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1
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Liang J, Bai Y, Ha FS, Luo Y, Deng HT, Gao YT. Combining local regional therapy and systemic therapy: Expected changes in the treatment landscape of recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1-18. [PMID: 36684055 PMCID: PMC9850755 DOI: 10.4251/wjgo.v15.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 12/06/2022] [Accepted: 12/27/2022] [Indexed: 01/10/2023] Open
Abstract
Improvements in early screening, new diagnostic techniques, and surgical treatment have led to continuous downward trends in hepatocellular carcinoma (HCC) morbidity and mortality rates. However, high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC. The clinical characteristics and prognosis of recurrent HCC are heterogeneous, and guidelines on treatment strategies for recurrent HCC are lacking. Therapies such as surgical resection, radiofrequency ablation, and transhepatic arterial chemoembolization are effective for tumors confined to the liver, and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis. With the deepening of the understanding of the immune microenvironment of HCC, blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC. In addition, improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment. Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC. This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment, demonstrates the basis for combining local treatment and systemic treatment, and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.
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Affiliation(s)
- Jing Liang
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Yi Bai
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China
| | - Fu-Shuang Ha
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying Luo
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Hui-Ting Deng
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying-Tang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- Tianjin Institute of Hepatobiliary Disease, The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China
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2
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Li JY, Wang LL, Fan J, Liu DX, Han JB, Zhang YF, Yin DD, Yi YX. New and effective method to develop primary hepatocytes from liver cancer patients. Exp Biol Med (Maywood) 2022; 247:972-981. [PMID: 35470702 DOI: 10.1177/15353702221085534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Liver cancer (LC) is one of the most common malignant tumors worldwide. Since the mechanism of LC pathogenesis and metastasis cannot be carried out directly on the human body, it is particularly important to establish human liver cancer cell lines for research in vitro. In this study, tissue block adherence method combined with cell clumps digestion method was used to establish primary human hepatocytes (PHHs) with a successful rate of 60% (45/75). Short tandem repeat (STR) analysis proved the cells were derived from its paired tissues. These cells from hepatocellular carcinoma (HCC) expressed NTCP and secreted ALB and AAT as detected by western blot, and expressed hepatocyte-specific membrane protein ASGR1 as detected by flow cytometry. Liver cancer biomarkers like CK7 in ICC (intrahepatic cholangiocarcinoma), AFP, and GPC3 in HCC expressed of different degree as detected by immunohistochemical analysis. These cells displayed typical liver cancer cell morphological characteristics and can passage stably. In conclusion, we developed an effective method to establish PHHs. Further studies are necessary to study if these cells maintaining other liver function and reproduce the physiology of the tumors and how these cells behavior in the drug development.
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Affiliation(s)
- Jia-Yan Li
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
| | - Li-Li Wang
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
| | - Jing Fan
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
| | - Du-Xian Liu
- Department of Pathology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
| | - Jian-Bo Han
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
| | - Yu-Feng Zhang
- Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
| | - Dan-Dan Yin
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
| | - Yong-Xiang Yi
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China.,Department of Hepatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, P.R. China
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3
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Tsui YM, Chan LK, Ng IOL. Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential. Br J Cancer 2020; 122:1428-1440. [PMID: 32231294 PMCID: PMC7217836 DOI: 10.1038/s41416-020-0823-9] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/30/2020] [Accepted: 03/09/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer stemness, referring to the stem-cell-like phenotype of cancer cells, has been recognised to play important roles in different aspects of hepatocarcinogenesis. A number of well-established cell-surface markers already exist for liver cancer stem cells, with potential new markers of liver cancer stem cells being identified. Both genetic and epigenetic factors that affect various signalling pathways are known to contribute to cancer stemness. In addition, the tumour microenvironment—both physical and cellular—is known to play an important role in regulating cancer stemness, and the potential interaction between cancer stem cells and their microenvironment has provided insight into the regulation of the tumour-initiating ability as well as the cellular plasticity of liver CSCs. Potential specific therapeutic targeting of liver cancer stemness is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcome by reducing chemoresistance.
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Affiliation(s)
- Yu-Man Tsui
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Lo-Kong Chan
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong. .,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong.
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4
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Liu S, Yang Z, Li G, Li C, Luo Y, Gong Q, Wu X, Li T, Zhang Z, Xing B, Xu X, Lu X. Multi-omics Analysis of Primary Cell Culture Models Reveals Genetic and Epigenetic Basis of Intratumoral Phenotypic Diversity. GENOMICS PROTEOMICS & BIOINFORMATICS 2020; 17:576-589. [PMID: 32205176 PMCID: PMC7212478 DOI: 10.1016/j.gpb.2018.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 05/29/2018] [Accepted: 07/24/2018] [Indexed: 12/27/2022]
Abstract
Uncovering the functionally essential variations related to tumorigenesis and tumor progression from cancer genomics data is still challenging due to the genetic diversity among patients, and extensive inter- and intra-tumoral heterogeneity at different levels of gene expression regulation, including but not limited to the genomic, epigenomic, and transcriptional levels. To minimize the impact of germline genetic heterogeneities, in this study, we establish multiple primary cultures from the primary and recurrent tumors of a single patient with hepatocellular carcinoma (HCC). Multi-omics sequencing was performed for these cultures that encompass the diversity of tumor cells from the same patient. Variations in the genome sequence, epigenetic modification, and gene expression are used to infer the phylogenetic relationships of these cell cultures. We find the discrepancy among the relationships revealed by single nucleotide variations (SNVs) and transcriptional/epigenomic profiles from the cell cultures. We fail to find overlap between sample-specific mutated genes and differentially expressed genes (DEGs), suggesting that most of the heterogeneous SNVs among tumor stages or lineages of the patient are functionally insignificant. Moreover, copy number alterations (CNAs) and DNA methylation variation within gene bodies, rather than promoters, are significantly correlated with gene expression variability among these cell cultures. Pathway analysis of CNA/DNA methylation-related genes indicates that a single cell clone from the recurrent tumor exhibits distinct cellular characteristics and tumorigenicity, and such an observation is further confirmed by cellular experiments both in vitro and in vivo. Our systematic analysis reveals that CNAs and epigenomic changes, rather than SNVs, are more likely to contribute to the phenotypic diversity among subpopulations in the tumor. These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered in personalized cancer medicine. This culture model may be applied to the further identification of plausible determinants of cancer metastasis and relapse.
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Affiliation(s)
- Sixue Liu
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zuyu Yang
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (3)Invasive Pathogens Laboratory, Institute of Environmental Science and Research, Porirua 5022, Wellington, New Zealand
| | - Guanghao Li
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chunyan Li
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanting Luo
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qiang Gong
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xin Wu
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Tao Li
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhiqian Zhang
- (4)Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research, Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Baocai Xing
- (5)Department of Hepatobiliary Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaolan Xu
- (6)National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
| | - Xuemei Lu
- (1)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; (2)University of Chinese Academy of Sciences, Beijing 100049, China; (7)CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
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5
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Zeniou M, Nguekeu-Zebaze L, Dantzer F. Therapeutic considerations of PARP in stem cell biology: Relevance in cancer and beyond. Biochem Pharmacol 2019; 167:107-115. [PMID: 31202733 DOI: 10.1016/j.bcp.2019.06.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/11/2019] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are of fundamental importance in tumor progression because of their tumor-initiating properties, their resistance to radio- and chemotherapy, their invasive properties and their propensity to escape immune responses that together contribute to tumor relapse. These highly aggressive features underscore the importance of constantly identifying new and innovative therapeutic solutions to eradicate these cells. In this narrative review we discuss recent findings on the involvement of PARP family members in cancer stem cell biology and the benefit of their inhibition. Nonetheless, an important limitation in the use of PARP inhibitors is the emergence of a prominent function of PARP1 in non-cancer stem cell biology including stem cell maintenance and differentiation during development, neurogenesis or adipogenesis. Thus, we also summarize the dominant discoveries revealing the importance of PARP1 in normal stem cell biology.
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Affiliation(s)
- M Zeniou
- Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412 Illkirch, France
| | - L Nguekeu-Zebaze
- Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412 Illkirch, France
| | - F Dantzer
- Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, CS10413, 67412 Illkirch, France.
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6
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Sun C, Shui B, Zhao W, Liu H, Li W, Lee JC, Doran R, Lee FK, Sun T, Shen QS, Wang X, Reining S, Kotlikoff MI, Zhang Z, Cheng H. Central role of IP 3R2-mediated Ca 2+ oscillation in self-renewal of liver cancer stem cells elucidated by high-signal ER sensor. Cell Death Dis 2019; 10:396. [PMID: 31113961 PMCID: PMC6529459 DOI: 10.1038/s41419-019-1613-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 04/23/2019] [Indexed: 12/28/2022]
Abstract
Ca2+ oscillation is a system-level property of the cellular Ca2+-handling machinery and encodes diverse physiological and pathological signals. The present study tests the hypothesis that Ca2+ oscillations play a vital role in maintaining the stemness of liver cancer stem cells (CSCs), which are postulated to be responsible for cancer initiation and progression. We found that niche factor-stimulated Ca2+ oscillation is a signature feature of CSC-enriched Hep-12 cells and purified α2δ1+ CSC fractions from hepatocellular carcinoma cell lines. In Hep-12 cells, the Ca2+ oscillation frequency positively correlated with the self-renewal potential. Using a newly developed high signal, endoplasmic reticulum (ER) localized Ca2+ sensor GCaMP-ER2, we demonstrated CSC-distinctive oscillatory ER Ca2+ release controlled by the type 2 inositol 1,4,5-trisphosphate receptor (IP3R2). Knockdown of IP3R2 severely suppressed the self-renewal capacity of liver CSCs. We propose that targeting the IP3R2-mediated Ca2+ oscillation in CSCs might afford a novel, physiologically inspired anti-tumor strategy for liver cancer.
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Affiliation(s)
- Cuiwei Sun
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
| | - Bo Shui
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Wei Zhao
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Hui Liu
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Wenwen Li
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
| | - Jane C Lee
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Robert Doran
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Frank K Lee
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Tao Sun
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
| | - Qing Sunny Shen
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
| | - Xianhua Wang
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
| | - Shaun Reining
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Michael I Kotlikoff
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Zhiqian Zhang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| | - Heping Cheng
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
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7
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Nakagawa S, Umezaki N, Yamao T, Kaida T, Okabe H, Mima K, Imai K, Hashimoto D, Yamashita YI, Ishiko T, Chikamoto A, Baba H. Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus-positive or non-B non-C patients who underwent curative resection. Hepatol Res 2018; 48:E126-E132. [PMID: 28696046 DOI: 10.1111/hepr.12936] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 06/17/2017] [Accepted: 07/10/2017] [Indexed: 02/08/2023]
Abstract
AIM The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)-positive or non-B non-C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV-positive and NBNC HCC patients. METHODS This study investigated 145 HBV-positive or NBNC patients who underwent hepatectomy for HCC between January 2001 and May 2009. Cumulative recurrence rate, overall survival (OS), and clinicopathological parameters were analyzed according to lymphocyte infiltration in tumor. RESULTS In patients with low lymphocyte infiltration, the 5-year recurrence rate was higher and OS was poor (86.4 and 44.1%, respectively) than that of the patients with high lymphocyte infiltration (55.3 and 83.7%, respectively). Multivariate analyses revealed that independent risk factors for recurrence were low albumin value (hazard ratio [HR] 2.33, P = 0.009), high American Joint Committee on Cancer (AJCC) T stage (HR 2.31, P < 0.0001), high α-fetoprotein (AFP) value (HR 2.06, P = 0.005), and low lymphocyte infiltration (HR 2.50, P = 0.0001). The independent risk factors for OS were low albumin value (HR 3.69, P = 0.003), high AJCC T stage (HR 2.10, P = 0.049), high AFP value (HR 3.98, P < 0.001), and low lymphocyte infiltration (HR 3.47, P = 0.001). CONCLUSIONS Lymphocyte infiltrate in tumor is significantly associated high recurrence rate and poor overall survival. Evaluation of the infiltrating lymphocyte could improve the prediction of prognosis in HCC patients after curative resection.
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Affiliation(s)
- Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Naoki Umezaki
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takanobu Yamao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takayoshi Kaida
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hirohisa Okabe
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Daisuke Hashimoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takatoshi Ishiko
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Akira Chikamoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
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8
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Nakamoto Y. Promising new strategies for hepatocellular carcinoma. Hepatol Res 2017; 47:251-265. [PMID: 27558453 DOI: 10.1111/hepr.12795] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. It usually arises based on a background of chronic liver diseases, defined as the hypercarcinogenic state. The current treatment options for HCC ranging from locoregional treatments to chemotherapies, including sorafenib, effectively regulate the limited sizes and numbers of the nodules. However, these treatments remain unsatisfactory because they have insufficient antitumor effects on the large and numerous nodules associated with HCC and because of a high recurrence rate in the surrounding inflamed liver. To develop novel and promising therapies with higher antitumor effects, recent progress in identifying molecular targets and developing immunological procedures for HCC are reviewed. The molecular targets discussed include the intracellular signaling pathways of protein kinase B/mammalian target of rapamycin and RAS/RAF/mitogen-activated protein kinase, Wnt/β-catenin and glutamine synthetase, insulin-like growth factor, signal transducer and activator of transcription 3, nuclear factor-κB and telomerase reverse transcriptase, and c-MET. Immunological studies have focused mainly on target identification, T cells, natural killer cells, dendritic cells, natural killer T cells, and vaccine development.
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Affiliation(s)
- Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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9
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Zhang X, Liu S, Shen C, Wu Y, Zhang L, Chen X, Lu F. DNA methylation consistency implicates the primary tumor cell origin of recurrent hepatocellular carcinoma. Epigenomics 2015; 7:581-92. [PMID: 25815780 DOI: 10.2217/epi.15.23] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
AIMS To investigate if DNA methylation pattern assay could be a new approach to identifying the primary tumor cell origin of the recurrent hepatocellular carcinoma (HCC). MATERIALS & METHODS Methylation of 24 genes and expression of 22 cancer stem cell (CSC) biomarkers were quantitatively measured in 10 paired primary and recurrent HCC specimens. The HBV viral-host junctions were determined in six pairs of them with HBV infection. RESULTS Similar DNA methylation patterns were observed among nine of ten pairs of primary and recurrent tumors. In five of six paired specimens with HBV infection, exactly same HBV DNA integrations were identified in each paired tumors. The expression of seven CSC biomarkers increased significantly in either primary or recurrent tumor tissues. CONCLUSION Recurrent HCCs mostly originate from their primary tumors. Assay of DNA methylation patterns could provide a new approach to determining the origin of recurrent HCC.
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Affiliation(s)
- Xiaolei Zhang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Shuang Liu
- Beijing Artificial Liver Treatment & Training Center, Beijing Youan Hospital, Capital Medical University, 8 Xi Tou Tiao, Beijing 100069, China
| | - Congle Shen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Yali Wu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Ling Zhang
- Department of Hepatobiliary Surgery, Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou 450008, Henan, China
| | - Xiangmei Chen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China
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10
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Chan LH, Luk ST, Ma S. Turning hepatic cancer stem cells inside out--a deeper understanding through multiple perspectives. Mol Cells 2015; 38:202-9. [PMID: 25666349 PMCID: PMC4363719 DOI: 10.14348/molcells.2015.2356] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 01/02/2015] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC), a highly malignant disease and the third leading cause of all cancer mortalities worldwide, often responses poorly to current treatments and results in dismal outcomes due to frequent chemoresistance and tumor relapse. The heterogeneity of HCC is an important attribute of the disease. It is the outcome of many factors, including the cross-talk between tumor cells within the tumor microenvironment and the acquisition and accumulation of genetic and epigenetic alterations in tumor cells. In addition, there is accumulating evidence in recent years to show that the malignancy of HCC can be attributed partly to the presence of cancer stem cell (CSC). CSCs are capable to self-renew, differentiate and initiate tumor formation. The regulation of the stem cell-like properties by several important signaling pathways have been found to endow the tumor cells with an increased level of tumorigenicity, chemoresistance, and metastatic ability. In this review, we will discuss the recent findings on hepatic CSCs, with special emphasis on their putative origins, relationship with hepatitis viruses, regulatory signaling networks, tumor microenvironment, and how these factors control the stemness of hepatic CSCs. We will also discuss some novel therapeutic strategies targeted at hepatic CSCs for combating HCC and perspectives of future investigation.
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Affiliation(s)
- Lok-Hei Chan
- Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Steve T. Luk
- Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
| | - Stephanie Ma
- Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
- State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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11
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Zhou Y, Chen JY. Progress in research of hepatic stem cells. Shijie Huaren Xiaohua Zazhi 2015; 23:64-70. [DOI: 10.11569/wcjd.v23.i1.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver disease is a rising cause of mortality and morbidity, and treatment options remain limited. Liver transplantation is curative but limited by donor organ availability, operative risk and long-term complications. There is currently a clear need for new therapies for liver disease, and it is possible that hepatic stem cell (HSC) therapy represents an exciting new therapeutic option. HSCs are undifferentiated cells with the unique ability to self-renew and potentially provide a source of human hepatocytes for regeneration of the injured liver. Evidence from pre-clinical studies is encouraging, but conclusive evidence that this translates into humans remains lacking. Further studies of the mechanisms responsible for the beneficial effects of HSC therapy are needed.
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Sun Z, Meng C, Wang S, Zhou N, Guan M, Bai C, Lu S, Han Q, Zhao RC. MicroRNA-1246 enhances migration and invasion through CADM1 in hepatocellular carcinoma. BMC Cancer 2014; 14:616. [PMID: 25159494 PMCID: PMC4150976 DOI: 10.1186/1471-2407-14-616] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 08/20/2014] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The aberrant expression of microRNAs has been demonstrated to play a crucial role in the initiation and progression of hepatocarcinoma. miR-1246 expression in High invasive ability cell line than significantly higher than that in low invasive ability cell line. METHODS Transwell chambers (8-uM pore size; Costar) were used in the in vitro migration and invison anssay. Dual luciferase reporter gene construct and Dual luciferase reporter assay to identify the target of miR-1246. CADM1 expression was evaluated by immunohistochemistric staining. The clinical manifestations, treatments and survival were collected for statistical analysis. RESULTS Inhibition of miR-1246 effectively reduced migration and invasion of hepatocellular carcinoma cell lines. Bioinformatics and luciferase reporter assay revealed that miR-1246 specifically targeted the 3'-UTR of Cell adhesion molecule 1 and regulated its expression. Down-regulation of CADM1 enhanced migration and invasion of HCC cell lines. Furthermore, in tumor tissues obtained from liver cancer patients, the expression of miR-1246 was negatively correlated with CADM1 and the high expression of miR-1246 combined with low expression of CADM1 might serve as a risk factor for stage1 liver cancer patients. CONCLUSIONS Our study showed that miR-1246, by down-regulation CADM1, enhances migration and invasion in HCC cells.
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Affiliation(s)
| | | | | | | | | | | | | | - Qin Han
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People's Republic of China.
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MicroRNA-9 enhances migration and invasion through KLF17 in hepatocellular carcinoma. Mol Oncol 2013; 7:884-94. [PMID: 23684102 DOI: 10.1016/j.molonc.2013.04.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Revised: 04/17/2013] [Accepted: 04/18/2013] [Indexed: 12/12/2022] Open
Abstract
Metastasis is one of the hallmarks of cancer malignancy that usually causes more detrimental effects than a primary tumor. Many microRNAs were reported to be involved in the process of tumor metastasis. Hep11 and Hep12 cells were derived from primary and recurrence (intrahepatic metastatic) sites of hepatocellular carcinoma (HCC), respectively. Hep12 exhibited a higher invasive and migratory potential than Hep11. There was also a significantly higher expression of miR-9 in Hep12 cells than in Hep11 cells. Further studies in HCC cell lines demonstrated that miR-9 could promote tumor cell migration and invasion. In addition, miR-9 downregulated KLF17 protein expression by targeting the 3'UTR region of the KLF17 gene directly. As a transcription factor, KLF17 directly acted on the promoters of EMT-related genes (ZO-1, Vimentin and Fibronectin (FN)) in HCC cell lines. Therefore, we conclude that miR-9 may possibly promote HCC migration and invasion through regulation of KLF17.
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