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Gong Y, Wang X, Chen W, Tsai HI, Liu Y. Cancer stem cells amino acid metabolism: Roles, mechanisms, and intervention strategies. Cell Signal 2025:111903. [PMID: 40449815 DOI: 10.1016/j.cellsig.2025.111903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2025] [Revised: 05/21/2025] [Accepted: 05/25/2025] [Indexed: 06/03/2025]
Abstract
Cancer stem cells (CSCs) are recognized as key drivers of tumor recurrence and therapy resistance due to their capacity for self-renewal and differentiation. Amino acid metabolic reprogramming, a hallmark of cancer, underpins CSC biology. Methionine, tryptophan, and glutamine support CSC survival and the maintenance of stemness, while proline plays a role in CSC differentiation and susceptibility to cell death. Consequently, the impact of amino acid metabolism on CSCs is multifaceted and complex. This review first outlines the intrinsic amino acid metabolic features of CSCs. It then provides a comprehensive analysis of the distinct roles of various amino acids in regulating CSC biology. Additionally, strategies targeting amino acid metabolism to eliminate CSCs in clinical therapies are discussed, offering new perspectives for the development of innovative tumor-targeting approaches.
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Affiliation(s)
- Yi Gong
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Xirui Wang
- Department of Biomedical Engineering, School of Medical Imaging Xuzhou Medical University, Xuzhou 221000, China
| | - Wenlong Chen
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Hsiang-I Tsai
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China.
| | - Yanfang Liu
- Department of Central Laboratory, Affiliated People's Hospital of Jiangsu University, Zhenjiang 212001, China.
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2
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Yousef EH, El Gayar AM, El-Magd NFA. Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects. Crit Rev Oncol Hematol 2025; 212:104765. [PMID: 40389183 DOI: 10.1016/j.critrevonc.2025.104765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/07/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
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Affiliation(s)
- Eman H Yousef
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
| | - Amal M El Gayar
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Nada F Abo El-Magd
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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3
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Muliawan GK, Lee TKW. The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma. Front Immunol 2024; 15:1400112. [PMID: 38868769 PMCID: PMC11167126 DOI: 10.3389/fimmu.2024.1400112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/15/2024] [Indexed: 06/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era of HCC treatment, their response rates are modest, which can be attributed to the immunosuppressive tumor microenvironment within HCC tumors. Accumulating evidence has shown that tumor growth is fueled by cancer stem cells (CSCs), which contribute to therapeutic resistance to the above treatments. Given that CSCs can regulate cellular and physical factors within the tumor niche by secreting various soluble factors in a paracrine manner, there have been increasing efforts toward understanding the roles of CSC-derived secretory factors in creating an immunosuppressive tumor microenvironment. In this review, we provide an update on how these secretory factors, including growth factors, cytokines, chemokines, and exosomes, contribute to the immunosuppressive TME, which leads to immune resistance. In addition, we present current therapeutic strategies targeting CSC-derived secretory factors and describe future perspectives. In summary, a better understanding of CSC biology in the TME provides a rational therapeutic basis for combination therapy with ICIs for effective HCC treatment.
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Affiliation(s)
- Gregory Kenneth Muliawan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Terence Kin-Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
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4
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Shi Y, Ye R, Gao Y, Xia F, Yu XF. A prognostic and immune related risk model based on zinc homeostasis in hepatocellular carcinoma. iScience 2024; 27:109389. [PMID: 38510110 PMCID: PMC10951649 DOI: 10.1016/j.isci.2024.109389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/15/2024] [Accepted: 02/28/2024] [Indexed: 03/22/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The dysfunction of zinc homeostasis participates in the early and advancing malignancy of HCC. However, the prognostic ability of zinc homeostasis in HCC has not been clarified yet. Here, we showed a zinc-homeostasis related risk model in HCC. Five signature genes including ADAMTS5, PLOD2, PTDSS2, KLRB1, and UCK2 were screened out via survival analyses and regression algorithms to construct the nomogram with clinical characteristics. Experimental researches indicated that UCK2 participated in the progression of HCC. Patients with higher risk scores always had worse outcomes and were more associated with immune suppression according to the analyses of immune related-pathway activation, cell infiltration, and gene expression. Moreover, these patients were likely to exhibit more sensitivity to sorafenib and other antitumor drugs. This study highlights the significant prognostic role of zinc homeostasis and suggests potential treatment strategies in HCC.
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Affiliation(s)
- Yifei Shi
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310016, P.R. China
| | - Runxin Ye
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310016, P.R. China
| | - Yuan Gao
- Department of Breast and Thyroid Surgery, Shaoxing People’s Hospital, Shaoxing 312035, P.R. China
| | - Fengyan Xia
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310016, P.R. China
| | - Xiao-Fang Yu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310016, P.R. China
- Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou 310016, P.R. China
- Cancer Center of Zhejiang University, Hangzhou 310016, P.R. China
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5
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Moreno-Londoño AP, Robles-Flores M. Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment. Stem Cell Rev Rep 2024; 20:25-51. [PMID: 37922108 PMCID: PMC10799829 DOI: 10.1007/s12015-023-10647-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2023] [Indexed: 11/05/2023]
Abstract
CD133 protein has been one of the most used surface markers to select and identify cancer cells with stem-like features. However, its expression is not restricted to tumoral cells; it is also expressed in differentiated cells and stem/progenitor cells in various normal tissues. CD133 participates in several cellular processes, in part orchestrating signal transduction of essential pathways that frequently are dysregulated in cancer, such as PI3K/Akt signaling and the Wnt/β-catenin pathway. CD133 expression correlates with enhanced cell self-renewal, migration, invasion, and survival under stress conditions in cancer. Aside from the intrinsic cell mechanisms that regulate CD133 expression in each cellular type, extrinsic factors from the surrounding niche can also impact CD33 levels. The enhanced CD133 expression in cells can confer adaptive advantages by amplifying the activation of a specific signaling pathway in a context-dependent manner. In this review, we do not only describe the CD133 physiological functions known so far, but importantly, we analyze how the microenvironment changes impact the regulation of CD133 functions emphasizing its value as a marker of cell adaptability beyond a cancer-stem cell marker.
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Affiliation(s)
- Angela Patricia Moreno-Londoño
- Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), 04510, Mexico City, Mexico
| | - Martha Robles-Flores
- Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), 04510, Mexico City, Mexico.
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Abdellateif MS, Zekri ARN. Stem cell therapy for hepatocellular carcinoma and end-stage liver disease. J Egypt Natl Canc Inst 2023; 35:35. [PMID: 37926787 DOI: 10.1186/s43046-023-00194-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 10/20/2023] [Indexed: 11/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide, especially for patients who are suffering from end-stage liver disease (ESLD). The ESLD is considered a great challenge for clinicians due to the limited chance for liver transplantation, which is the only curative treatment for those patients. Stem cell-based therapy as a part of regenerative medicine represents a promising application for ESLD patients. Many clinical trials were performed to assess the utility of bone marrow-derived stem cells as a potential therapy for patients with liver diseases. The aim of the present study is to present and review the various types of stem cell-based therapy, including the mesenchymal stem cells (MSCs), BM-derived mononuclear cells (BM-MNCs), CD34 + hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and cancer stem cells.Though this type of therapy achieved promising results for the treatment of ESLD, however still there is a confounding data regarding its clinical application. A large body of evidence is highly required to evaluate the stem cell-based therapy after long-term follow-up, with respect to the incidence of toxicity, immunogenicity, and tumorigenesis that developed in many patients.
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Affiliation(s)
- Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt.
| | - Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, NCI, Cairo University, Cairo, 11976, Egypt
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7
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Lee SY, Kim S, Song Y, Kim N, No J, Kim KM, Seo HR. Sorbitol dehydrogenase induction of cancer cell necroptosis and macrophage polarization in the HCC microenvironment suppresses tumor progression. Cancer Lett 2022; 551:215960. [PMID: 36244575 DOI: 10.1016/j.canlet.2022.215960] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 09/30/2022] [Accepted: 10/08/2022] [Indexed: 11/26/2022]
Abstract
Hepatocellular carcinoma (HCC) is among the most common malignant cancers worldwide, with an increasing incidence associated with an increase in deaths due to liver cancer. HCC is typically detected at an advanced stage in patients with underlying liver dysfunction, resulting in high mortality. The identification of HCC-specific targets represents a desired but unmet need for liver cancer treatment. To identify potentially novel HCC therapeutic targets, we performed a secretome analysis using HCC spheroids. Sorbitol dehydrogenase (SORD) was identified as uniquely enriched in the secretomes and lysates derived from HCC spheroids, and high SORD expression in HCC tissues was associated with favorable effects on overall survival among patients with liver cancer. We found that the introduction of excess SORD in HCC cells inhibited tumor growth and stemness by enhancing necroptosis signal and bypassing energy-yielding pathways through regulation of lactate dehydrogenase A (LDHA) expression and mitochondrial dynamics. Treatment with human recombinant SORD (hrSORD) controlled HCC cell growth and regulated macrophage polarization in the tumor microenvironment. These results demonstrate that SORD plays critical functional roles in HCC suppression through polyol pathway-independent mechanisms, suggesting that targeting SORD expression might represent a promising therapeutic strategy for liver cancer therapy.
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Affiliation(s)
- Su-Yeon Lee
- Advanced Biomedical Research Laboratory, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Sanghwa Kim
- Advanced Biomedical Research Laboratory, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Yeonhwa Song
- Advanced Biomedical Research Laboratory, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Namjeong Kim
- Advanced Biomedical Research Laboratory, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Joohwan No
- Host-Parasite Research Laboratory, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Kang Mo Kim
- Department Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Olympic-ro 43-gil 88, Songpa-gu, Seoul, 05505, South Korea
| | - Haeng Ran Seo
- Advanced Biomedical Research Laboratory, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
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8
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Luo J, Liu S, Lu H, Chen Q, Shi Y. A comprehensive review of microorganism-derived cyclic peptides: Bioactive functions and food safety applications. Compr Rev Food Sci Food Saf 2022; 21:5272-5290. [PMID: 36161470 DOI: 10.1111/1541-4337.13038] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/09/2022] [Accepted: 08/21/2022] [Indexed: 01/28/2023]
Abstract
Cyclic peptides possess advanced structural characteristics of stability and play a vital role in medical treatment and agriculture. However, the biological functions of microorganism-derived cyclic peptides (MDCPs) and their applications in food industry were relatively absent. MDCPs are derived from extensive fermented food or soil. In this review, the synthesis approaches and structural characteristics are overviewed, while the interrelationship between bioactivities and functions is emphasized. This review summarizes the bioactivities of MDCPs from in vitro to in vivo, including antimicrobial activities, immune regulation, and antiviral cell activation. Their multiple functions as well as applications during food product processing, packaging, and storage are also comprehensively reviewed. Remarkably, some potential risks and cytotoxicity of MDCPs are also critically discussed. Moreover, future applications of MDCPs in the development of novel food additives and bioengineering materials are organized. Based on this review of native MDCPs, it is noteworthy that expected improvements of synthetic cyclic peptides in bioactive properties present potential valuable applications in future food, including artificial meat.
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Affiliation(s)
- Jiaqi Luo
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China
| | - Siyu Liu
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China
| | - Hongyun Lu
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China
| | - Qihe Chen
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China
| | - Ying Shi
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China
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9
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Actinomycin D Arrests Cell Cycle of Hepatocellular Carcinoma Cell Lines and Induces p53-Dependent Cell Death: A Study of the Molecular Mechanism Involved in the Protective Effect of IRS-4. PHARMACEUTICALS (BASEL, SWITZERLAND) 2021; 14:ph14090845. [PMID: 34577545 PMCID: PMC8472101 DOI: 10.3390/ph14090845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/17/2021] [Accepted: 08/23/2021] [Indexed: 01/01/2023]
Abstract
Actinomycin D (ActD) is an FDA-approved NCI oncology drug that specifically targets and downregulates stem cell transcription factors, which leads to a depletion of stem cells within the tumor bulk. Recently, our research group demonstrated the importance of IRS-4 in the development of liver cancer. In this study, we evaluated the protective effects of IRS-4 against ActD. For this study, three hepatocellular carcinoma cell lines (HepG2, Huh7, and Chang cells) were used to study the mechanism of actinomycin D. Most assays were carried out in the Hep G2 cell line, due to the high expression of stem cell biomarkers. We found that ActD caused HepG2 cell necroptosis characterized by DNA fragmentation, decreased mitochondrial membrane potential, cytochrome c depletion, and decreased the levels of reduced glutathione. However, we did not observe a clear increase in apoptosis markers such as annexin V presence, caspase 3 activation, or PARP fragmentation. ActD produced an activation of MAP kinases (ERK, p38, and JNK) and AKT. ActD-induced activation of AKT and MAP kinases produced an activation of the Rb-E2F cascade together with a blockage of cell cycle transitions, due to c-jun depletion. ActD led to the inhibition of pCdK1 and pH3 along with DNA fragmentation resulting in cell cycle arrest and the subsequent activation of p53-dependent cell death in the HepG2 cell line. Only JNK and AKT inhibitors were protective against the effects of ActD. N-Acetyl-L-cysteine also had a protective effect as it restored GSH levels. A likely mechanism for this is IRS-4 stimulating GCL-GSH and inhibiting the Brk-CHK1-p53 pathway. The assessment of the IRS-4 in cancer biopsies could be of interest to carry out a personalized treatment with ActD.
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11
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Yang Y, Mao H, Chen L, Li L. Targeting signal pathways triggered by cyclic peptides in cancer: Current trends and future challenges. Arch Biochem Biophys 2021; 701:108776. [PMID: 33515532 DOI: 10.1016/j.abb.2021.108776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/04/2021] [Accepted: 01/19/2021] [Indexed: 10/22/2022]
Abstract
Cancer is a global health issue that origins thousands of deaths annually worldwide. Cyclic peptides are polypeptide chains which are formed by cyclic sequence of amide bonds between proteinogenic or non-proteinogenic amino acids. Numerous evidences indicate that cyclic peptides are implicated with the occurrence and development of cancer. This review presents the current knowledge about the role of cyclic peptides in cancer, such as liver cancer, colorectal cancer, ovarian cancer, breast cancer as well as prostate cancer. Specifically, the precise molecular mechanisms between cyclic peptides and cancer are elaborated. Some cyclic peptides from nature and synthesis prevent the occurrence and development of cancer. However, some other cyclic peptides including endothelin-1, urotensinⅡand melanin-concentrating hormone deteriorate the pathogenesis of cancer. Given the pleiotropic actions of cyclic peptides, the identification and development of cyclic peptides and their derivates as drug may be a potent therapeutic strategy for cancer.
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Affiliation(s)
- Yiyuan Yang
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China
| | - Hui Mao
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China.
| | - Lanfang Li
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China.
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12
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Liu L, Borlak J. Advances in Liver Cancer Stem Cell Isolation and their Characterization. Stem Cell Rev Rep 2021; 17:1215-1238. [PMID: 33432485 DOI: 10.1007/s12015-020-10114-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2020] [Indexed: 12/24/2022]
Abstract
Over the last decade research on cancer stem cells (CSC) significantly contributed to a better understanding of tumor biology. Given their similarity to normal stem cells, i.e. self-renewal and pluripotency the need arises to develop robust protocols for the isolation and characterization of CSCs. As with other malignancies, hepatic tumors are composed of a heterogeneous population of cells including liver cancer stem cells (LCSC). Yet, a precise understanding of why stem cells become cancerous is still lacking. There is unmet need to develop robust protocols for the successful isolation of LCSCs from human tissue resection material as to assist in the development of molecular targeted therapies. Here we review the research progress made in the isolation and characterization of LCSCs by considering a wide range of cell surface markers and sorting methods, as applied to side populations, microsphere cultures and the gradient centrifugation method. We emphasize the different fluorescence activated cell sorting methods and the possibility to enrich LCSCs by immunomagnetic beads. We review the specificity of functional assays by considering ABCG transporter and ALDH1 enzyme activities and evaluate the in vivo tumorigenicity of LCSCs in highly sensitive bioassays. Finally, we evaluate different LCSC markers in association with viral and non-viral liver disease and explore the potential of novel drug delivery systems targeting CD133, EpCAM, CD13 and CD90 for the development of molecular targeted therapies. Graphical Abstract.
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Affiliation(s)
- Lu Liu
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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13
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Amino Acid-Mediated Metabolism: A New Power to Influence Properties of Stem Cells. Stem Cells Int 2019; 2019:6919463. [PMID: 31885621 PMCID: PMC6915148 DOI: 10.1155/2019/6919463] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 11/05/2019] [Accepted: 11/15/2019] [Indexed: 01/10/2023] Open
Abstract
The self-renewal and differentiation potentials of stem cells are dependent on amino acid (AA) metabolism. We review the literature on the metabolic preference of both cancer and noncancer stem cells. The balance in AA metabolism is responsible for maintaining the functionality of noncancer stem cells, and altering the levels of AAs can influence the malignant biological behavior of cancer stem cells. AAs are considered nutrients participating in metabolism and playing a critical role in maintaining the activity of normal stem cells and the effect of therapy of cancer stem cells. Targeting AA metabolism helps inhibit the stemness of cancer stem cells and remodels the function of normal stem cells. This review summarizes the metabolic characteristics and regulation pathways of AA in different stem cells, not only from the nutritional perspective but also from the genomic perspective that have been reported in the recent five years. In addition, we briefly survey new therapeutic modalities that may help eradicate cancer stem cells by exploiting nutrient deprivation. Understanding AA uptake characteristics helps researchers define the preference for AA in different stem cells and enables clinicians make timely interventions to specifically target the cell behavior.
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