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13 pages, 1742 KiB

Open AccessArticle

Identification of the Novel Oncogenic Role of SAAL1 and Its Therapeutic Potential in Hepatocellular Carcinoma

by Pei-Yi Chu, Shiao-Lin Tung, Kuo-Wang Tsai, Fang-Ping Shen and Shih-Hsuan Chan

Cancers 2020, 12(7), 1843; https://doi.org/10.3390/cancers12071843 - 8 Jul 2020

Cited by 7 | Viewed by 3502

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, affecting over 700,000 people per year. The treatment effect in advanced HCC is still disappointing and prognosis of advanced HCC remains poor. Hence, to find more effective therapeutic targets to improve [...] Read more.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, affecting over 700,000 people per year. The treatment effect in advanced HCC is still disappointing and prognosis of advanced HCC remains poor. Hence, to find more effective therapeutic targets to improve the treatment outcome of HCC is of urgent need. In this study, we reported the novel oncogenic function of SAAL1 (serum amyloid A-like 1) in HCC, which previously is considered as an inflammation-related gene. We found that SAAL1 was significantly upregulated in HCC tumor tissues when compared to the adjacent normal tissues and high expression of SAAL1 correlated with shorter overall survival in The Cancer Genome Atlas (TCGA) HCC database. Functionally, we showed that the depletion of SAAL1 significantly reduced cell proliferation, 3D colony formation, and migration/invasion abilities of HCC cancer cells. Furthermore, suppression of SAAL1 impaired the HGF/Met-driven Akt/mTOR phosphorylation cascade and increased the chemosensitivity of HCC cells to sorafenib and foretinib treatment. Our data indicated that SAAL1 plays an important role in HCC via mediating oncogenic HGF/Met-driven Akt/mTOR signaling and could serve as an independent prognostic marker, as well as a promising therapeutic target for HCC patients. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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16 pages, 1684 KiB

Open AccessArticle

Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma

by Nada Chaoul, Serena Mancarella, Luigi Lupo, Gianluigi Giannelli and Francesco Dituri

Cancers 2020, 12(3), 627; https://doi.org/10.3390/cancers12030627 - 8 Mar 2020

Cited by 25 | Viewed by 3805

Abstract

Different subsets of lymphocytes have the capacity to promote or counteract the progression of solid cancers, including hepatocellular carcinoma (HCC). Therefore, to determine the infiltrative ability and functional status of major immune cell subtypes into tumor may lead to novel insights from the [...] Read more.

Different subsets of lymphocytes have the capacity to promote or counteract the progression of solid cancers, including hepatocellular carcinoma (HCC). Therefore, to determine the infiltrative ability and functional status of major immune cell subtypes into tumor may lead to novel insights from the perspective of immunotherapy. After obtaining single cell suspensions from freshly collected specimens of HCC tumor, along with paired peritumor tissues and peripheral blood mononuclear cells (PBMCs) from 14 patients, we flow-cytometrically identified and quantified the relative frequencies of lymphocyte subsets within the tissues of origin. We found that the recruitment in the tumor of cytotoxic cells, namely the terminally differentiated CD4+ and CD8+ T cells (TEFF), is impaired, whereas the effector memory CD4+ T cells (TEM) are more attracted in this site. Concerning the other subsets, the frequency of NK CD56hi and NKT CD56hi cells infiltration in the tumor is increased, whereas that of NKT CD56low is reduced. Although CD4+ and CD8+ T cells settled in the tumor show a higher degree of activation than the circulating counterpart, they occur with a more exhausted phenotype. Overall, these data demonstrate the prevalently immunosuppressive nature of HCC microenvironment, and prompt us to search for strategies to enhance the activity of anti-tumor immune cell subsets. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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21 pages, 3225 KiB

Open AccessArticle

Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues

by Israa T. Ismail, Oliver Fiehn, Ashraf Elfert, Marwa Helal, Ibrahim Salama and Hala El-Said

Cancers 2020, 12(2), 484; https://doi.org/10.3390/cancers12020484 - 19 Feb 2020

Cited by 16 | Viewed by 5947

Abstract

The major risk factors for hepatocellular carcinoma (HCC) are hepatitis C and B viral infections that proceed to Chronic Liver Disease (CLD). Yet, the early diagnosis and treatment of HCC are challenging because the pathogenesis of HCC is not fully defined. To better [...] Read more.

The major risk factors for hepatocellular carcinoma (HCC) are hepatitis C and B viral infections that proceed to Chronic Liver Disease (CLD). Yet, the early diagnosis and treatment of HCC are challenging because the pathogenesis of HCC is not fully defined. To better understand the onset and development of HCC, untargeted GC-TOF MS metabolomics data were acquired from resected human HCC tissues and their paired non-tumor hepatic tissues (n = 46). Blood samples of the same HCC subjects (n = 23) were compared to CLD (n = 15) and healthy control (n = 15) blood samples. The participants were recruited from the National Liver Institute in Egypt. The GC-TOF MS data yielded 194 structurally annotated compounds. The most strikingly significant alteration was found for the class of sugar alcohols that were up-regulated in blood of HCC patients compared to CLD subjects (p < 2.4 × 10⁻¹²) and CLD compared to healthy controls (p = 4.1 × 10⁻⁷). In HCC tissues, sugar alcohols were the most significant (p < 1 × 10⁻⁶) class differentiating resected HCC tissues from non-malignant hepatic tissues for all HCC patients. Alteration of sugar alcohol levels in liver tissues also defined early-stage HCC from their paired non-malignant hepatic tissues (p = 2.7 × 10⁻⁶). In blood, sugar alcohols differentiated HCC from CLD subjects with an ROC-curve of 0.875 compared to 0.685 for the classic HCC biomarker alpha-fetoprotein. Blood sugar alcohol levels steadily increased from healthy controls to CLD to early stages of HCC and finally, to late-stage HCC patients. The increase in sugar alcohol levels indicates a role of aldo-keto reductases in the pathogenesis of HCC, possibly opening novel diagnostic and therapeutic options after in-depth validation. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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16 pages, 4224 KiB

Open AccessArticle

Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma

by Kenya Kamimura, Takeshi Yokoo, Hiroyuki Abe, Norihiro Sakai, Takuro Nagoya, Yuji Kobayashi, Masato Ohtsuka, Hiromi Miura, Akira Sakamaki, Hiroteru Kamimura, Norio Miyamura, Hiroshi Nishina and Shuji Terai

Cancers 2020, 12(2), 472; https://doi.org/10.3390/cancers12020472 - 18 Feb 2020

Cited by 17 | Viewed by 5347

Abstract

Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells; recurrence is highly probable, and some patients develop resistances to the [...] Read more.

Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells; recurrence is highly probable, and some patients develop resistances to the therapies. Accordingly, the development of a novel therapy is essential. We assessed gene therapy for HCC using a diphtheria toxin fragment A (DTA) gene-expressing plasmid, utilizing a non-viral hydrodynamics-based procedure. The antitumor effect of DTA expression in HCC cell lines (and alpha-fetoprotein (AFP) promoter selectivity) is assessed in vitro by examining HCC cell growth. Moreover, the effect and safety of the AFP promoter-selective DTA expression was examined in vivo using an HCC mice model established by the hydrodynamic gene delivery of the yes-associated protein (YAP)-expressing plasmid. The protein synthesis in DTA transfected cells is inhibited by the disappearance of tdTomato and GFP expression co-transfected upon the delivery of the DTA plasmid; the HCC cell growth is inhibited by the expression of DTA in HCC cells in an AFP promoter-selective manner. A significant inhibition of HCC occurrence and the suppression of the tumor marker of AFP and des-gamma-carboxy prothrombin can be seen in mice groups treated with hydrodynamic gene delivery of DTA, both 0 and 2 months after the YAP gene delivery. These results suggest that DTA gene therapy is effective for HCC. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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17 pages, 3361 KiB

Open AccessArticle

Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis

by Kanehiko Suwa, Takashi Yamaguchi, Katsunori Yoshida, Miki Murata, Mayuko Ichimura, Koichi Tsuneyama, Toshihito Seki and Kazuichi Okazaki

Cancers 2020, 12(2), 286; https://doi.org/10.3390/cancers12020286 - 24 Jan 2020

Cited by 7 | Viewed by 2852

Abstract

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-β signaling in hepatocytic nuclei is implicated in fibrosis [...] Read more.

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-β signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-βtype I receptor (TβRI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3, resulting in 2 distinct phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). In mature hepatocytes, oncogenic signaling via the JNK/pSmad3L pathway antagonizes signaling via the tumor-suppressive TβRI/pSmad3C pathway. We immunohistochemically examined domain-specific Smad3 phosphorylation in liver biopsy specimens from 30 NASH patients representing different fibrotic stages and 20 chronically infected hepatitis C patients as controls, correlating Smad3 phosphorylation with clinical course. HCC occurred during follow-up in 11 of 12 NASH patients with abundant pSmad3L and limited pSmad3C but in only 2 of 18 with limited pSmad3L. In contrast, HCC developed in 12 of 15 NASH patients with limited pSmad3C but only 1 of 15 with abundant pSmad3C. Two of fourteen NASH patients with mild fibrosis developed HCC, their hepatocytic nuclei showed abundant pSmad3L and limited pSmad3C. Five of sixteen patients with severe fibrosis did not develop HCC, their hepatocytic nuclei showed limited pSmad3L and abundant pSmad3C. Smad phospho-isoforms may represent important biomarkers predicting HCC in NASH and potential therapeutic targets for preventing NASH-related HCC. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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18 pages, 8349 KiB

Open AccessArticle

Glucose Depletion Enhances the Stem Cell Phenotype and Gemcitabine Resistance of Cholangiocarcinoma Organoids through AKT Phosphorylation and Reactive Oxygen Species

by Nao Yoshikawa, Yoshimasa Saito, Hiroki Manabe, Toshiaki Nakaoka, Ryoei Uchida, Ryo Furukawa, Toshihide Muramatsu, Yuko Sugiyama, Masaki Kimura and Hidetsugu Saito

Cancers 2019, 11(12), 1993; https://doi.org/10.3390/cancers11121993 - 11 Dec 2019

Cited by 10 | Viewed by 3146

Abstract

Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead [...] Read more.

Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead to glucose depletion. In the present study, we investigated how cholangiocarcinoma cells adapt to glucose depletion using a 3D organoid culture system. We cultured organoids derived from cholangiocarcinoma under glucose-free condition and investigated cell proliferation, expression of stem cell markers and resistance to gemcitabine. Cholangiocarcinoma organoids cultured under glucose-free condition showed reduced proliferation but were able to survive. We also observed an increase in the expression of stem cell markers including LGR5 and enhancement of stem cell phenotypic characteristics such as resistance to gemcitabine through AKT phosphorylation and reactive oxygen species. These findings indicate that cholangiocarcinoma cells are able to adapt to glucose depletion through enhancement of their stem cell phenotype in response to changes in microenvironmental conditions. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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28 pages, 18361 KiB

Open AccessArticle

SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

by Stefania Cannito, Beatrice Foglia, Gianmarco Villano, Cristian Turato, Teresa C Delgado, Elisabetta Morello, Fabrizio Pin, Erica Novo, Lucia Napione, Santina Quarta, Mariagrazia Ruvoletto, Silvano Fasolato, Giacomo Zanus, Sebastiano Colombatto, Fernando Lopitz-Otsoa, David Fernández-Ramos, Federico Bussolino, Salvatore Sutti, Emanuele Albano, Maria Luz Martínez-Chantar, Patrizia Pontisso and Maurizio Parola Show full author list Hide full author list

Cancers 2019, 11(12), 1933; https://doi.org/10.3390/cancers11121933 - 4 Dec 2019

Cited by 24 | Viewed by 4394

Abstract

Background: SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2α-dependent cysteine-protease inhibitor up-regulated in hepatocellular carcinoma (HCC), released by cancer cells and able to stimulate proliferation and epithelial-to-mesenchymal-transition. Methods: In the study we employed transgenic and knock out SerpinB3 mice, liver cancer [...] Read more.

Background: SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2α-dependent cysteine-protease inhibitor up-regulated in hepatocellular carcinoma (HCC), released by cancer cells and able to stimulate proliferation and epithelial-to-mesenchymal-transition. Methods: In the study we employed transgenic and knock out SerpinB3 mice, liver cancer cell line, human HCC specimens, and mice receiving diethyl-nitrosamine (DEN) administration plus choline-deficient L-amino acid refined (CDAA) diet (DEN/CDAA protocol). Results: We provide detailed and mechanistic evidence that SB3 can act as a paracrine mediator able to affect the behavior of surrounding cells by differentially up-regulating, in normoxic conditions, HIF-1α and HIF-2α. SB3 acts by (i) up-regulating HIF-1α transcription, facilitating cell survival in a harsh microenvironment and promoting angiogenesis, (ii) increasing HIF-2α stabilization via direct/selective NEDDylation, promoting proliferation of liver cancer cells, and favoring HCC progression. Moreover (iii) the highest levels of NEDD8-E1 activating enzyme (NAE1) mRNA were detected in a subclass of HCC patients expressing the highest levels of HIF-2α transcripts; (iv) mice undergoing DEN/CDAA carcinogenic protocol showed a positive correlation between SB3 and HIF-2α transcripts with the highest levels of NAE1 mRNA detected in nodules expressing the highest levels of HIF-2α transcripts. Conclusions: These data outline either HIF-2α and NEDDylation as two novel putative therapeutic targets to interfere with the procarcinogenic role of SerpinB3 in the development of HCC. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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18 pages, 6469 KiB

Open AccessArticle

HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

by Yuan-Hsi Wang, Chao-Lien Liu, Wan-Chun Chiu, Yuh-Ching Twu and Yi-Jen Liao

Cancers 2019, 11(12), 1876; https://doi.org/10.3390/cancers11121876 - 26 Nov 2019

Cited by 59 | Viewed by 7136

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. The aims of this study were to verify the mechanisms and therapeutic potential of the ketogenesis rate-limiting enzyme 3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in HCC. Immunohistochemical staining of human liver disease tissue arrays showed that HMGCS2 is abundantly expressed in normal liver tissues but is downregulated in cirrhosis and HCC tissues. In HCC patients, lower HMGCS2 expression was correlated with higher pathological grades and clinical stages. In our investigation of the molecular mechanisms of HMGCS2 in HCC, we showed that knockdown of HMGCS2 decreased ketone production, which promoted cell proliferation, cell migration, and xenograft tumorigenesis by enhancing c-Myc/cyclinD1 and EMT signaling and by suppressing the caspase-dependent apoptosis pathway. Ketone body treatment reduced the proliferation- and migration-promoting effects of HMGCS2 knockdown in cells. In contrast, HMGCS2 overexpression increased the intracellular ketone level and inhibited cell proliferation, cell migration, and xenograft tumorigenesis. Finally, ketogenic diet administration significantly inhibited liver cancer cell growth in mice. Our studies highlight the potential therapeutic strategy of targeting HMGCS2-mediated ketogenesis in liver cancer. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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14 pages, 9450 KiB

Open AccessArticle

[¹⁸F] Clofarabine for PET Imaging of Hepatocellular Carcinoma

by Olga Sergeeva, Vladimir Kepe, Yifan Zhang, Galen A. Miller-Atkins, Jonathan D. Keynon, Renuka Iyer, Sandra Sexton, Amad Awadallah, Wei Xin, Yogen Saunthararajah, E. Ricky Chan and Zhenghong Lee

Cancers 2019, 11(11), 1748; https://doi.org/10.3390/cancers11111748 - 7 Nov 2019

Cited by 4 | Viewed by 2682

Abstract

Clinical diagnosis of hepatocellular carcinoma (HCC) relies heavily on radiological imaging. However, information pertaining to liver cancer treatment such as the proliferation status is lacking. Imaging tumor proliferation can be valuable in patient management. This study investigated ¹⁸F-labeled clofarabine ([¹⁸F]CFA) [...] Read more.

Clinical diagnosis of hepatocellular carcinoma (HCC) relies heavily on radiological imaging. However, information pertaining to liver cancer treatment such as the proliferation status is lacking. Imaging tumor proliferation can be valuable in patient management. This study investigated ¹⁸F-labeled clofarabine ([¹⁸F]CFA) targeting deoxycytidine kinase (dCK) for PET imaging of dCK-dependent proliferation in HCC. Since clinical PET scans showed a high liver background uptake of [¹⁸F]CFA, the aim of this study was to reduce this liver background uptake. A clinically relevant animal model of spontaneously developed HCC in the woodchucks was used for imaging experiments. Several modifiers were tested and compared with the baseline PET scan: Forodesine, probenecid, and cold clofarabine, all applied before the hot [¹⁸F]CFA injection to evaluate the reduction in liver background uptake. Application of forodesine before hot [¹⁸F]CFA injection did not reduce the background uptake. Instead, it increased the background by 11.6–36.3%. Application of probenecid also increased the liver background uptake by 16.6–32.1%. Cold CFA application did reduce the liver background uptake of [¹⁸F]CFA, comparing to the baseline scan. Combining cold CFA with [¹⁸F]CFA for PET imaging of liver cancers is a promising strategy, worthy of further clinical evaluation. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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14 pages, 889 KiB

Open AccessArticle

Tumor Marker-Based Definition of the Transarterial Chemoembolization-Refractoriness in Intermediate-Stage Hepatocellular Carcinoma: A Multi-Cohort Study

by Jun Sik Yoon, Dong Hyun Sinn, Jeong-Hoon Lee, Hwi Young Kim, Cheol-Hyung Lee, Sun Woong Kim, Hyo Young Lee, Joon Yeul Nam, Young Chang, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Hyo-Cheol Kim, Jin Wook Chung, Yoon Jun Kim and Jung-Hwan Yoon

Cancers 2019, 11(11), 1721; https://doi.org/10.3390/cancers11111721 - 4 Nov 2019

Cited by 9 | Viewed by 2942

Abstract

Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE [...] Read more.

Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre- and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (ΔMoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ΔMoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ΔMoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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17 pages, 4109 KiB

Open AccessArticle

High Expression of MicroRNA-196a is Associated with Progression of Hepatocellular Carcinoma in Younger Patients

by Shen-Yung Wang, Chih-Li Chen, Yu-Chen Hu, Yi Chi, Yen-Hua Huang, Chien-Wei Su, Wen-Juei Jeng, Yuh-Jin Liang and Jaw-Ching Wu

Cancers 2019, 11(10), 1549; https://doi.org/10.3390/cancers11101549 - 13 Oct 2019

Cited by 15 | Viewed by 3454

Abstract

MicroRNAs are small RNAs involved in various biological processes and cancer metastasis. miR-196a was associated with aggressive behaviors in several cancers. The role of miR-196a in hepatocellular carcinoma (HCC) metastasis remains unknown. This study aimed to examine the role of miR-196a in HCC [...] Read more.

MicroRNAs are small RNAs involved in various biological processes and cancer metastasis. miR-196a was associated with aggressive behaviors in several cancers. The role of miR-196a in hepatocellular carcinoma (HCC) metastasis remains unknown. This study aimed to examine the role of miR-196a in HCC progression. Expression of miR-196a was measured in 83 human HCC samples. The HCC patients with high miR-196a expression had younger ages, lower albumin levels, higher frequency with alpha-fetoprotein (AFP) levels ≥20 ng/mL, more macrovascular invasion, and non-early stages. Kaplan–Meier analysis showed that high miR-196a expression was associated with lower recurrence-free survival. Knockdown of miR-196a decreased transwell invasiveness, sphere formation, transendothelial invasion, and Slug, Twist, Oct4, and Sox2 expression, suppressed angiogenesis, and reduced sizes of xenotransplants and number of pulmonary metastasis. Down-regulation of miR-196a decreased Runx2 and osteopontin (OPN) levels. Knockdown of Runx2 in vitro resulted in comparable phenotypes with miR-196a down-regulation. Restoration of Runx2 in miR-196a-knockdown HCC reverted tumor phenotypes. This study showed that high expression of miR-196a is associated with HCC progression in a subset of younger patients. miR-196a mediates HCC progression via upregulation of Runx2, OPN, epithelial–mesenchymal transition (EMT) regulators, and stemness genes. We proposed that miR-196a can be used as a prognostic marker and a potential therapeutic target. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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10 pages, 793 KiB

Open AccessFeature PaperArticle

Sorafenib-Regorafenib Sequential Therapy in Japanese Patients with Unresectable Hepatocellular Carcinoma—Relative Dose Intensity and Post-Regorafenib Therapies in Real World Practice

by Wan Wang, Kaoru Tsuchiya, Masayuki Kurosaki, Yutaka Yasui, Kento Inada, Sakura Kirino, Koji Yamashita, Shuhei Sekiguchi, Yuka Hayakawa, Leona Osawa, Mao Okada, Mayu Higuchi, Kenta Takaura, Chiaki Maeyashiki, Shun Kaneko, Nobuharu Tamaki, Hiroyuki Nakanishi, Jun Itakura, Yuka Takahashi, Yasuhiro Asahina, Nobuyuki Enomoto and Namiki Izumi Show full author list Hide full author list

Cancers 2019, 11(10), 1517; https://doi.org/10.3390/cancers11101517 - 9 Oct 2019

Cited by 36 | Viewed by 4087

Abstract

Background: We aimed to explore the relative dose intensity (RDI) and post-regorafenib treatments in regorafenib therapy. Methods: The medical records of 38 patients treated with regorafenib between July 2017 and June 2019 at our institution were collected. The RDI of regorafenib for the [...] Read more.

Background: We aimed to explore the relative dose intensity (RDI) and post-regorafenib treatments in regorafenib therapy. Methods: The medical records of 38 patients treated with regorafenib between July 2017 and June 2019 at our institution were collected. The RDI of regorafenib for the first month (1M-RDI) was calculated. Results: The overall survival (OS) and progression-free survival (PFS) were 12.4 and 3.7 months. The objective response rate and disease control rate were 13.2% and 71.1%. The median total dose of regorafenib in the first month was 2080 mg (240–3360 mg), and the median 1M-RDI was 61.9% (7.1–100%). Patients with 1M-RDI ≥ 50% showed significantly longer OS and PFS than patients with 1M-RDI < 50% (HR 0.19, 95% CI 0.08–0.48, p = 0.0004 and HR 0.2, 95% CI 0.08–0.52, p = 0.0008). A 1M-RDI ≥ 50% (HR 0.18, 95% CI 0.06–0.55, p = 0.002) and hand–foot skin reaction (HR 0.03, 95% CI 0.008–0.16, p < 0.0001) were independently associated with OS. Post-regorafenib therapies were performed in 19 (86.4%) of 22 patients who had stopped regorafenib due to disease progression. Conclusion: A 1M-RDI ≥ 50% is clinically significant. Post-regorafenib therapies are commonly performed in real-world practice. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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17 pages, 3819 KiB

Open AccessArticle

CRISPR Loss-of-Function Screen Identifies the Hippo Signaling Pathway as the Mediator of Regorafenib Efficacy in Hepatocellular Carcinoma

by Shigeki Suemura, Takahiro Kodama, Yuta Myojin, Ryoko Yamada, Minoru Shigekawa, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi and Tetsuo Takehara

Cancers 2019, 11(9), 1362; https://doi.org/10.3390/cancers11091362 - 13 Sep 2019

Cited by 24 | Viewed by 5064

Abstract

Regorafenib is used for hepatocellular carcinoma (HCC), but its response does not last long, partly due to chemoresistance acquisition. We performed a clustered regularly interspaced short palindromic repeats (CRISPR)-based loss-of-function genetic screen and aimed to discover molecules involved in regorafenib resistance in HCC. [...] Read more.

Regorafenib is used for hepatocellular carcinoma (HCC), but its response does not last long, partly due to chemoresistance acquisition. We performed a clustered regularly interspaced short palindromic repeats (CRISPR)-based loss-of-function genetic screen and aimed to discover molecules involved in regorafenib resistance in HCC. Xenograft tumors established from Cas9-expressing HCC cells with pooled CRISPR kinome libraries were treated with regorafenib or a vehicle. Sequencing analysis identified 31 genes, with the abundance of multiple guide RNAs increased in regorafenib-treated tumors compared to that in vehicle-treated tumors, including 2 paralogues, LATS2 and LATS1, core components of the Hippo signaling pathway. Notably, all eight designed guide RNAs targeting LATS2 increased in regorafenib-treated tumors, suggesting that LATS2 deletion confers regorafenib resistance in HCC cells. LATS2 knockdown significantly mitigated the cytotoxic and proapoptotic effects of regorafenib on HCC cells. LATS2 inhibition stabilized the Hippo signaling mediator YAP, leading to the upregulation of antiapoptotic Bcl-xL and the multidrug resistance transporter ABCB1. Among 12 hepatoma cell lines, the half maximal inhibitory concentration (IC50) values of regorafenib were positively correlated with any of YAP, Bcl-xL and ABCB1 levels. The inhibition of YAP or Bcl-xL in regorafenib-insensitive HCC cells restored their susceptibility to regorafenib. In conclusion, our screen identified the Hippo signaling pathway as the mediator of regorafenib efficacy in HCC. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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24 pages, 7179 KiB

Open AccessArticle

A Novel AURKA Mutant-Induced Early-Onset Severe Hepatocarcinogenesis Greater than Wild-Type via Activating Different Pathways in Zebrafish

by Zhong-Liang Su, Chien-Wei Su, Yi-Luen Huang, Wan-Yu Yang, Bonifasius Putera Sampurna, Toru Ouchi, Kuan-Lin Lee, Chen-Sheng Wu, Horng-Dar Wang and Chiou-Hwa Yuh

Cancers 2019, 11(7), 927; https://doi.org/10.3390/cancers11070927 - 2 Jul 2019

Cited by 16 | Viewed by 4127

Abstract

Aurora A kinase (AURKA) is an important regulator in mitotic progression and is overexpressed frequently in human cancers, including hepatocellular carcinoma (HCC). Many AURKA mutations were identified in cancer patients. Overexpressing wild-type Aurka developed a low incidence of hepatic tumors after long latency [...] Read more.

Aurora A kinase (AURKA) is an important regulator in mitotic progression and is overexpressed frequently in human cancers, including hepatocellular carcinoma (HCC). Many AURKA mutations were identified in cancer patients. Overexpressing wild-type Aurka developed a low incidence of hepatic tumors after long latency in mice. However, none of the AURKA mutant animal models have ever been described. The mechanism of mutant AURKA-mediated hepatocarcinogenesis is still unclear. A novel AURKA mutation with a.a.352 Valine to Isoleucine (V352I) was identified from clinical specimens. By using liver-specific transgenic fish overexpressing both the mutant and wild-type AURKA, the AURKA(V352I)-induced hepatocarcinogenesis was earlier and much more severe than wild-type AURKA. Although an increase of the expression of lipogenic enzyme and lipogenic factor was observed in both AURKA(V352I) and AURKA(WT) transgenic fish, AURKA(V352I) has a greater probability to promote fibrosis at 3 months compared to AURKA(WT). Furthermore, the expression levels of cell cycle/proliferation markers were higher in the AURKA(V352I) mutant than AURKA(WT) in transgenic fish, implying that the AURKA(V352I) mutant may accelerate HCC progression. Moreover, we found that the AURKA(V352I) mutant activates AKT signaling and increases nuclear β-catenin, but AURKA(WT) only activates membrane form β-catenin, which may account for the differences. In this study, we provide a new insight, that the AURKA(V352I) mutation contributes to early onset hepatocarcinogenesis, possibly through activation of different pathways than AURKA(WT). This transgenic fish may serve as a drug-screening platform for potential precision medicine therapeutics. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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19 pages, 3631 KiB

Open AccessArticle

Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility

by Rosalba D’Alessandro, Maria Grazia Refolo, Palma Aurelia Iacovazzi, Pasqua Letizia Pesole, Caterina Messa and Brian Irving Carr

Cancers 2019, 11(6), 787; https://doi.org/10.3390/cancers11060787 - 7 Jun 2019

Cited by 11 | Viewed by 3914

Abstract

Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination [...] Read more.

Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination of sorafenib and regorafenib might also be effective at very low concentrations, with resulting potential for lessened clinical toxicity. MTT test, clonogenic assay, Ki67 staining and cell cycle analysis were assessed for cell proliferation and Annexin V and western blotting analysis relative to the expression of cleaved Caspase-3 and BID for cell apoptosis. In these experimental conditions cell growth and migration were potently inhibited and apoptosis induced even in HCC cells producing high alpha fetoprotein (AFP) levels (clinically worse prognosis). The combination also inhibited levels of the two HCC biomarkers, AFP and des gamma carboxy prothrombin (DCP). Additional inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR) or Insulin-like Growth Factor 1 Receptor (IGF1R) enhanced effects on AFP and DCP levels, cell growth inhibition and MAPK and PI3K/Akt signaling inhibition due to sorafenib/regorafenib combination. These combinations have the potential for decreased toxicity while simultaneously enhancing therapeutic effects. This potential decrease in toxicity is being explored in ongoing studies. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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15 pages, 3886 KiB

Open AccessArticle

Collagen 1A1 (COL1A1) Is a Reliable Biomarker and Putative Therapeutic Target for Hepatocellular Carcinogenesis and Metastasis

by Hon-Ping Ma, Hang-Lung Chang, Oluwaseun Adebayo Bamodu, Vijesh Kumar Yadav, Ting-Yi Huang, Alexander T. H. Wu, Chi-Tai Yeh, Shin-Han Tsai and Wei-Hwa Lee

Cancers 2019, 11(6), 786; https://doi.org/10.3390/cancers11060786 - 7 Jun 2019

Cited by 148 | Viewed by 10180

Abstract

Increasing evidence shows that hepatocellular carcinoma (HCC) is a principal cause of cancer-related mortality globally, especially among Asian and African populations. Collagen type I α1 (COL1A1) is the major component of type I collagen. While aberrant expression of COL1A1 and COL1A2 is implicated [...] Read more.

Increasing evidence shows that hepatocellular carcinoma (HCC) is a principal cause of cancer-related mortality globally, especially among Asian and African populations. Collagen type I α1 (COL1A1) is the major component of type I collagen. While aberrant expression of COL1A1 and COL1A2 is implicated in numerous cancers, the differential role of COL1A1 in malignant, premalignant and normal tissues remains unclear, and its clinical significance in HCC has not been elucidated. In this study, using bioinformatics analysis of publicly-available HCC microarray data from Gene Expression Omnibus (GEO) and RNAseq data from The Cancer Genome Atlas (TCGA) database, we determined that COL1A1 is significantly upregulated in HCC tumor tissues in comparison to normal tissues. Our analysis also revealed that COL1A1 confers survival advantage and enhanced oncogenicity on HCC cells. Interestingly, the siRNA-mediated silencing of COL1A1 expression (siCOLIA1) suppressed HCC cells clonogenicity, motility, invasiveness and tumorsphere formation. Concomitantly, siCOL1A1 abrogated Slug-dependent epithelial-to-mesenchymal transition (EMT) and HCC stemness gene-signature, by attenuating expression of stemness markers SOX2, OCT4 and CD133. The present study provides some mechanistic insight into COL1A1 activity in HCC and highlights its putative role as an important diagnostic biomarker and potential therapeutic target in early development and metastasis of HCC. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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18 pages, 8111 KiB

Open AccessArticle

Perilipin 5 and Lipocalin 2 Expression in Hepatocellular Carcinoma

by Anastasia Asimakopoulou, Mihael Vucur, Tom Luedde, Silvia Schneiders, Stavroula Kalampoka, Thomas S. Weiss and Ralf Weiskirchen

Cancers 2019, 11(3), 385; https://doi.org/10.3390/cancers11030385 - 19 Mar 2019

Cited by 26 | Viewed by 6434

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers worldwide. Therefore, current global research focuses on molecular tools for early diagnosis of HCC, which can lead to effective treatment at an early stage. Perilipin 5 (PLIN5) has been studied as [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers worldwide. Therefore, current global research focuses on molecular tools for early diagnosis of HCC, which can lead to effective treatment at an early stage. Perilipin 5 (PLIN5) has been studied as one of the main proteins of the perilipin family, whose role is to maintain lipid homeostasis by inhibiting lipolysis. In this study, we show for the first time that PLIN5 is strongly expressed in tumors of human patients with HCC as well as in mouse livers, in which HCC was genetically or experimentally induced by treatment with the genotoxic agent diethylnitrosamine. Moreover, the secreted acute phase glycoprotein Lipocalin 2 (LCN2) established as a biomarker of acute kidney injury, is also proven to indicate liver injury with upregulated expression in numerous cases of hepatic damage, including steatohepatitis. LCN2 has been studied in various cancers, and it has been assigned roles in multiple cellular processes such as the suppression of the invasion of HCC cells and their metastatic abilities. The presence of this protein in blood and urine, in combination with the presence of

α

-Fetoprotein (AFP), is hypothesized to serve as a biomarker of early stages of HCC. In the current study, we show in humans and mice that LCN2 is secreted into the serum from liver cancer tissue. We also show that AFP-positive hepatocytes represent the main source for the massive expression of LCN2 in tumoral tissue. Thus, the strong presence of PLIN5 and LCN2 in HCC and understanding their roles could establish them as markers for diagnosis or as treatment targets against HCC. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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Review

Jump to: Research

26 pages, 704 KiB

Open AccessEditor’s ChoiceReview

The Cancer Stem Cell in Hepatocellular Carcinoma

by Lucas-Alexander Schulte, Juan Carlos López-Gil, Bruno Sainz, Jr. and Patrick C. Hermann

Cancers 2020, 12(3), 684; https://doi.org/10.3390/cancers12030684 - 14 Mar 2020

Cited by 40 | Viewed by 6657

Abstract

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC [...] Read more.

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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23 pages, 1368 KiB

Open AccessEditor’s ChoiceReview

Inflammatory Mechanisms of HCC Development

by Maria Grazia Refolo, Caterina Messa, Vito Guerra, Brian Irving Carr and Rosalba D’Alessandro

Cancers 2020, 12(3), 641; https://doi.org/10.3390/cancers12030641 - 10 Mar 2020

Cited by 123 | Viewed by 11420

Abstract

HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the [...] Read more.

HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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31 pages, 1656 KiB

Open AccessReview

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

by Chandramohan Kiruthiga, Kasi Pandima Devi, Seyed M. Nabavi and Anupam Bishayee

Cancers 2020, 12(3), 562; https://doi.org/10.3390/cancers12030562 - 29 Feb 2020

Cited by 65 | Viewed by 7671

Abstract

Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, [...] Read more.

Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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19 pages, 1070 KiB

Open AccessReview

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma

by Manali Dimri and Ande Satyanarayana

Cancers 2020, 12(2), 491; https://doi.org/10.3390/cancers12020491 - 20 Feb 2020

Cited by 223 | Viewed by 15825

Abstract

Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating [...] Read more.

Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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11 pages, 2947 KiB

Open AccessReview

Imaging of Colorectal Liver Metastases: New Developments and Pending Issues

by Matteo Renzulli, Alfredo Clemente, Anna Maria Ierardi, Irene Pettinari, Francesco Tovoli, Stefano Brocchi, Giuliano Peta, Salvatore Cappabianca, Gianpaolo Carrafiello and Rita Golfieri

Cancers 2020, 12(1), 151; https://doi.org/10.3390/cancers12010151 - 8 Jan 2020

Cited by 35 | Viewed by 5565

Abstract

Computed tomography (CT), magnetic resonance imaging (MRI), and 18-fluorideoxyglucose positron emission tomography (¹⁸FDG-PET) are historically the most accurate imaging techniques for diagnosing liver metastases. Recently, the combination of diffusion-weighted imaging and hepatospecific contrast media, such as gadoxetic acid in MRI, have [...] Read more.

Computed tomography (CT), magnetic resonance imaging (MRI), and 18-fluorideoxyglucose positron emission tomography (¹⁸FDG-PET) are historically the most accurate imaging techniques for diagnosing liver metastases. Recently, the combination of diffusion-weighted imaging and hepatospecific contrast media, such as gadoxetic acid in MRI, have been demonstrated to have the highest diagnostic accuracy, sensitivity, and specificity for detecting liver metastases. Various recent meta-analyses have confirmed the diagnostic superiority of this combination (diffusion-weighted imaging and gadoxetic acid-enhanced MRI), especially in terms of per lesion sensitivity, as compared with CT and ¹⁸FDG-PET, even for smaller lesions (≤1 cm). However, none of the oncological guidelines have suggested the use of MRI as a first-line technique for liver metastasis detection during the staging process of oncological patients. This review analyzes the history of the principal imaging techniques for the diagnosis of liver metastases, in particular of colorectal liver metastases, focusing on the most accurate method (diffusion-weighted imaging combined with gadoxetic acid-enhanced MRI), possible reasons for the lack of its diffusion in the guidelines, and possible future scenarios. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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23 pages, 907 KiB

Open AccessReview

Immune Therapy for Liver Cancers

by Marc Hilmi, Angélique Vienot, Benoît Rousseau and Cindy Neuzillet

Cancers 2020, 12(1), 77; https://doi.org/10.3390/cancers12010077 - 27 Dec 2019

Cited by 38 | Viewed by 5509

Abstract

Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened [...] Read more.

Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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23 pages, 1384 KiB

Open AccessReview

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

by Simona Todisco, Paolo Convertini, Vito Iacobazzi and Vittoria Infantino

Cancers 2020, 12(1), 68; https://doi.org/10.3390/cancers12010068 - 25 Dec 2019

Cited by 61 | Viewed by 8317

Abstract

Hepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical [...] Read more.

Hepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical player in promoting tumor survival and proliferation to sustain increased metabolic needs of cancer cells. Among the metabolic pathways, the tricarboxylic acid (TCA) cycle is a primary route for bioenergetic, biosynthetic, and redox balance requirements of cells. In recent years, a large amount of evidence has highlighted the relevance of the TCA cycle rewiring in a variety of cancers. Indeed, aberrant gene expression of several key enzymes and changes in levels of critical metabolites have been observed in many solid human tumors. In this review, we summarize the role of the TCA cycle rewiring in HCC by reporting gene expression and activity dysregulation of enzymes relating not only to the TCA cycle but also to glutamine metabolism, malate/aspartate, and citrate/pyruvate shuttles. Regarding the transcriptional regulation, we focus on the link between NF-κB-HIF1 transcriptional factors and TCA cycle reprogramming. Finally, the potential of metabolic targets for new HCC treatments has been explored. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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12 pages, 1412 KiB

Open AccessReview

Efficacy of Regorafenib in Hepatocellular Carcinoma Patients: A Systematic Review and Meta-Analysis

by Antonio Facciorusso, Mohamed A. Abd El Aziz and Rodolfo Sacco

Cancers 2020, 12(1), 36; https://doi.org/10.3390/cancers12010036 - 20 Dec 2019

Cited by 57 | Viewed by 4579

Abstract

Regorafenib showed promising results as a second-line agent after sorafenib failure in hepatocellular carcinoma patients. The aim of this meta-analysis was to evaluate the efficacy and safety of regorafenib in hepatocarcinoma patients. A computerized bibliographic search was performed on the main databases. The [...] Read more.

Regorafenib showed promising results as a second-line agent after sorafenib failure in hepatocellular carcinoma patients. The aim of this meta-analysis was to evaluate the efficacy and safety of regorafenib in hepatocarcinoma patients. A computerized bibliographic search was performed on the main databases. The primary outcome was overall survival. Secondary outcomes were progression-free survival, tumor response, and the adverse events rate. Outcomes were pooled through a random-effects model and summary estimates were expressed in terms of median and 95% confidence interval or rates, as appropriate. One randomized-controlled trial and seven non-randomized studies with 809 patients were included. The great majority of recruited patients were in Child-Pugh A and ECOG 0 stage. Median overall survival was 11.08 months (9.46–12.71) and sensitivity analyses confirmed this finding, with a median survival ranging from 10.2 to 13.8 months. Duration of regorafenib therapy was 3.58 months, whereas median progression-free survival was 3.24 months (2.68–3.86). The pooled objective response rate was 10.1% (7.8–12.5%) while the disease control rate was 65.5% (61.3–69.7%) with no evidence of heterogeneity (I² = 0%; Diarrhea, fatigue, and hand-foot skin reaction were the most frequent adverse events. The current meta-analysis shows that regorafenib represents a valuable and relatively safe therapeutic option in intermediate/advanced hepatocellular carcinomapatients who progress on sorafenib. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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29 pages, 798 KiB

Open AccessReview

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

by Kenya Kamimura, Takeshi Yokoo, Hiroyuki Abe and Shuji Terai

Cancers 2019, 11(12), 1865; https://doi.org/10.3390/cancers11121865 - 25 Nov 2019

Cited by 32 | Viewed by 5449

Abstract

The liver is a key organ for metabolism, protein synthesis, detoxification, and endocrine function, and among liver diseases, including hepatitis, cirrhosis, malignant tumors, and congenital disease, liver cancer is one of the leading causes of cancer-related deaths worldwide. Conventional therapeutic options such as [...] Read more.

The liver is a key organ for metabolism, protein synthesis, detoxification, and endocrine function, and among liver diseases, including hepatitis, cirrhosis, malignant tumors, and congenital disease, liver cancer is one of the leading causes of cancer-related deaths worldwide. Conventional therapeutic options such as embolization and chemotherapy are not effective against advanced-stage liver cancer; therefore, continuous efforts focus on the development of novel therapeutic options, including molecular targeted agents and gene therapy. In this review, we will summarize the progress toward the development of gene therapies for liver cancer, with an emphasis on recent clinical trials and preclinical studies. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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13 pages, 538 KiB

Open AccessReview

A Role for the Biological Clock in Liver Cancer

by Gianluigi Mazzoccoli, Luca Miele, Giuseppe Marrone, Tommaso Mazza, Manlio Vinciguerra and Antonio Grieco

Cancers 2019, 11(11), 1778; https://doi.org/10.3390/cancers11111778 - 11 Nov 2019

Cited by 14 | Viewed by 4164

Abstract

The biological clock controls at the molecular level several aspects of mammalian physiology, by regulating daily oscillations of crucial biological processes such as nutrient metabolism in the liver. Disruption of the circadian clock circuitry has recently been identified as an independent risk factor [...] Read more.

The biological clock controls at the molecular level several aspects of mammalian physiology, by regulating daily oscillations of crucial biological processes such as nutrient metabolism in the liver. Disruption of the circadian clock circuitry has recently been identified as an independent risk factor for cancer and classified as a potential group 2A carcinogen to humans. Hepatocellular carcinoma (HCC) is the prevailing histological type of primary liver cancer, one of the most important causes of cancer-related death worldwide. HCC onset and progression is related to B and C viral hepatitis, alcoholic and especially non-alcoholic fatty liver disease (NAFLD)-related milieu of fibrosis, cirrhosis, and chronic inflammation. In this review, we recapitulate the state-of-the-art knowledge on the interplay between the biological clock and the oncogenic pathways and mechanisms involved in hepatocarcinogenesis. Finally, we propose how a deeper understanding of circadian clock circuitry–cancer pathways’ crosstalk is promising for developing new strategies for HCC prevention and management. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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20 pages, 1946 KiB

Open AccessReview

New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma

by Monica Mossenta, Davide Busato, Lorena Baboci, Federica Di Cintio, Giuseppe Toffoli and Michele Dal Bo

Cancers 2019, 11(8), 1086; https://doi.org/10.3390/cancers11081086 - 31 Jul 2019

Cited by 41 | Viewed by 5638

Abstract

Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis that is determined by an augmented production of proangiogenesis factors by tumor and adjacent cells. This unbalanced angiogenesis process is a key feature of HCC carcinogenesis and progression. Proangiogenic factors also have a relevant [...] Read more.

Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis that is determined by an augmented production of proangiogenesis factors by tumor and adjacent cells. This unbalanced angiogenesis process is a key feature of HCC carcinogenesis and progression. Proangiogenic factors also have a relevant role in the generation and maintenance of an immunosuppressive tumor microenvironment. Several therapeutic options for HCC treatment are based on the inhibition of angiogenesis, both in the early/intermediate stages of the disease and in the late stages of the disease. Conventional treatment options employing antiangiogenic approaches provide for the starving of tumors of their blood supply to avoid the refueling of oxygen and nutrients. An emerging alternative point of view is the normalization of vasculature leading to enhance tumor perfusion and oxygenation, potentially capable, when proposed in combination with other treatments, to improve delivery and efficacy of other therapies, including immunotherapy with checkpoint inhibitors. The introduction of novel biomarkers can be useful for the definition of the most appropriate dose and scheduling for these combination treatment approaches. The present review provides a wide description of the pharmaceutical compounds with an antiangiogenic effect proposed for HCC treatment and investigated in clinical trials, including antibodies and small-molecule kinase inhibitors. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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