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Zhang J, Guo H, Gong C, Shen J, Jiang G, Liu J, Liang T, Guo L. Therapeutic targets in the Wnt signaling pathway: Treating cancer with specificity. Biochem Pharmacol 2025; 236:116848. [PMID: 40049295 DOI: 10.1016/j.bcp.2025.116848] [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: 12/16/2024] [Revised: 02/16/2025] [Accepted: 03/03/2025] [Indexed: 04/20/2025]
Abstract
The Wnt signaling pathway is a critical regulatory mechanism that governs cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, and the tumor immune microenvironment, while also maintaining tissue homeostasis. Dysregulated activation of this pathway is implicated in various cancers, closely linked to tumor initiation, progression, and metastasis. The Wnt/β-catenin axis plays a central role in the pathogenesis of common cancers, including colorectal cancer (CRC), breast cancer (BC), liver cancer, and lung cancer. Unlike traditional chemotherapy, targeted therapy offers a more precise approach to cancer treatment. As a key regulator of oncogenesis, the Wnt pathway represents a promising target for clinical interventions. This review provides a comprehensive analysis of the Wnt signaling pathway, exploring its roles in tumor biology and its implications in human malignancies. It further examines the molecular mechanisms and modes of action across different cancers, detailing how the Wnt pathway contributes to tumor progression through mechanisms such as metastasis promotion, immune modulation, drug resistance, and enhanced cellular proliferation. Finally, therapeutic strategies targeting Wnt pathway components are discussed, including inhibitors targeting extracellular members, as well as those within the cell membrane, cytoplasm, and nucleus. The potential of these targets in the development of novel therapeutic agents underscores the critical importance of intervening in the Wnt signaling pathway for effective cancer treatment.
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Affiliation(s)
- Jiaxi Zhang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China
| | - Haochuan Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China
| | - Chengxuan Gong
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China
| | - Jie Shen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China
| | - Guijie Jiang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China
| | - Jiarui Liu
- State Key Laboratory of Flexible Electronics (LoFE), Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China
| | - Tingming Liang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China.
| | - Li Guo
- State Key Laboratory of Flexible Electronics (LoFE), Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China.
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2
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Henry M, Ngwegya T, Lekena N, Barth S. In vitro anti-tumor activities of a novel recombinant immunotoxin targeting differentially overexpressed Leucine-rich repeat-containing G-protein-coupled receptor 5 in cervical cancer. Immunopharmacol Immunotoxicol 2025:1-10. [PMID: 40376858 DOI: 10.1080/08923973.2025.2504904] [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: 01/20/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025]
Abstract
OBJECTIVE The study aims to develop a novel recombinant anti-LGR5 immunotoxin candidate based on a truncated form of Pseudomonas exotoxin A (ETA). METHODS To develop this LGR5-specific recombinant immunotoxin, a corresponding single chain antibody fragment (αLGR5(scFv)) fused to ETA, was expressed under osmotic stress in the presence of compatible solutes in Escherichia coli BL21 DE3 cells. Expression was monitored by Western blot analysis facilitated by an N-terminal 10x-His tag. Purification was done using immobilized metal affinity chromatography (IMAC) and size exclusion chromatography (SEC). The recombinant immunotoxin (rIT) was assessed for cell surface binding on cervical cancer cell lines using confocal microscopy and flow cytometry. The rIT was then used in an XTT cell viability assay to assess targeted cell killing. RESULTS AND DISCUSSION Upon confirmation of full-length protein by Western blot, purified protein was used to confirm binding on LGR5-positive cervical cancer cell lines via confocal microscopy and flow cytometry using anti-His PE antibody as a secondary antibody. Selective cell-killing of this novel recombinant immunotoxin was illustrated by the dose-dependent reduction in cell viability at IC50 values in nanomolar concentrations on antigen-positive but not antigen-negative cell lines. CONCLUSIONS In conclusion, the rIT described is a promising candidate to treat cervical cancer, which however, would finally need to be confirmed by preclinical in vivo studies.
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Affiliation(s)
- Marc Henry
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Takunda Ngwegya
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Nkhasi Lekena
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Stefan Barth
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
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3
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Fu L, Gu X, Lou N, Li J, Xue C. Current research of the Notch pathway in hepatocellular carcinoma. Eur J Med Res 2025; 30:402. [PMID: 40394648 PMCID: PMC12090635 DOI: 10.1186/s40001-025-02626-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/22/2025] [Indexed: 05/22/2025] Open
Abstract
Notch signaling is a widely preserved communication pathway that supports essential cellular functions by allowing adjacent cells to interact. The Notch signaling pathway consists of Notch ligands (DSL proteins), Notch receptors, DNA-binding proteins, and downstream target genes. Hepatocellular carcinoma (HCC) represents the predominant cause of cancer-related deaths globally and poses a significant threat to human health. For highly malignant HCC, current treatment options, including chemotherapy, radiotherapy, immunotherapy, targeted therapies, and surgical procedures, often have poor prognoses. Therefore, there is a need to explore additional therapeutic strategies. Many studies have found that abnormal activation of the Notch signaling pathway contributes to tumor initiation and progression by promoting HCC proliferation, metastasis, stem cell-like properties, and drug resistance. In this research, we reveal the composition and activation mechanisms of the Notch signaling pathway, as well as the molecular mechanism underlying its aberrant activation in HCC. Furthermore, we summarize recent advances in targeting Notch signaling for the treatment of HCC. This review aims to highlight the promising potential of investigating the Notch pathway as a therapeutic target in HCC.
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Affiliation(s)
- Leiya Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Na Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China.
| | - Chen Xue
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China.
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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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5
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Castaneda M, den Hollander P, Werden S, Ramirez-Peña E, Vasaikar SV, Kuburich NA, Gould C, Soundararajan R, Mani SA. β-Catenin Drives the FOXC2-Mediated Epithelial-Mesenchymal Transition and Acquisition of Stem Cell Properties. Cancers (Basel) 2025; 17:1114. [PMID: 40227590 PMCID: PMC11987759 DOI: 10.3390/cancers17071114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 03/03/2025] [Accepted: 03/17/2025] [Indexed: 04/15/2025] Open
Abstract
Background: Aggressive forms of breast cancer, such as triple-negative breast cancer (TNBC), are associated with an increase in cancer cells that exhibit stem cell properties. The activation of the epithelial-mesenchymal transition (EMT) program, mediated by the transcription factor FOXC2, generates these stem-like cells. FOXC2 is linked to poor prognoses across various cancer types and is notably upregulated in TNBC, where it establishes and sustains these stem-like cells within the tumor population. Methods: Here, we decode the pathways regulating FOXC2 activation using EMT-enriched cell line models. Stemness was assessed using mammosphere assays and mesenchymal markers by western blot. Expression correlations with clinical data was examined using the EMTome. Results: We demonstrate that β-catenin serves as a critical mediator of mesenchymal and stemness characteristics through FOXC2 upregulation. By disrupting β-catenin, we find that FOXC2 expression, mesenchymal properties, and stemness are reduced; however, the introduction of exogenous FOXC2 expression in β-catenin deficient cells is enough to restore the mesenchymal and stemness phenotype. These findings support the idea that FOXC2 acts as the downstream regulator of β-catenin and influences both mesenchymal and stemness properties. Moreover, there is a positive correlation between the expression of β-catenin and FOXC2 in various cancer subtypes observed in clinical patient samples. Conclusions: Our study clarifies the role of the β-catenin/FOXC2 signaling axis in maintaining stemness properties, suggesting potential targets for TNBC and other cancers driven by EMT-related mesenchymal and stemness characteristics.
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Affiliation(s)
- Maria Castaneda
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Research Center, Houston, TX 77030, USA; (M.C.); (R.S.)
| | - Petra den Hollander
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; (P.d.H.); (N.A.K.); (C.G.)
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Steve Werden
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Research Center, Houston, TX 77030, USA; (M.C.); (R.S.)
| | - Esmeralda Ramirez-Peña
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Research Center, Houston, TX 77030, USA; (M.C.); (R.S.)
| | - Suhas V. Vasaikar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Research Center, Houston, TX 77030, USA; (M.C.); (R.S.)
| | - Nick A. Kuburich
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; (P.d.H.); (N.A.K.); (C.G.)
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Claire Gould
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; (P.d.H.); (N.A.K.); (C.G.)
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Rama Soundararajan
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Research Center, Houston, TX 77030, USA; (M.C.); (R.S.)
| | - Sendurai A. Mani
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; (P.d.H.); (N.A.K.); (C.G.)
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
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Ferreira JM, Gonçalves CS, Costa BM. Emerging roles and biomarker potential of WNT6 in human cancers. Cell Commun Signal 2024; 22:538. [PMID: 39529066 PMCID: PMC11552340 DOI: 10.1186/s12964-024-01892-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 10/13/2024] [Indexed: 11/16/2024] Open
Abstract
The WNT6 ligand is a well-known activator of the WNT signaling pathway, considered a vital player in several important physiologic processes during embryonic development and maintaining homeostasis throughout life, regulating the proliferation and differentiation of multiple stem/progenitor cell types. More recently, as it is the case for many key molecular regulators of embryonic development, dysregulation of WNT6 has been implicated in cancer development and progression in multiple studies. In this review, we overview the most significant recent findings regarding WNT6 in the context of human malignancies, exploring its influence on multiple dimensions of tumor pathophysiology and highlighting the putative underlying WNT6-associated molecular mechanisms. We also discuss the potential clinical implications of WNT6 as a prognostic and therapeutic biomarker. This critical review highlights the emerging relevance of WNT6 in multiple human cancers, and its potential as a clinically-useful biomarker, addressing key unanswered questions that could lead to new opportunities in patient diagnosis, stratification, and the development of rationally-designed precision therapies.
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Affiliation(s)
- Joana M Ferreira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Céline S Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bruno M Costa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal.
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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Hazra R, Chattopadhyay S, Mallick A, Gayen S, Roy S. Unravelling CD24-Siglec-10 pathway: Cancer immunotherapy from basic science to clinical studies. Immunology 2024; 173:442-469. [PMID: 39129256 DOI: 10.1111/imm.13847] [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: 03/22/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024] Open
Abstract
Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid-binding Ig-like lectin 10 (Siglec-10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec-10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec-10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec-10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec-10 modulates immune responses and facilitates immune escape in cancer. Siglec-10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec-10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec-10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics.
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Affiliation(s)
- Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
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Xun J, Ma Y, Wang B, Jiang X, Liu B, Gao R, Zhai Q, Cheng R, Wu X, Wu Y, Zhang Q. RGS1 targeted by miR-191-3p inhibited the stemness properties of esophageal cancer cells by suppressing CXCR4/PI3K/AKT signaling. Acta Histochem 2024; 126:152190. [PMID: 39173233 DOI: 10.1016/j.acthis.2024.152190] [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: 03/15/2024] [Revised: 07/27/2024] [Accepted: 08/15/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND Esophageal cancer is one of the most common malignant tumors in the world. It is urgent to prevent the development and progression of esophageal cancer. Cancer stem cells (CSCs) were reported to have the ability to initiate tumorigenesis, and reducing the stem cell-like characteristics of tumors is an important strategy to inhibit the occurrence and development of tumors. miRNAs are key regulators of the stemness of cancer. Here, we aimed to investigate the role and regulatory mechanism of miR-191-3p in the stemness properties of esophageal cancer cells. METHODS Esophageal cancer cells with stable expression of miR-191-3p were established by lentivirus system. CCK-8 assay, transwell assay, wound healing assay were used to evaluate the effect of miR-191-3p on proliferation and metastasis of esophageal cancer cells. The expression of stemness-related markers (NANOG, OCT4, SOX2), ALDH activity, sphere-forming assay and subcutaneous tumor model in nude mice were performed to evaluate the stemness properties of esophageal cancer cells in vitro and in vivo. Dual-luciferase reporter assay was used to verify the molecular mechanism. RESULT Here we found that overexpression of miR-191-3p promoted the stemness properties of esophageal cancer cells in vitro and in vivo, including increasing esophageal cancer cell proliferation and metastasis ability, the expression of stemness-related markers NANOG, OCT4, and SOX2, ALDH activity, the number of spheres formed and tumor growth. Bioinformatic analysis and dual-luciferase assay demonstrated that regulator of G protein signaling 1 (RGS1) was the directed target gene of miR-191-3p and attenuated the promotion effect of miR-191-3p on the stemness of esophageal cancer cells. Furthermore, we found that RGS1 knockdown activated the PI3K/AKT pathway by negatively regulating CXCR4 to promote the stemness of esophageal cancer cells. CONCLUSIONS Our findings revealed that RGS1 targeted by miR-191-3p inhibited the stemness of esophageal cancer cells by suppressing the CXCR4/PI3K/AKT pathway, which provide potential prognostic markers and therapeutic targets in the future.
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Affiliation(s)
- Jing Xun
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Yuan Ma
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Botao Wang
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China
| | - Xiaolin Jiang
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Bin Liu
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Ruifang Gao
- Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin 300020, China
| | - Qiongli Zhai
- Department of Pathology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060, China
| | - Runfen Cheng
- Department of Pathology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060, China
| | - Xueliang Wu
- The First Affiliated Hospital of Hebei North University, Hebei 075000, China
| | - Yu Wu
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China.
| | - Qi Zhang
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300100, China; Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China.
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Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt‐Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (Beijing) 2024; 5:e710. [PMID: 39309691 PMCID: PMC11416093 DOI: 10.1002/mco2.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology LabDepartment of BiotechnologyMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Ravi Bhushan
- Department of ZoologyM.S. CollegeMotihariBiharIndia
| | - Caiming Xu
- Department of General SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research InstituteCity of HopeMonroviaCaliforniaUSA
| | - Bhana Ram Gadi
- Stress Physiology and Molecular Biology LaboratoryDepartment of BotanyJai Narain Vyas UniversityJodhpurRajasthanIndia
| | | | - Vikas Yadav
- School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
| | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of BioinformaticsInternational Technology ParkBangaloreIndia
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
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Sepehr A, Aghamohammad S, Ghanavati R, Bavandpour AK, Talebi M, Rohani M, Pourshafie MR. The inhibitory effects of the novel Lactobacillus cocktail on colorectal cancer development through modulating BMP signaling pathway: In vitro and in vivo study. Heliyon 2024; 10:e36554. [PMID: 39281652 PMCID: PMC11402137 DOI: 10.1016/j.heliyon.2024.e36554] [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: 05/14/2023] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 09/18/2024] Open
Abstract
This study investigates the impact of a five-strain Lactobacillus cocktail (comprising two strains of L. plantarum, and one strain each of L. brevis, L. reuteri, and L. rhamnosus) on colorectal cancer (CRC) modulation by targeting the bone morphogenetic proteins (BMP) signaling pathway. Both in vitro and in vivo (models were employed. The antiproliferative effects of the Lactobacillus cocktail on HT-29 cells were assessed via the MTT assay. Mice were divided into three groups: a negative control (treated with PBS), a positive control (treated with azoxymethane (AOM)/dextran sulfate sodium (DSS) + PBS), and a test group (treated with AOM/DSS + Lactobacillus cocktail in PBS). The role of the Lactobacillus cocktail in inhibiting the BMP signaling pathway was evaluated using qRT-PCR for gene expression analysis and western blotting for β-catenin protein assessment in both models. The MTT assay results demonstrated a significant, time-dependent reduction in HT-29 cell proliferation. qRT-PCR indicated downregulation of the BMP signaling pathway in treated cells, which subsequently led to decreased expression of the hes1 gene, crucial for cell differentiation and proliferation control. This inhibitory effect was corroborated in the mice model, showing significant downregulation of BMP pathway genes and hes1 in the AOM/DSS/Lactobacillus cocktail-treated group. Additionally, western blotting revealed a marked decrease in β-catenin expression in both in vitro and in vivo experiments. Collectively, these findings suggest that the Lactobacillus cocktail may aid in CRC prevention by downregulating the BMP signaling pathway.
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Affiliation(s)
- Amin Sepehr
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | | | | | - Ali Karimi Bavandpour
- Department of Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA
| | - Malihe Talebi
- Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahdi Rohani
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
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11
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Kumari B, Tiwari A, Meena S, Ahirwar DK. Inflammation-Associated Stem Cells in Gastrointestinal Cancers: Their Utility as Prognostic Biomarkers and Therapeutic Targets. Cancers (Basel) 2024; 16:3134. [PMID: 39335106 PMCID: PMC11429849 DOI: 10.3390/cancers16183134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Stem cells are critical for the development and homeostasis of the gastrointestinal (GI) tract. Inflammatory molecules are known to regulate the activity of stem cells. A comprehensive review specifically describing the role of inflammatory molecules in the regulation of stem cells within the GI tract and in GI cancers (GICs) is not available. This review focuses on understanding the role of inflammatory molecules and stem cells in maintaining homeostasis of the GI tract. We further discuss how inflammatory conditions contribute to the transformation of stem cells into tumor-initiating cells. We also describe the molecular mechanisms of inflammation and stem cell-driven progression and metastasis of GICs. Furthermore, we report on studies describing the prognostic value of cancer stem cells and the clinical trials evaluating their therapeutic utility. This review provides a detailed overview on the role of inflammatory molecules and stem cells in maintaining GI tract homeostasis and their implications for GI-related malignancies.
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Affiliation(s)
- Beauty Kumari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Aniket Tiwari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Sakshi Meena
- School of Life Sciences, Devi Ahilya Vishwavidyalaya Indore, Indore 452001, Madhya Pradesh, India;
| | - Dinesh Kumar Ahirwar
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
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12
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Niharika, Ureka L, Roy A, Patra SK. Dissecting SOX2 expression and function reveals an association with multiple signaling pathways during embryonic development and in cancer progression. Biochim Biophys Acta Rev Cancer 2024; 1879:189136. [PMID: 38880162 DOI: 10.1016/j.bbcan.2024.189136] [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: 05/09/2023] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024]
Abstract
SRY (Sex Determining Region) box 2 (SOX2) is an essential transcription factor that plays crucial roles in activating genes involved in pre- and post-embryonic development, adult tissue homeostasis, and lineage specifications. SOX2 maintains the self-renewal property of stem cells and is involved in the generation of induced pluripotency stem cells. SOX2 protein contains a particular high-mobility group domain that enables SOX2 to achieve the capacity to participate in a broad variety of functions. The information about the involvement of SOX2 with gene regulatory elements, signaling networks, and microRNA is gradually emerging, and the higher expression of SOX2 is functionally relevant to various cancer types. SOX2 facilitates the oncogenic phenotype via cellular proliferation and enhancement of invasive tumor properties. Evidence are accumulating in favor of three dimensional (higher order) folding of chromatin and epigenetic control of the SOX2 gene by chromatin modifications, which implies that the expression level of SOX2 can be modulated by epigenetic regulatory mechanisms, specifically, via DNA methylation and histone H3 modification. In view of this, and to focus further insights into the roles SOX2 plays in physiological functions, involvement of SOX2 during development, precisely, the advances of our knowledge in pre- and post-embryonic development, and interactions of SOX2 in this scenario with various signaling pathways in tumor development and cancer progression, its potential as a therapeutic target against many cancers are summarized and discussed in this article.
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Affiliation(s)
- Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Lina Ureka
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
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13
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Zhao K, Wu C, Li X, Niu M, Wu D, Cui X, Zhao H. From mechanism to therapy: the journey of CD24 in cancer. Front Immunol 2024; 15:1401528. [PMID: 38881902 PMCID: PMC11176514 DOI: 10.3389/fimmu.2024.1401528] [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: 03/15/2024] [Accepted: 04/25/2024] [Indexed: 06/18/2024] Open
Abstract
CD24 is a glycosylphosphatidylinositol-anchored protein that is expressed in a wide range of tissues and cell types. It is involved in a variety of physiological and pathological processes, including cell adhesion, migration, differentiation, and apoptosis. Additionally, CD24 has been studied extensively in the context of cancer, where it has been found to play a role in tumor growth, invasion, and metastasis. In recent years, there has been growing interest in CD24 as a potential therapeutic target for cancer treatment. This review summarizes the current knowledge of CD24, including its structure, function, and its role in cancer. Finally, we provide insights into potential clinical application of CD24 and discuss possible approaches for the development of targeted cancer therapies.
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Affiliation(s)
- Kai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Caifeng Wu
- Department of Hand and Foot, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiangjun Li
- Department of Breast Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mengchao Niu
- Department of Operation Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dan Wu
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaofeng Cui
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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14
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Kulus M, Farzaneh M, Bryja A, Zehtabi M, Azizidoost S, Abouali Gale Dari M, Golcar-Narenji A, Ziemak H, Chwarzyński M, Piotrowska-Kempisty H, Dzięgiel P, Zabel M, Mozdziak P, Bukowska D, Kempisty B, Antosik P. Phenotypic Transitions the Processes Involved in Regulation of Growth and Proangiogenic Properties of Stem Cells, Cancer Stem Cells and Circulating Tumor Cells. Stem Cell Rev Rep 2024; 20:967-979. [PMID: 38372877 PMCID: PMC11087301 DOI: 10.1007/s12015-024-10691-w] [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] [Accepted: 02/01/2024] [Indexed: 02/20/2024]
Abstract
Epithelial-mesenchymal transition (EMT) is a crucial process with significance in the metastasis of malignant tumors. It is through the acquisition of plasticity that cancer cells become more mobile and gain the ability to metastasize to other tissues. The mesenchymal-epithelial transition (MET) is the return to an epithelial state, which allows for the formation of secondary tumors. Both processes, EMT and MET, are regulated by different pathways and different mediators, which affects the sophistication of the overall tumorigenesis process. Not insignificant are also cancer stem cells and their participation in the angiogenesis, which occur very intensively within tumors. Difficulties in effectively treating cancer are primarily dependent on the potential of cancer cells to rapidly expand and occupy secondarily vital organs. Due to the ability of these cells to spread, the concept of the circulating tumor cell (CTC) has emerged. Interestingly, CTCs exhibit molecular diversity and stem-like and mesenchymal features, even when derived from primary tumor tissue from a single patient. While EMT is necessary for metastasis, MET is required for CTCs to establish a secondary site. A thorough understanding of the processes that govern the balance between EMT and MET in malignancy is crucial.
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Affiliation(s)
- Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Artur Bryja
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
| | - Mojtaba Zehtabi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Azizidoost
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahrokh Abouali Gale Dari
- Department of Obstetrics and Gynecology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Afsaneh Golcar-Narenji
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC, USA
| | - Hanna Ziemak
- Veterinary Clinic of the Nicolaus Copernicus University in Torun, Torun, Poland
| | - Mikołaj Chwarzyński
- Veterinary Clinic of the Nicolaus Copernicus University in Torun, Torun, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
- Department of Physiotherapy, Wroclaw University School of Physical Education, Wroclaw, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, Zielona Góra, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC, USA
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC, USA
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland.
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland.
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC, USA.
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, Brno, Czech Republic.
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland
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15
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Gajos-Michniewicz A, Czyz M. WNT/β-catenin signaling in hepatocellular carcinoma: The aberrant activation, pathogenic roles, and therapeutic opportunities. Genes Dis 2024; 11:727-746. [PMID: 37692481 PMCID: PMC10491942 DOI: 10.1016/j.gendis.2023.02.050] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/28/2022] [Accepted: 02/14/2023] [Indexed: 09/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver cancer, highly heterogeneous both at the histopathological and molecular levels. It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways, including canonical WNT/β-catenin, AKT/mTOR, MAPK pathways as well as signaling associated with telomere maintenance, p53/cell cycle regulation, epigenetic modifiers, and oxidative stress. The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established, whereas in development and progression of HCC is extensively studied. Herein, we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development, acquisition of stemness features, metastasis, and resistance to treatment. We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC. We discuss the pivotal roles of CTNNB1 mutations, aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
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Affiliation(s)
- Anna Gajos-Michniewicz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
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16
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Yokoi A, Murayama A, Hashimura M, Oguri Y, Harada Y, Fukagawa N, Hayashi M, Ono M, Ohhigata K, Saegusa M. A Complex Interplay between Notch Effectors and β-Catenin Signaling in Morular Differentiation of Endometrial Carcinoma Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:459-470. [PMID: 38096983 DOI: 10.1016/j.ajpath.2023.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/02/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023]
Abstract
Notch signaling contributes to tissue development and homeostasis, but little is known about its role in morular differentiation of endometrial carcinoma (Em Ca) cells. The current study focused on crosstalk between Notch and β-catenin signaling in Em Ca with morules. Promoters of hairy and enhancer of split 1 (Hes1) and mastermind-like 2 (MAML2) were activated by Notch intracellular domain 1 but not β-catenin, and a positive feedback loop between Hes1 and MAML2 was observed. Immunoreactivities for nuclear β-catenin, Hes1, and MAML2, as well as the interaction between β-catenin and Hes1 or MAML2, were significantly higher in morular lesions compared with surrounding carcinoma in Em Ca. Inhibition of glycogen synthase kinase-3β (GSK-3β) increased expression of total nuclear and cytoplasmic GSK-3β and its phosphorylated forms, as well as Notch intracellular domain 1, Hes1, and active β-catenin. GSK-3β inhibition also decreased proliferation and migration, consistent with the response of cells stably overexpressing Hes1. Finally, the nuclear/cytoplasmic GSK-3β score was significantly higher in morules compared with surrounding carcinoma in Em Ca, and it was positively correlated with nuclear β-catenin, Hes1, and MAML2 scores. This complex interplay between Notch effectors and β-catenin signaling through GSK-3β inhibition contributes to the establishment and maintenance of β-catenin-mediated morular differentiation, which is, in turn, associated with reduced proliferation and inhibition of migration in Em Ca.
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Affiliation(s)
- Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akari Murayama
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yohei Harada
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Naomi Fukagawa
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Misato Hayashi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Mototsugu Ono
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kensuke Ohhigata
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.
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17
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Huang S, Zhang X, Wei Y, Xiao Y. Checkpoint CD24 function on tumor and immunotherapy. Front Immunol 2024; 15:1367959. [PMID: 38487533 PMCID: PMC10937401 DOI: 10.3389/fimmu.2024.1367959] [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: 01/09/2024] [Accepted: 02/12/2024] [Indexed: 03/17/2024] Open
Abstract
CD24 is a protein found on the surface of cells that plays a crucial role in the proliferation, invasion, and spread of cancer cells. It adheres to cell membranes through glycosylphosphatidylinositol (GPI) and is associated with the prognosis and survival rate of cancer patients. CD24 interacts with the inhibitory receptor Siglec-10 that is present on immune cells like natural killer cells and macrophages, leading to the inhibition of natural killer cell cytotoxicity and macrophage-mediated phagocytosis. This interaction helps tumor cells escape immune detection and attack. Although the use of CD24 as a immune checkpoint receptor target for cancer immunotherapy is still in its early stages, clinical trials have shown promising results. Monoclonal antibodies targeting CD24 have been found to be well-tolerated and safe. Other preclinical studies are exploring the use of chimeric antigen receptor (CAR) T cells, antibody-drug conjugates, and gene therapy to target CD24 and enhance the immune response against tumors. In summary, this review focuses on the role of CD24 in the immune system and provides evidence for CD24 as a promising immune checkpoint for cancer immunotherapy.
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Affiliation(s)
- Shiming Huang
- Department of Radiology, First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- Graduate School, Chinese PLA Medical School, Beijing, China
- Department of Nuclear Medicine, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, China
| | - Xiaobo Zhang
- Department of Radiology, First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Yingtian Wei
- Department of Radiology, First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Yueyong Xiao
- Department of Radiology, First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
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18
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Zhang HL, Li N, Dong L, Ma HX, Yang MC. Prox1 Suppresses Proliferation and Drug Resistance of Retinoblastoma Cells via Targeting Notch1. Curr Med Sci 2024; 44:223-231. [PMID: 38277016 DOI: 10.1007/s11596-023-2803-9] [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: 01/06/2022] [Accepted: 03/21/2022] [Indexed: 01/27/2024]
Abstract
OBJECTIVE Retinoblastoma (RB) is a prevalent type of eye cancer in youngsters. Prospero homeobox 1 (Prox1) is a homeobox transcriptional repressor and downstream target of the proneural gene that is relevant in lymphatic, hepatocyte, pancreatic, heart, lens, retinal, and cancer cells. The goal of this study was to investigate the role of Prox1 in RB cell proliferation and drug resistance, as well as to explore the underlying Notch1 mechanism. METHODS Human RB cell lines (SO-RB50 and Y79) and a primary human retinal microvascular endothelial cell line (ACBRI-181) were used in this study. The expression of Prox1 and Notch1 mRNA and protein in RB cells was detected using quantitative real time-polymerase chain reaction (RT-qPCR) and Western blotting. Cell proliferation was assessed after Prox1 overexpression using the Cell Counting Kit-8 and the MTS assay. Drug-resistant cell lines (SO-RB50/vincristine) were generated and treated with Prox1 to investigate the role of Prox1 in drug resistance. We employed pcDNA-Notch1 to overexpress Notch1 to confirm the role of Notch1 in the protective function of Prox1. Finally, a xenograft model was constructed to assess the effect of Prox1 on RB in vivo. RESULTS Prox1 was significantly downregulated in RB cells. Overexpression of Prox1 effectively decreased RB cell growth while increasing the sensitivity of drug-resistant cells to vincristine. Notch1 was involved in Prox1's regulatory effects. Notch1 was identified as a target gene of Prox1, which was found to be upregulated in RB cells and repressed by increased Prox1 expression. When pcDNA-Notch1 was transfected, the effect of Prox1 overexpression on RB was removed. Furthermore, by downregulating Notch1, Prox1 overexpression slowed tumor development and increased vincristine sensitivity in vivo. CONCLUSION These data show that Prox1 decreased RB cell proliferation and drug resistance by targeting Notch1, implying that Prox1 could be a potential therapeutic target for RB.
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Affiliation(s)
- Hong-Li Zhang
- Department of Ophthalmology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Na Li
- Department of Ophthalmology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Lin Dong
- Department of Ophthalmology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Hong-Xia Ma
- Department of Ophthalmology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Mo-Chi Yang
- Department of Ophthalmology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
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Gisina A, Kim Y, Yarygin K, Lupatov A. Can CD133 Be Regarded as a Prognostic Biomarker in Oncology: Pros and Cons. Int J Mol Sci 2023; 24:17398. [PMID: 38139228 PMCID: PMC10744290 DOI: 10.3390/ijms242417398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The CD133 cell membrane glycoprotein, also termed prominin-1, is expressed on some of the tumor cells of both solid and blood malignancies. The CD133-positive tumor cells were shown to exhibit higher proliferative activity, greater chemo- and radioresistance, and enhanced tumorigenicity compared to their CD133-negative counterparts. For this reason, CD133 is regarded as a potential prognostic biomarker in oncology. The CD133-positive cells are related to the cancer stem cell subpopulation in many types of cancer. Recent studies demonstrated the involvement of CD133 in the regulation of proliferation, autophagy, and apoptosis in cancer cells. There is also evidence of its participation in the epithelial-mesenchymal transition associated with tumor progression. For a number of malignant tumor types, high CD133 expression is associated with poor prognosis, and the prognostic significance of CD133 has been confirmed in a number of meta-analyses. However, some published papers suggest that CD133 has no prognostic significance or even demonstrate a certain correlation between high CD133 levels and a positive prognosis. This review summarizes and discusses the existing evidence for and against the prognostic significance of CD133 in cancer. We also consider possible reasons for conflicting findings from the studies of the clinical significance of CD133.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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20
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Ding J, Su Y, Liu Y, Xu Y, Yang D, Wang X, Hao S, Zhou H, Li H. The role of CSTF2 in cancer: from technology to clinical application. Cell Cycle 2023; 22:2622-2636. [PMID: 38166492 PMCID: PMC10936678 DOI: 10.1080/15384101.2023.2299624] [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: 03/17/2023] [Revised: 12/03/2023] [Accepted: 12/20/2023] [Indexed: 01/04/2024] Open
Abstract
A protein called cleavage-stimulating factor subunit 2 (CSTF2, additionally called CSTF-64) binds RNA and is needed for the cleavage and polyadenylation of mRNA. CSTF2 is an important component subunit of the cleavage stimulating factor (CSTF), which is located on the X chromosome and encodes 557 amino acids. There is compelling evidence linking elevated CSTF2 expression to the pathological advancement of cancer and on its impact on the clinical aspects of the disease. The progression of cancers, including hepatocellular carcinoma, melanoma, prostate cancer, breast cancer, and pancreatic cancer, is correlated with the upregulation of CSTF2 expression. This review provides a fresh perspective on the investigation of the associations between CSTF2 and various malignancies and highlights current studies on the regulation of CSTF2. In particular, the mechanism of action and potential clinical applications of CSTF2 in cancer suggest that CSTF2 can serve as a new biomarker and individualized treatment target for a variety of cancer types.
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Affiliation(s)
- Jiaxiang Ding
- Clinical Trial Center of the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- School of Public Foundation, Bengbu Medical University, Bengbu, Anhui, China
| | - Yue Su
- Clinical Trial Center of the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- School of Public Foundation, Bengbu Medical University, Bengbu, Anhui, China
| | - Youru Liu
- The People’s Hospital of Bozhou, Bozhou, Anhui, China
| | - Yuanyuan Xu
- Clinical Trial Center of the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- School of Pharmacy, Bengbu Medical University, Bengbu, Anhui, China
| | - Dashuai Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province; School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Xuefeng Wang
- Clinical Trial Center of the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- School of Pharmacy, Bengbu Medical University, Bengbu, Anhui, China
| | - Shuli Hao
- The People’s Hospital of Bozhou, Bozhou, Anhui, China
| | - Huan Zhou
- Clinical Trial Center of the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- School of Public Foundation, Bengbu Medical University, Bengbu, Anhui, China
- School of Pharmacy, Bengbu Medical University, Bengbu, Anhui, China
| | - Hongtao Li
- Clinical Trial Center of the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
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Kahm YJ, Kim RK. BIRC5: A novel therapeutic target for lung cancer stem cells and glioma stem cells. Biochem Biophys Res Commun 2023; 682:141-147. [PMID: 37806253 DOI: 10.1016/j.bbrc.2023.10.008] [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: 09/08/2023] [Revised: 09/23/2023] [Accepted: 10/02/2023] [Indexed: 10/10/2023]
Abstract
Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) is also known as survivin. BIRC5, a member of the apoptosis inhibitor (IAP) family, negatively regulates apoptosis or programmed cell death by inhibiting caspase activation. Due to these properties, overexpression of BIRC5 enables specific survival and division associated with cancer malignancies. In addition, BIRC5 is highly expressed in stem cells, but not present at all in terminally differentiated cells. On this basis, there is speculation that BIRC5 may be involved in the regulation of cancer stem cells (CSCs), but few study results have been reported. In addition, the molecular mechanisms of BIRC5 regulation are not yet well understood. Through the present study, it was confirmed that BIRC5 is a key factor regulating CSCs and epithelial to mesenchymal transition (EMT). BIRC5 was simultaneously overexpressed in lung cancer stem cells (LCSCs) and glioma stem cells (GSCs), and when the expression was suppressed, the characteristics of CSCs disappeared. In addition, plasminogen activator inhibitor-1 (PAI-1), a secreted factor regulated by BIRC5, is involved in signaling mechanisms that regulate cancer stem cells and EMT, and PAI-1 forms an autocrine chain. Based on these results, BIRC5 is proposed as a novel therapeutic target protein for LCSCs and GSCs.
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Affiliation(s)
- Yeon-Jee Kahm
- Department of Environmental Safety Technology Research, Korea Atomic Energy Research Institute, Yuseong-Gu, Daejeon, 34057, Republic of Korea; Department of Radiation Life Science, Korea University of Science and Technology, Yuseong-Gu, Daejeon, 34113, Republic of Korea
| | - Rae-Kwon Kim
- Department of Environmental Safety Technology Research, Korea Atomic Energy Research Institute, Yuseong-Gu, Daejeon, 34057, Republic of Korea; Department of Radiation Life Science, Korea University of Science and Technology, Yuseong-Gu, Daejeon, 34113, Republic of Korea.
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22
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Amin MN, El-Far YM, El-Mowafy M, Elgaml A. Tazemetostat decreases β-catenin and CD13 protein expression in HEPG-2 and Hepatitis B virus-transfected HEPG-2 with decreased cell viability. Clin Epigenetics 2023; 15:180. [PMID: 37941056 PMCID: PMC10634085 DOI: 10.1186/s13148-023-01593-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the global health concerns. Hepatitis B virus (HBV) is one of the major causes of HCC. Poor clinical outcome of HCC patients is attributed to a small population of cancer cells known as cancer stem cells (CSCs). In this work, we studied the effect of inhibiting the enhancer of zeste homologue 2 (EZH2), a histone methyltransferase known to be overexpressed in CSCs, using tazemetostat (Taz). The effect of Taz was assessed in the HCC cell line (HEPG2) and Hepatitis B virus-transfected HEPG2 (HBV/HEPG2) cells. MTT assay showed a significant decrease in HEPG2 cells viability after 48 h treatment with either 0.5, 1, 4 or 6 μM Taz. HEPG2 and HBV/HEPG2 cells were incubated with either 0.5 or 1 μM Taz for 48 h, and then, the cells and supernatants were collected for protein expression analysis of EZH2, CD13, epithelial cell adhesion molecule (EpCAM) and β-catenin using enzyme-linked immunosorbent assay (ELISA). Taz showed a significant dose-dependent inhibition of EZH2, CD13 and β-catenin in HEPG2 and HBV/HEPG2 cells. Also, EpCAM protein levels were significantly decreased in HBV/HEPG2 but not in HEPG2 cell line alone. Our results indicate that Taz inhibition of EZH2 leads to downregulation of β-catenin signaling and eventually decreased expression of CD13 and EpCAM, which are characteristic for CSCs. The present study suggests that Taz could be a promising treatment for HCC including HBV-induced HCC that might be used in combination with radio/chemotherapy to target CSCs and prevent tumor relapse.
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Affiliation(s)
- Mohamed N Amin
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Yousra M El-Far
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Mohammed El-Mowafy
- Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Abdelaziz Elgaml
- Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
- Microbiology and Immunology Department, Faculty of Pharmacy, Horus University, New Damietta, 34518, Egypt.
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23
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Yang Y, Zhu G, Yang L, Yang Y. Targeting CD24 as a novel immunotherapy for solid cancers. Cell Commun Signal 2023; 21:312. [PMID: 37919766 PMCID: PMC10623753 DOI: 10.1186/s12964-023-01315-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/13/2023] [Indexed: 11/04/2023] Open
Abstract
Cluster of differentiation 24 (CD24), a mucin-like highly glycosylated molecule has been extensively studied as a cancer stem cell marker in a variety of solid cancers. The functional role of CD24 is either fulfilled by combining with ligands or participating in signal transduction, which mediate the initiation and progression of neoplasms. Recently, CD24 was also described as an innate immune checkpoint with apparent significance in several types of solid cancers. Herein, we review the current understanding of the molecular fundamentals of CD24, the role of CD24 in tumorigenesis and cancer progression, the possibility as a promising therapeutic target and summarized different therapeutic agents or strategies targeting CD24 in solid cancers. Video Abstract.
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Affiliation(s)
- Yan Yang
- Xinxiang Engineering Technology Research Center of Tumor-Targeted Drug Development, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453000, Henan, China
| | - Guangming Zhu
- Clinical Laboratory, The First People's Hospital of Taian, Taian 271000, Shandong, China
| | - Li Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou Key Laboratory of Endometrial Disease Prevention and Treatment Zhengzhou China, Zhengzhou, 450052, Henan, China
| | - Yun Yang
- Xinxiang Engineering Technology Research Center of Tumor-Targeted Drug Development, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453000, Henan, China.
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24
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Kiran A, Altaf A, Sarwar M, Malik A, Maqbool T, Ali Q. Phytochemical profiling and cytotoxic potential of Arnebia nobilis root extracts against hepatocellular carcinoma using in-vitro and in-silico approaches. Sci Rep 2023; 13:11376. [PMID: 37452082 PMCID: PMC10349071 DOI: 10.1038/s41598-023-38517-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023] Open
Abstract
Hepatocellular carcinoma is the fifth most prevalent cancer worldwide. The emergence of drug resistance and other adverse effects in available anticancer options are challenging to explore natural sources. The current study was designed to decipher the Arnebia nobilis (A. nobilis) extracts for detecting phytochemicals, in-vitro evaluation of antioxidative and cytotoxic potentials, and in-silico prediction of potent anticancer compounds. The phytochemical analysis revealed the presence of flavonoids, phenols, tannins, alkaloids, quinones, and cardiac glycosides, in the ethanol (ANE) and n-hexane (ANH) extracts of A. nobilis. ANH extract exhibited a better antioxidant potential to scavenge DPPH, nitric oxide and superoxide anion radicals than ANE extract, which showed better potential only against H2O2 radicals. In 24 h treatment, ANH extract revealed higher cytotoxicity (IC50 value: 22.77 µg/mL) than ANH extract (IC50 value: 46.74 µg/mL) on cancer (HepG2) cells without intoxicating the normal (BHK) cells using MTT assay. A better apoptotic potential was observed in ANH extract (49.10%) compared to ANE extract (41.35%) on HepG2 cells using the annexin V/PI method. GCMS analysis of ANH extract identified 35 phytocompounds, from which only 14 bioactive compounds were selected for molecular docking based on druggability criteria and toxicity filters. Among the five top scorers, deoxyshikonin exhibited the best binding affinities of - 7.2, - 9.2, - 7.2 and - 9.2 kcal/mol against TNF-α, TGF-βR1, Bcl-2 and iNOS, respectively, followed by ethyl cholate and 2-Methyl-6-(4-methylphenyl)hept-2-en-4-one along with their desirable ADMET properties. The phytochemicals of ANH extract could be used as a promising drug candidate for liver cancer after further validations.
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Affiliation(s)
- Asia Kiran
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54300, Pakistan
| | - Awais Altaf
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54300, Pakistan.
| | - Muhammad Sarwar
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54300, Pakistan
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54300, Pakistan
| | - Tahir Maqbool
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54300, Pakistan
| | - Qurban Ali
- Department of Plant Breeding and Genetics, Faculty of Agricultural Sciences, University of the Punjab, Lahore, Pakistan.
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25
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Razi S, Haghparast A, Chodari Khameneh S, Ebrahimi Sadrabadi A, Aziziyan F, Bakhtiyari M, Nabi-Afjadi M, Tarhriz V, Jalili A, Zalpoor H. The role of tumor microenvironment on cancer stem cell fate in solid tumors. Cell Commun Signal 2023; 21:143. [PMID: 37328876 PMCID: PMC10273768 DOI: 10.1186/s12964-023-01129-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/15/2023] [Indexed: 06/18/2023] Open
Abstract
In the last few decades, the role of cancer stem cells in initiating tumors, metastasis, invasion, and resistance to therapies has been recognized as a potential target for tumor therapy. Understanding the mechanisms by which CSCs contribute to cancer progression can help to provide novel therapeutic approaches against solid tumors. In this line, the effects of mechanical forces on CSCs such as epithelial-mesenchymal transition, cellular plasticity, etc., the metabolism pathways of CSCs, players of the tumor microenvironment, and their influence on the regulating of CSCs can lead to cancer progression. This review focused on some of these mechanisms of CSCs, paving the way for a better understanding of their regulatory mechanisms and developing platforms for targeted therapies. While progress has been made in research, more studies will be required in the future to explore more aspects of how CSCs contribute to cancer progression. Video Abstract.
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Affiliation(s)
- Sara Razi
- Vira Pioneers of Modern Science (VIPOMS), Tehran, Iran
| | | | | | - Amin Ebrahimi Sadrabadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
- Cytotech and Bioinformatics Research Group, Tehran, Iran
| | - Fatemeh Aziziyan
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Maryam Bakhtiyari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Vahideh Tarhriz
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, P.O. Box 5163639888, Tabriz, Iran.
| | - Arsalan Jalili
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran.
- Parvaz Research Ideas Supporter Institute, Tehran, Iran.
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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26
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Li L, Ni R, Zheng D, Chen L. Eradicating the tumor "seeds": nanomedicines-based therapies against cancer stem cells. Daru 2023; 31:83-94. [PMID: 36971921 PMCID: PMC10238364 DOI: 10.1007/s40199-023-00456-0] [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: 08/17/2022] [Accepted: 03/05/2023] [Indexed: 03/29/2023] Open
Abstract
OBJECTIVES Cancer stem cells (CSCs), a small subpopulation of cells with high tumorigenesis and strong intrinsic drug resistance, exhibit self-renewal and differentiation abilities. CSCs play a crucial role in tumor progression, drug resistance, recurrence and metastasis,and conventional therapy is not enough to eradicate them. Therefore, developing novel therapies targeting CSCs to increase drug sensitivity and preventing relapse is essential. The objective of this review is to present nanotherapies that target and eradicate the tumor "seeds". EVIDENCE ACQUISITION Evidence was collected and sorted from the literature ranging from 2000 to 2022, using appropriate keywords and key phrases as search terms within scientific databases such as Web of Science, PubMed and Google Scholar. RESULTS Nanoparticle drug delivery systems have been successfully applied to gain longer circulation time, more precise targeting capability and better stability during cancer treatment. Nanotechnology-based strategies that have been used to target CSCs, include (1) encapsulating small molecular drugs and genes by nanotechnology, (2) targeting CSC signaling pathways, (3) utilizing nanocarriers targeting for specific markers of CSCs, (4) improving photothermal/ photodynamic therapy (PTT/PDT), 5)targeting the metabolism of CSCs and 6) enhancing nanomedicine-aided immunotherapy. CONCLUSION This review summarizes the biological hallmarks and markers of CSCs, and the nanotechnology-based therapies to kill them. Nanoparticle drug delivery systems are appropriate means for delivering drugs to tumors through enhanced permeability and retention (EPR) effect. Furthermore, surface modification with special ligands or antibodies improves the recognition and uptake of tumor cells or CSCs. It is expected that this review can offer insights into features of CSCs and the exploration of targeting nanodrug delivery systems.
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Affiliation(s)
- Lin Li
- Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, 401147, Chongqing, China
| | - Rui Ni
- Department of Pharmacy, Daping Hospital, Army Medical University, 400042, Chongqing, China
| | - Dan Zheng
- Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, 401147, Chongqing, China
| | - Lin Chen
- Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, 401147, Chongqing, China.
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27
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Mohamed EH, Abo El-Magd NF, El Gayar AM. Carvacrol enhances anti-tumor activity and mitigates cardiotoxicity of sorafenib in thioacetamide-induced hepatocellular carcinoma model through inhibiting TRPM7. Life Sci 2023; 324:121735. [PMID: 37142088 DOI: 10.1016/j.lfs.2023.121735] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/16/2023] [Accepted: 04/22/2023] [Indexed: 05/06/2023]
Abstract
AIMS Sorafenib (Sora) represents one of the few effective drugs for the treatment of advanced hepatocellular carcinoma (HCC), while resistance and cardiotoxicity limit its therapeutic efficacy. This study investigated the effect of transient receptor potential melastatin 7 (TRPM7) inhibitor, carvacrol (CARV), on overcoming Sora resistance and cardiotoxicity in thioacetamide (TAA) induced HCC in rats. MATERIALS AND METHODS TAA (200 mg/kg/twice weekly, intraperitoneal) was administered for 16 weeks to induce HCC. Rats were treated with Sora (10 mg/Kg/day; orally) and CARV (15 mg/kg/day; orally) alone or in combination, for six weeks after HCC induction. Liver and heart functions, antioxidant capacity, and histopathology were performed. Apoptosis, proliferation, angiogenesis, metastasis, and drug resistance were assessed by quantitative real time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. KEY FINDINGS CARV/Sora combination significantly improved survival rate, and liver functions, reduced Alpha-Fetoprotein level, and attenuated HCC progression compared with Sora group. CARV coadministration almost obviated Sora-induced changes in cardiac and hepatic tissues. The CARV/Sora combination suppressed drug resistance and stemness by downregulating ATP-binding cassette subfamily G member 2, NOTCH1, Spalt like transcription factor 4, and CD133. CARV boosted Sora antiproliferative and apoptotic activities by decreasing cyclin D1 and B-cell leukemia/lymphoma 2 and increasing BCL2-Associated X and caspase-3. SIGNIFICANCE CARV/Sora is a promising combination for tumor suppression and overcoming Sora resistance and cardiotoxicity in HCC by modulating TRPM7. To our best knowledge, this study represents the first study to investigate the efficiency of CARV/ Sora on the HCC rat model. Moreover, no previous studies have reported the effect of inhibiting TRPM7 on HCC.
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Affiliation(s)
- Eman H Mohamed
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Biochemistry Department, Faculty of Pharmacy, Horus University-Egypt, Damietta 34511, Egypt.
| | - Nada F Abo El-Magd
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amal M El Gayar
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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28
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Ebrahimi N, Afshinpour M, Fakhr SS, Kalkhoran PG, Shadman-Manesh V, Adelian S, Beiranvand S, Rezaei-Tazangi F, Khorram R, Hamblin MR, Aref AR. Cancer stem cells in colorectal cancer: Signaling pathways involved in stemness and therapy resistance. Crit Rev Oncol Hematol 2023; 182:103920. [PMID: 36702423 DOI: 10.1016/j.critrevonc.2023.103920] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/07/2022] [Accepted: 01/20/2023] [Indexed: 01/24/2023] Open
Abstract
Colorectal cancer (CRC) is the third cause of cancer death worldwide. Although, in some cases, treatment can increase patient survival and reduce cancer recurrence, in many cases, tumors can develop resistance to therapy leading to recurrence. One of the main reasons for recurrence and therapy resistance is the presence of cancer stem cells (CSCs). CSCs possess a self-renewal ability, and their stemness properties lead to the avoidance of apoptosis, and allow a new clone of cancer cells to emerge. Numerous investigations inidicated the involvment of cellular signaling pathways in embryonic development, and growth, repair, and maintenance of tissue homeostasis, also participate in the generation and maintenance of stemness in colorectal CSCs. This review discusses the role of Wnt, NF-κB, PI3K/AKT/mTOR, Sonic hedgehog, and Notch signaling pathways in colorectal CSCs, and the possible modulating drugs that could be used in treatment for resistant CRC.
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Affiliation(s)
- Nasim Ebrahimi
- Division of Genetics, Department of cell and molecular & microbiology, Faculty of Science and technology, University of Isfahan, Isfahan, Iran
| | - Maral Afshinpour
- Department of chemistry and Biochemistry, South Dakota State University (SDSU), Brookings, SD, USA
| | - Siavash Seifollahy Fakhr
- Department of Biotechnology; Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus Hamar, Norway
| | - Paniz Ghasempour Kalkhoran
- Department of Cellular and Molecular Biology_Microbiology, Faculty of Advanced Science and Technology, Tehran Medical science, Islamic Azad University, Tehran, Iran
| | - Vida Shadman-Manesh
- Department of Biomedical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sheida Beiranvand
- Department of Biotechnology, School of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA 02210, USA.
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29
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Jeng KS, Chang CF, Sheen IS, Jeng CJ, Wang CH. Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:1417. [PMID: 36674932 PMCID: PMC9861908 DOI: 10.3390/ijms24021417] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - I-Shyang Sheen
- Department of Hepato Gastroenterology, Linkou Medical Center, Chang-Gung University, Taoyuan City 33305, Taiwan
| | - Chi-Juei Jeng
- Postgraduate of Institute of Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Chih-Hsuan Wang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
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30
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The Role of Cancer Stem Cells and Their Extracellular Vesicles in the Modulation of the Antitumor Immunity. Int J Mol Sci 2022; 24:ijms24010395. [PMID: 36613838 PMCID: PMC9820747 DOI: 10.3390/ijms24010395] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Cancer stem cells (CSCs) are a population of tumor cells that share similar properties to normal stem cells. CSCs are able to promote tumor progression and recurrence due to their resistance to chemotherapy and ability to stimulate angiogenesis and differentiate into non-CSCs. Cancer stem cells can also create a significant immunosuppressive environment around themselves by suppressing the activity of effector immune cells and recruiting cells that support tumor escape from immune response. The immunosuppressive effect of CSCs can be mediated by receptors located on their surface, as well as by secreted molecules, which transfer immunosuppressive signals to the cells of tumor microenvironment. In this article, the ability of CSCs to regulate the antitumor immune response and a contribution of CSC-derived EVs into the avoidance of the immune response are discussed.
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31
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Bao H, Wu W, Li Y, Zong Z, Chen S. WNT6 participates in the occurrence and development of ovarian cancer by upregulating/activating the typical Wnt pathway and Notch1 signaling pathway. Gene 2022; 846:146871. [PMID: 36075327 DOI: 10.1016/j.gene.2022.146871] [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: 12/13/2021] [Revised: 08/06/2022] [Accepted: 09/01/2022] [Indexed: 11/04/2022]
Abstract
Wnt/β-catenin pathway is associated with the progression of various cancers such as gastric cancer, colorectal cancer, and endometrial cancer. Using the Kaplan-Meier Plotter database, we found that WNT6 was associated with progression-free survival (PFS) outcomes. Immunohistochemical analysis of ovarian cancer samples and normal ovaries showed that the expression of WNT6 protein was significantly increased in ovarian cancer samples. Further, we explored the possible role of WNT6 in the occurrence and development of ovarian cancer. Our results showed that the mRNA and protein expression of WNT6 were significantly higher in CAOV3 and OVCAR3 cells compared with other ovarian cancer cell lines and normal ovarian cell line IOSE-80 as well. The transformation of CAOV3 and OVCAR3 cells with short interfering WNT6 (siWNT6) significantly inhibited their proliferation and lamellipodia formation, causing cell cycle arrest and promoting cell apoptosis. Western blot experiments confirmed that the down-regulation of WNT6 inhibited the expression of β-catenin and Notch1. These results suggest that WNT6 plays an important role in the occurrence and development of ovarian cancer.
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Affiliation(s)
- Haijuan Bao
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Wu Wu
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Ying Li
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Zhihong Zong
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China; China Medical University, Shenyang 110001, China.
| | - Shuo Chen
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
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32
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Schultz CW, Nevler A. Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug. Biomedicines 2022; 10:3249. [PMID: 36552005 PMCID: PMC9775650 DOI: 10.3390/biomedicines10123249] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022] Open
Abstract
Pyrvinium, a lipophilic cation belonging to the cyanine dye family, has been used in the clinic as a safe and effective anthelminthic for over 70 years. Its structure, similar to some polyaminopyrimidines and mitochondrial-targeting peptoids, has been linked with mitochondrial localization and targeting. Over the past two decades, increasing evidence has emerged showing pyrvinium to be a strong anti-cancer molecule in various human cancers in vitro and in vivo. This efficacy against cancers has been attributed to diverse mechanisms of action, with the weight of evidence supporting the inhibition of mitochondrial function, the WNT pathway, and cancer stem cell renewal. Despite the overwhelming evidence demonstrating the efficacy of pyrvinium for the treatment of human cancers, pyrvinium has not yet been repurposed for the treatment of cancers. This review provides an in-depth analysis of the history of pyrvinium as a therapeutic, the rationale and data supporting its use as an anticancer agent, and the challenges associated with repurposing pyrvinium as an anti-cancer agent.
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Affiliation(s)
- Christopher W. Schultz
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Avinoam Nevler
- Jefferson Pancreas, Biliary, and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Redox-Regulation in Cancer Stem Cells. Biomedicines 2022; 10:biomedicines10102413. [PMID: 36289675 PMCID: PMC9598867 DOI: 10.3390/biomedicines10102413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/19/2022] [Accepted: 09/21/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.
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Evodiamine as an anticancer agent: a comprehensive review on its therapeutic application, pharmacokinetic, toxicity, and metabolism in various cancers. Cell Biol Toxicol 2022; 39:1-31. [PMID: 36138312 DOI: 10.1007/s10565-022-09772-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 09/07/2022] [Indexed: 11/02/2022]
Abstract
Evodiamine is a major alkaloid component found in the fruit of Evodia rutaecarpa. It shows the anti-proliferative potential against a wide range of cancers by suppressing cell growth, invasion, and metastasis and inducing apoptosis both in vitro and in vivo. Evodiamine shows its anticancer potential by modulating aberrant signaling pathways. Additionally, the review focuses on several therapeutic implications of evodiamine, such as epigenetic modification, cancer stem cells, and epithelial to mesenchymal transition. Moreover, combinatory drug therapeutics along with evodiamine enhances the anticancer efficacy of chemotherapeutic drugs in various cancers by overcoming the chemo resistance and radio resistance shown by cancer cells. It has been widely used in preclinical trials in animal models, exhibiting very negligible side effects against normal cells and effective against cancer cells. The pharmacokinetic and pharmacodynamics-based collaborations of evodiamine are also included. Due to its poor bioavailability, synthetic analogs of evodiamine and its nano capsule have been formulated to enhance its bioavailability and reduce toxicity. In addition, this review summarizes the ongoing research on the mechanisms behind the antitumor potential of evodiamine, which proposes an exciting future for such interests in cancer biology.
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Safa AR. Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:850-872. [PMID: 36627897 PMCID: PMC9771762 DOI: 10.20517/cdr.2022.20] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/10/2022] [Accepted: 05/26/2022] [Indexed: 01/13/2023]
Abstract
Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.
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Affiliation(s)
- Ahmad R. Safa
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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36
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Survivin Inhibition by Piperine Sensitizes Glioblastoma Cancer Stem Cells and Leads to Better Drug Response. Int J Mol Sci 2022; 23:ijms23147604. [PMID: 35886952 PMCID: PMC9323232 DOI: 10.3390/ijms23147604] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 11/17/2022] Open
Abstract
Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are one of the strongest contributing factors to treatment resistance in GBM. Identification of biomarkers capable of directly affecting these cells within the bulk tumor is a major challenge associated with the development of new targeting strategies. In this study, we focus on understanding the potential of the multifunctional extraordinaire survivin as a biomarker for GSCs. We analyzed the expression profiles of this gene using various publicly available datasets to understand its importance in stemness and other cancer processes. The findings from these studies were further validated using human GSCs isolated from a GBM cell line. In these GSCs, survivin was inhibited using the dietary phytochemical piperine (PIP) and the subsequent effects on stemness, cancer processes and Temozolomide were investigated. In silico analysis identified survivin to be one of the most significant differentially regulated gene in GSCs, in comparison to common stemness markers. Further validation studies on the isolated GSCs showed the importance of survivin in stemness, cancer progression and therapy resistance. Taken together, our study identifies survivin as a more consistent GSC marker and also suggests the possibility of using survivin inhibitors along with standard of care drugs for better therapeutic outcomes.
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Chen Z, Hao W, Tang J, Gao WQ, Xu H. CSTF2 Promotes Hepatocarcinogenesis and Hepatocellular Carcinoma Progression via Aerobic Glycolysis. Front Oncol 2022; 12:897804. [PMID: 35875122 PMCID: PMC9304882 DOI: 10.3389/fonc.2022.897804] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/09/2022] [Indexed: 12/24/2022] Open
Abstract
Background The shortening of 3’ untranslated regions (3’UTRs) of messenger RNAs(mRNAs) by alternative polyadenylation (APA) is an important mechanism for oncogene activation. Cleavage stimulation factor 2 (CSTF2), an important regulator of APA, has been reported to have a tumorigenic function in urothelial carcinoma of the bladder and lung cancers. However, the tumor-promoting role of CSTF2 in hepatocellular carcinoma (HCC) and its underlying molecular mechanism remains unclear. Methods Multiple databases were used to analyze the expression level and prognostic value of CSTF2 in HCC. Function enrichment analysis was used to investigate the molecular mechanism of CSTF2 for the occurrence and development of HCC. The biological function in HCC cell lines in vitro was determined by CCK8, colony formation, Transwell migration, and invasion assay. Moreover, the tumorigenic function of CSTF2 in vivo was measured by a subcutaneous tumor formation or injecting four plasmids into a mouse tail vein within 5–7 s in an immunocompetent HCC mouse model. In addition, aerobic glycolysis in HCC cells was determined by measuring the extracellular acid rate (ECAR) and extracellular glucose and lactate levels. Results Bioinformatics analysis revealed that CSTF2 was overexpressed in HCC tissues. The high expression of CSTF2 was correlated with a poor prognosis and high histological grades. CSTF2 knockout inhibited the proliferation, migration, and invasion of HCC cells. In addition, CSTF2 knockout HCC cells failed to form tumors by a subcutaneous graft experiment. Furthermore, endogenous CSTF2 knockout attenuated hepatocarcinogenesis in an immunocompetent HCC mouse model. Function enrichment analysis suggested that the high expression of CSTF2 was associated with enhanced glycolysis. Moreover, we found that CSTF2 knockout reduced the level of the short 3’ UTR isoform of hexokinase 2 and increased its level of long 3’UTR. Furthermore, CSTF2 knockout inhibited ECAR levels, glucose uptake, and lactate production. Conclusion Our results indicated that CSTF2 is highly expressed in HCC and is correlated with a poor prognosis and high histological grade. The knockout of CSTF2 inhibits the tumorigenesis and procession of HCC both in vitro and in vivo. Moreover, CSTF2 is associated with enhanced glycolysis. Therefore, this study suggests that CSTF2 might be a new prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Zhimin Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Weijie Hao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jingzhi Tang
- Department of Ultrasound, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Med-X Research Institute and School of Biological Medical Engineering, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Huiming Xu, ; Wei-Qiang Gao,
| | - Huiming Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Huiming Xu, ; Wei-Qiang Gao,
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Chen H, Chen J, Yuan H, Li X, Li W. Hypoxia‑inducible factor‑1α: A critical target for inhibiting the metastasis of hepatocellular carcinoma (Review). Oncol Lett 2022; 24:284. [PMID: 35814827 PMCID: PMC9260738 DOI: 10.3892/ol.2022.13404] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/03/2022] [Indexed: 11/06/2022] Open
Abstract
Metastasis is one of the major reasons for patient mortality in hepatocellular carcinoma (HCC), and the progression of HCC to a metastatic state depends on the local microenvironment. Hypoxia is a key condition affecting the microenvironment of HCC. Currently, various studies have shown that the expression of hypoxia-ainducible factor-1α (HIF-1α) is associated with the invasion and metastasis of HCC. High expression of HIF-1α often leads to poor prognosis in patients with HCC. In this review, the molecular structure of HIF-1α is described, and the expression pattern of HIF-1α in HCC under hypoxia, which is associated with metastasis and poor prognosis in HCC, is explained. The molecular mechanisms of HIF-1α function and the metastasis of HCC are further discussed. The modulation of HIF-1α can reduce sorafenib resistance and improve the prognosis of patients after TACE. Therefore, HIF-1α may be a critical target for inhibiting HCC metastasis in the future.
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Affiliation(s)
- Huan Chen
- Integrated Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Jing Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Huixin Yuan
- Integrated Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiuhui Li
- Integrated Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Weihua Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
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Zhang X, Yu Z. Comprehensive Diagnostic Medical System Based on Notch1 Signaling Pathway to Inhibit the Growth of Small-Cell Lung Carcinoma. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:2311471. [PMID: 35646297 PMCID: PMC9135563 DOI: 10.1155/2022/2311471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/13/2021] [Accepted: 08/03/2021] [Indexed: 11/30/2022]
Abstract
With the gradual application of big data and other technologies to the medical field, more and more people tend to get online medical services. This article mainly studies the comprehensive diagnostic medical system based on Notch1 signaling pathway to inhibit the growth of small-cell lung carcinoma. In the experiment, we used the rapid thawing method to recover the cells and took the logarithmic growth phase cells for cell passage. We calculated the cell concentration and diluted the cells according to the experimental requirements. According to the standard curve, the corresponding sample protein concentration was calculated; at the same time, the Trizol method was used to extract the total RNA, the NanoDrop8000 spectrophotometer was used to determine the RNA concentration, and the RNA quality was detected by agarose gel electrophoresis. We used immunohistochemical staining to complete the staining of lung cancer cells. Finally, black box testing was used to test the functional modules of the system. Experimental data show that the accuracy rate of data obtained by the system reaches 98%, which greatly facilitates doctors and patients. The results show that the system has good ease of use and reliability and improves the diagnosis and treatment of hospital patients.
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Affiliation(s)
- Xiaoli Zhang
- Department of Pathology, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China
| | - Ziying Yu
- Department of Emergency, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China
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Wang LL, Wan XY, Liu CQ, Zheng FM. NDR1 increases NOTCH1 signaling activity by impairing Fbw7 mediated NICD degradation to enhance breast cancer stem cell properties. Mol Med 2022; 28:49. [PMID: 35508987 PMCID: PMC9066784 DOI: 10.1186/s10020-022-00480-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 04/18/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The existence of breast cancer stem cells (BCSCs) causes tumor relapses, metastasis and resistance to conventional therapy in breast cancer. NDR1 kinase, a component of the Hippo pathway, plays important roles in multiple biological processes. However, its role in cancer stem cells has not been explored. The purpose of this study was to investigate the roles of NDR1 in modulating BCSCs. METHODS The apoptosis was detected by Annexin V/Propidium Iodide staining and analyzed by flow cytometry. BCSCs were detected by CD24/44 or ALDEFLUOR staining and analyzed by flow cytometry. The proliferation ability of BCSCs was evaluated by sphere formation assay. The expression of interested proteins was detected by western blot analysis. The expression of HES-1 and c-MYC was detected by real-time PCR. Notch1 signaling activation was detected by luciferase reporter assay. Protein interaction was evaluated by immunoprecipitation. Protein degradation was evaluated by ubiquitination analysis. The clinical relevance of NDR1 was analyzed by Kaplan-Meier Plotter. RESULTS NDR1 regulates apoptosis and drug resistance in breast cancer cells. The upregulation of NDR1 increases CD24low/CD44high or ALDEFLUORhigh population and sphere-forming ability in SUM149 and MCF-7 cells, while downregulation of NDR1 induces opposite effects. NDR1 increased the expression of the Notch1 intracellular domain (NICD) and activated the transcription of its downstream target (HES-1 and c-MYC). Critically, both suppression of Notch pathway activation by DAPT treatment or downregulation of Notch1 expression by shRNA reverses NDR1 enhanced BCSC properties. Mechanically, NDR1 interactes with both NICD or Fbw7 in a kinase activity-independent manner. NDR1 reduces the proteolytic turnover of NICD by competing with Fbw7 for NICD binding, thereby leading to Notch pathway activation. Furthermore, NDR1 might function as a hub to modulate IL-6, TNF-α or Wnt3a induced activation of Notch1 signaling pathway and enrichment of breast cancer stem cells. Moreover, we find that the elevation of NDR1 expression predictes poor survival (OS, RFS, DMFS and PPS) in breast cancer. CONCLUSION Our study revealed a novel function of NDR1 in regulating BCSC properties by activating the Notch pathway. These data might provide a potential strategy for eradicating BCSC to overcome tumor relapses, metastasis and drug resistance.
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Affiliation(s)
- Ling-Ling Wang
- Department of Medical Oncology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, No.58, Zhong Shan Er Lu, Guangzhou, 510080, China.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Yun Wan
- Department of Medical Oncology, Guangzhou Panyu Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chun-Qi Liu
- Department of Thoracic Surgery, Panyu Central Hospital, Guangzhou, China
| | - Fei-Meng Zheng
- Department of Medical Oncology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, No.58, Zhong Shan Er Lu, Guangzhou, 510080, China. .,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
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Store-Operated Calcium Entry and Its Implications in Cancer Stem Cells. Cells 2022; 11:cells11081332. [PMID: 35456011 PMCID: PMC9032688 DOI: 10.3390/cells11081332] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/12/2022] [Indexed: 12/25/2022] Open
Abstract
Tumors are composed by a heterogeneous population of cells. Among them, a sub-population of cells, termed cancer stem cells, exhibit stemness features, such as self-renewal capabilities, disposition to differentiate to a more proliferative state, and chemotherapy resistance, processes that are all mediated by Ca2+. Ca2+ homeostasis is vital for several physiological processes, and alterations in the patterns of expressions of the proteins and molecules that modulate it have recently become a cancer hallmark. Store-operated Ca2+ entry is a major mechanism for Ca2+ entry from the extracellular medium in non-excitable cells that leads to increases in the cytosolic Ca2+ concentration required for several processes, including cancer stem cell properties. Here, we focus on the participation of STIM, Orai, and TRPC proteins, the store-operated Ca2+ entry key components, in cancer stem cell biology and tumorigenesis.
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Song M, Kuerban M, Zhao L, Peng X, Xu Y. Inhibition of RFX6 Suppresses the Invasive Ability of Tumor Cells Through the Notch Pathway and Affects Tumor Immunity in Hepatocellular Carcinoma. Front Oncol 2022; 11:801222. [PMID: 34988028 PMCID: PMC8721116 DOI: 10.3389/fonc.2021.801222] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/23/2021] [Indexed: 11/23/2022] Open
Abstract
Background The DNA-binding protein RFX6 was overexpressed in hepatocellular carcinoma, and its expression level was correlated with the prognosis and immune cell infiltration in liver hepatocellular carcinoma. However, the mechanism of the abnormal expression and the biological effects of RFX6 in liver cancer remains unknown. Methods To understand the specific expression mechanism of RFX6 in liver cancer, we performed bioinformatic prediction, CHIP-qPCR assay, co-IP, and dual-luciferase assay to assess the regulating mechanism of RFX6. In the meantime, a series of biological experiments in vivo and in vitro were conducted to analyze the biological significance of RFX6 in hepatocellular carcinoma. Results We demonstrated that knockdown of RFX6 in liver cancer cells significantly suppressed the proliferation, migration, and invasion of cancer cells. Moreover, inhibition of RFX6 could affect the immune response of T cells. Among a number of interacting proteins, we revealed that RFX6 directly binds to DTX2, a regulator of the Notch signaling pathway by targeting NOTCH1, and helps in its transcription stability. Furthermore, we discovered that miRNA-542-3p, the expression of which was decreased in hepatocellular carcinoma, was directly involved in the negative regulation of the expression of RFX6. Conclusion In summary, we discovered that the miRNA-542-3p–RFX6–DTX2–NOTCH1 regulatory pathway played significant roles in the tumor progression of liver hepatocellular carcinoma.
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Affiliation(s)
- Mu Song
- Department of Surgical Oncology, The Second Affiliated Hospital, Xinjiang Medical University, Urumqi, China.,Department of Thyroid and Breast Surgery, The Seventh Affiliated Hospital, Southern Medical University, Foshan, China
| | - Mulati Kuerban
- Department of Surgical Oncology, The Seventh Affiliated Hospital, Xinjiang Medical University, Urumqi, China
| | - Lu Zhao
- Department of Surgical Oncology, The Second Affiliated Hospital, Xinjiang Medical University, Urumqi, China.,Department of Thyroid and Breast Surgery, The Seventh Affiliated Hospital, Southern Medical University, Foshan, China
| | - Xiaolin Peng
- Department of Thyroid and Breast Surgery, The Seventh Affiliated Hospital, Southern Medical University, Foshan, China
| | - Youqin Xu
- Department of Thyroid and Breast Surgery, The Seventh Affiliated Hospital, Southern Medical University, Foshan, China
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Tian D, Luo L, Wang T, Qiao J. MiR-296-3p inhibits cell proliferation by the SOX4-Wnt/β-catenin pathway in triple-negative breast cancer. J Biosci 2021. [DOI: 10.1007/s12038-021-00219-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Jiang X, Liang L, Chen G, Liu C. Modulation of Immune Components on Stem Cell and Dormancy in Cancer. Cells 2021; 10:2826. [PMID: 34831048 PMCID: PMC8616319 DOI: 10.3390/cells10112826] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/10/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) refer to a certain subpopulation within the tumor entity that is characterized by restricted cellular proliferation and multipotent differentiation potency. The existence of CSCs has been proven to contribute to the heterogeneity of malignancies, accounting for intensified tumorigenesis, treatment resistance, and metastatic spread. Dormancy was proposed as a reversible state of cancer cells that are temporarily arrested in the cell cycle, possessing several hallmarks that facilitate their survival within a devastating niche. This transient period is evoked to enter an actively proliferating state by multiple regulatory alterations, and one of the most significant and complex factors comes from local and systemic inflammatory reactions and immune components. Although CSCs and dormant cancer cells share several similarities, the clear relationship between these two concepts remains unclear. Thus, the detailed mechanism of immune cells interacting with CSCs and dormant cancer cells also warrants elucidation for prevention of cancer relapse and metastasis. In this review, we summarize recent findings and prospective studies on CSCs and cancer dormancy to conclude the relationship between these two concepts. Furthermore, we aim to outline the mechanism of immune components in interfering with CSCs and dormant cancer cells to provide a theoretical basis for the prevention of relapse and metastasis.
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Affiliation(s)
| | | | | | - Caigang Liu
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang 110004, China; (X.J.); (L.L.); (G.C.)
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Wang K, Qiu X, Zhao Y, Wang H, Chen L. The Wnt/β-catenin signaling pathway in the tumor microenvironment of hepatocellular carcinoma. Cancer Biol Med 2021; 19:j.issn.2095-3941.2021.0306. [PMID: 34591416 PMCID: PMC8958883 DOI: 10.20892/j.issn.2095-3941.2021.0306] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/20/2021] [Indexed: 11/11/2022] Open
Abstract
The Wnt/β-catenin signaling pathway regulates many aspects of tumor biology, and many studies have focused on the role of this signaling pathway in tumor cells. However, it is now clear that tumor development and metastasis depend on the two-way interaction between cancer cells and their environment, thereby forming a tumor microenvironment (TME). In this review, we discuss how Wnt/β-catenin signaling regulates cross-interactions among different components of the TME, including immune cells, stem cells, tumor vasculature, and noncellular components of the TME in hepatocellular carcinoma. We also investigate their preclinical and clinical insights for primary liver cancer intervention, and explore the significance of using Wnt/β-catenin mutations as a biomarker to predict resistance in immunotherapy.
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Affiliation(s)
- Kaiting Wang
- School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Xinyao Qiu
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yan Zhao
- School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Hongyang Wang
- Institute of Metabolism & Integrative Biology (IMIB), Fudan University, Shanghai 200438, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Lei Chen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers. Cancers (Basel) 2021; 13:cancers13184550. [PMID: 34572776 PMCID: PMC8472624 DOI: 10.3390/cancers13184550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.
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Siejka-Zielińska P, Cheng J, Jackson F, Liu Y, Soonawalla Z, Reddy S, Silva M, Puta L, McCain MV, Culver EL, Bekkali N, Schuster-Böckler B, Palamara PF, Mann D, Reeves H, Barnes E, Sivakumar S, Song CX. Cell-free DNA TAPS provides multimodal information for early cancer detection. SCIENCE ADVANCES 2021; 7:eabh0534. [PMID: 34516908 PMCID: PMC8442905 DOI: 10.1126/sciadv.abh0534] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 07/14/2021] [Indexed: 05/05/2023]
Abstract
Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection, but it is technologically challenging. Recently, we developed TET-assisted pyridine borane sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here, we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and noncancer controls. From only 10 ng of cfDNA (1 to 3 ml of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.
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Affiliation(s)
- Paulina Siejka-Zielińska
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Jingfei Cheng
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Felix Jackson
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Department of Computer Science, University of Oxford, Oxford, UK
| | - Yibin Liu
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | - Srikanth Reddy
- Oxford Transplant Centre, Churchill Hospital, Oxford, UK
| | - Michael Silva
- Department of HPB Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Luminita Puta
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Misti Vanette McCain
- Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK
- Newcastle University Centre for Cancer, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Emma L. Culver
- Peter Medawar Building and Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Noor Bekkali
- Department of Gastroenterology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Benjamin Schuster-Böckler
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Big Data Institute, University of Oxford, Oxford, UK
| | - Pier Francesco Palamara
- Department of Statistics, University of Oxford, Oxford, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Derek Mann
- Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Helen Reeves
- Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK
- Newcastle University Centre for Cancer, The Medical School, Newcastle University, Newcastle upon Tyne, UK
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Eleanor Barnes
- Peter Medawar Building and Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Shivan Sivakumar
- Department of Oncology, University of Oxford, Oxford, UK
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Chun-Xiao Song
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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Yu F, Yu C, Li F, Zuo Y, Wang Y, Yao L, Wu C, Wang C, Ye L. Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther 2021; 6:307. [PMID: 34456337 PMCID: PMC8403677 DOI: 10.1038/s41392-021-00701-5] [Citation(s) in RCA: 378] [Impact Index Per Article: 94.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 06/19/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.
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Affiliation(s)
- Fanyuan Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Changhao Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Feifei Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanqin Zuo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Yitian Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Yao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenglin Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China.
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Abd Elhameed AG, Helal MG, Said E, Salem HA. Saxagliptin defers thioacetamide-induced hepatocarcinogenesis in rats: A novel suppressive impact on Wnt/Hedgehog/Notch1 signaling. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 86:103668. [PMID: 33945853 DOI: 10.1016/j.etap.2021.103668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/24/2021] [Accepted: 04/29/2021] [Indexed: 06/12/2023]
Abstract
AIM Hepatocellular carcinoma (HCC) is a highly invasive form of hepatic cancer. It is a highly intricate disease with multiple pathophysiological mechanisms underlying its pathogenesis. MATERIALS AND METHODS The results of the current investigation shed light on the ability of saxagliptin (SAXA) (12.5 mg/kg) to defer HCC progression in an experimental model of thioacetamide (TAA)-induced hepatocarcinogenesis. RESULTS SAXA administration improved liver function biomarkers, with a concomitant histopathological recovery. Mechanistically, the observed hepatoprotective impact was associated with significant suppression of the hepatic content of Wnt3a, β-catenin, Notch1, Smo, and Gli2 and enhanced expression of GSK 3β. Nevertheless, the hepatic expression of PCNA, P53, and cyclin D1 was significantly enhanced, with a parallel increase in the tumor expression of caspase-3. Thus, it appears that SAXA significantly enhanced tumor apoptosis, with concomitant suppression of HCC proliferation. CONCLUSION SAXA deferred experimentally-induced HCC via suppressing Wnt/Hedgehog/Notch1 Signaling, with enhanced tumor apoptosis and suppressed proliferation.
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Affiliation(s)
- Ahmed G Abd Elhameed
- Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Dep. of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt
| | - Manar G Helal
- Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Eman Said
- Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
| | - Hatem A Salem
- Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Lv D, Chen L, Du L, Zhou L, Tang H. Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:691410. [PMID: 34368140 PMCID: PMC8339910 DOI: 10.3389/fcell.2021.691410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/01/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide. A growing body of evidence supports the hypothesis that HCC is driven by a population of cells called liver cancer stem cells (LCSCs). LCSCs have been proposed to contribute to malignant HCC progression, including promoting tumor occurrence and growth, mediating tumor metastasis, and treatment resistance, but the regulatory mechanism of LCSCs in HCC remains unclear. Understanding the signaling pathways responsible for LCSC maintenance and survival may provide opportunities to improve patient outcomes. Here, we review the current literature about the origin of LCSCs and the niche composition, describe the current evidence of signaling pathways that mediate LCSC stemness, then highlight several mechanisms that modulate LCSC properties in HCC progression, and finally, summarize the new developments in therapeutic strategies targeting LCSCs markers and regulatory pathways.
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Affiliation(s)
- Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy and Center of Infectious Diseases, Division of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
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