalassemia has increased over time, as better chelation therapy confers a sufficiently long lifespan for the development of HCC. The mechanisms of iron-overloading-associated HCC development include the increased reactive oxygen species (ROS), inflammation cytokines, dysregulated hepcidin, and ferroportin metabolism. The treatment of HCC in patients with thalassemia was basically similar to those in general population. However, due to the younger age of HCC onset in thalassemia, regular surveillance for HCC development is mandatory in TDT and NTDT. Other supplemental therapies and experiences of novel treatments for HCC in the thalassemia population were also reviewed in this article. Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

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18 pages, 1137 KiB

Open AccessReview

Multiple Roles of LOXL2 in the Progression of Hepatocellular Carcinoma and Its Potential for Therapeutic Targeting

by Jelena Radić, Bojana Kožik, Ivan Nikolić, Ivana Kolarov-Bjelobrk, Tijana Vasiljević, Bojana Vranjković and Sanja Despotović

Int. J. Mol. Sci. 2023, 24(14), 11745; https://doi.org/10.3390/ijms241411745 - 21 Jul 2023

Cited by 3 | Viewed by 2758

Abstract

LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with an aggressive phenotype and represents a poor prognostic factor. Here, we focus on the mechanisms through which LOXL2 [...] Read more.

LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with an aggressive phenotype and represents a poor prognostic factor. Here, we focus on the mechanisms through which LOXL2 orchestrates multiple oncogenic functions in HCC development. We performed a review of the current knowledge on the roles LOXL2 performs in the modulation of the HCC tumor microenvironment, formation of premetastatic niches, and epithelial–mesenchymal transition. We also highlighted the complex interplay between LOXL2 and hypoxia, angiogenesis, and vasculogenic mimicry in HCC. At the end of the review, we summarize the current LOXL2 inhibitors and discuss their potential in HCC precision treatment. Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

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21 pages, 928 KiB

Open AccessReview

Immune System and Hepatocellular Carcinoma (HCC): New Insights into HCC Progression

by Maria Kotsari, Vassiliki Dimopoulou, John Koskinas and Athanasios Armakolas

Int. J. Mol. Sci. 2023, 24(14), 11471; https://doi.org/10.3390/ijms241411471 - 14 Jul 2023

Cited by 28 | Viewed by 4461

Abstract

According to the WHO’s recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies [...] Read more.

According to the WHO’s recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods. Full article

(This article belongs to the Special Issue Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies)

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