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1
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Wang Z, Li R, Yang G, Wang Y. Cancer stem cell biomarkers and related signalling pathways. J Drug Target 2024; 32:33-44. [PMID: 38095181 DOI: 10.1080/1061186x.2023.2295222] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/10/2023] [Indexed: 12/20/2023]
Abstract
Cancer stem cells (CSCs) represent a distinct subset of neoplastic cells characterised by their heightened capacity for tumorigenesis. These cells are implicated in the facilitation of cancer metastasis, recurrence, and resistance to conventional therapeutic interventions. Extensive scientific research has been devoted to the identification of biomarkers and the elucidation of molecular mechanisms in order to improve targeted therapeutic approaches. Accurate identification of cancer stem cells based on biomarkers can provide a theoretical basis for drug combinations of malignant tumours. Targeted biomarker-based therapies also offer a silver lining for patients with advanced malignancies. This review aims comprehensively to consolidate the latest findings on CSCs biomarkers, targeted agents as well as biomarkers associated signalling pathways in well-established cancer types, thereby contributing to improved prognostic outcomes.
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Affiliation(s)
- Zhe Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Infectious Disease, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Rui Li
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Guilin Yang
- Department of Infectious Disease, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Yijin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
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2
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 83.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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Klinkovskij A, Shepelev M, Isaakyan Y, Aniskin D, Ulasov I. Advances of Genome Editing with CRISPR/Cas9 in Neurodegeneration: The Right Path towards Therapy. Biomedicines 2023; 11:3333. [PMID: 38137554 PMCID: PMC10741756 DOI: 10.3390/biomedicines11123333] [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: 11/08/2023] [Revised: 12/06/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
The rate of neurodegenerative disorders (NDDs) is rising rapidly as the world's population ages. Conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia are becoming more prevalent and are now the fourth leading cause of death, following heart disease, cancer, and stroke. Although modern diagnostic techniques for detecting NDDs are varied, scientists are continuously seeking new and improved methods to enable early and precise detection. In addition to that, the present treatment options are limited to symptomatic therapy, which is effective in reducing the progression of neurodegeneration but lacks the ability to target the root cause-progressive loss of neuronal functioning. As a result, medical researchers continue to explore new treatments for these conditions. Here, we present a comprehensive summary of the key features of NDDs and an overview of the underlying mechanisms of neuroimmune dysfunction. Additionally, we dive into the cutting-edge treatment options that gene therapy provides in the quest to treat these disorders.
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Affiliation(s)
- Aleksandr Klinkovskij
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre “Digital Biodesign and Personalized Healthcare”, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia; (A.K.); (D.A.)
| | - Mikhail Shepelev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Str., Moscow 119334, Russia
| | - Yuri Isaakyan
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8 Trubetskaya Str., Moscow 119991, Russia;
| | - Denis Aniskin
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre “Digital Biodesign and Personalized Healthcare”, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia; (A.K.); (D.A.)
| | - Ilya Ulasov
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre “Digital Biodesign and Personalized Healthcare”, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia; (A.K.); (D.A.)
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4
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Pospieszna J, Dams-Kozlowska H, Udomsak W, Murias M, Kucinska M. Unmasking the Deceptive Nature of Cancer Stem Cells: The Role of CD133 in Revealing Their Secrets. Int J Mol Sci 2023; 24:10910. [PMID: 37446085 DOI: 10.3390/ijms241310910] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Cancer remains a leading cause of death globally, and its complexity poses a significant challenge to effective treatment. Cancer stem cells and their markers have become key players in tumor growth and progression. CD133, a marker in various cancer types, is an active research area as a potential therapeutic target. This article explores the role of CD133 in cancer treatment, beginning with an overview of cancer statistics and an explanation of cancer stem cells and their markers. The rise of CD133 is discussed, including its structure, functions, and occurrence in different cancer types. Furthermore, the article covers CD133 as a therapeutic target, focusing on gene therapy, immunotherapy, and approaches to affect CD133 expression. Nanoparticles such as gold nanoparticles and nanoliposomes are also discussed in the context of CD133-targeted therapy. In conclusion, CD133 is a promising therapeutic target for cancer treatment. As research in this area progresses, it is hoped that CD133-targeted therapies will offer new and effective treatment options for cancer patients in the future.
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Affiliation(s)
- Julia Pospieszna
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznan, Poland
| | - Wachirawit Udomsak
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
| | - Marek Murias
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University in Poznan, Uniwersytetu Poznanskiego 10 Street, 61-614 Poznan, Poland
| | - Malgorzata Kucinska
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 10 Uniwersytetu Poznanskiego Street, 60-631 Poznan, Poland
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He C, Jaffar Ali D, Qi Y, Li Y, Sun B, Liu R, Sun B, Xiao Z. Engineered extracellular vesicles mediated CRISPR-induced deficiency of IQGAP1/FOXM1 reverses sorafenib resistance in HCC by suppressing cancer stem cells. J Nanobiotechnology 2023; 21:154. [PMID: 37202772 DOI: 10.1186/s12951-023-01902-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/18/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND Sorafenib resistance poses therapeutic challenges in HCC treatment, in which cancer stem cells (CSCs) plays a crucial role. CRISPR/Cas9 can be utilized as a potential technique to overcome the drug resistance. However, a safe, efficient and target specific delivery of this platform remains challenging. Extracellular vesicles (EVs), the active components of cell to cell communication, hold promising benefits as delivery platform. RESULTS Herein we report the normal epithelial cell -derived EVs engineered with HN3(HLC9-EVs) show competing tumor targeting ability. Anchoring HN3 to the membrane of the EVs through LAMP2, drastically increased the specific homing of HLC9-EVs to GPC3+Huh-7 cancer cells rather than co-cultured GPC3-LO2 cells. Combination therapy of HCC with sorafenib and HLC9-EVs containing sgIF to silence IQGAP1 (protein responsible for reactivation of Akt/PI3K signaling in sorafenib resistance) and FOXM1 (self-renewal transcription factor in CSCs attributed to sorafenib resistance), exhibited effective synergistic anti-cancer effect both in vitro and in vivo. Our results also showed that disruption of IQGAP1/FOXM1 resulted in the reduction of CD133+ population that contribute to the stemness of liver cancer cells. CONCLUSION By reversing sorafenib resistance using combination therapeutic approach with engineered EVs encapsulated CRISPR/Cas9 and sorafenib, our study foreshadows a path for a better, accurate, reliable and successful anti-cancer therapy in the future.
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Affiliation(s)
- Cong He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, Jiangsu, China
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Doulathunnisa Jaffar Ali
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, Jiangsu, China.
| | - Yuhua Qi
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, Jiangsu, China
| | - Yumin Li
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, Jiangsu, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Rui Liu
- Department of Genetic Engineering, College of Natural Science, University of Suwon, Kyunggi-Do, 445-743, Republic of Korea
| | - Bo Sun
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, Jiangsu, China.
| | - Zhongdang Xiao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, Jiangsu, China.
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NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing PINK1/Parkin-Mediated Mitophagy. Int J Mol Sci 2022; 23:ijms232214397. [PMID: 36430876 PMCID: PMC9692527 DOI: 10.3390/ijms232214397] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/22/2022] Open
Abstract
A long noncoding RNA, nuclear paraspeckle assembly transcript 1 (NEAT1) variant 1 (NEAT1v1), confers radioresistance to hepatocellular carcinoma (HCC) cells by inducing autophagy via γ-aminobutyric acid A receptor-associated protein (GABARAP). Radiation induces oxidative stress to damage cellular components and organelles, but it remains unclear how NEAT1v1 protects HCC cells from radiation-induced oxidative stress via autophagy. To address this, we precisely investigated NEAT1v1-induced autophagy in irradiated HCC cell lines. X-ray irradiation significantly increased cellular and mitochondrial oxidative stress and mitochondrial DNA content in HCC cells while NEAT1v1 suppressed them. NEAT1v1 concomitantly induced the phosphatase and tensin homolog-induced kinase 1 (PINK1)/parkin-mediated mitophagy. Interestingly, parkin expression was constitutively upregulated in NEAT1v1-overexpressing HCC cells, leading to increased mitochondrial parkin levels. Superoxide dismutase 2 (SOD2) was also upregulated by NEAT1v1, and GABARAP or SOD2 knockdown in NEAT1v1-overexpressing cells increased mitochondrial oxidative stress and mitochondrial DNA content after irradiation. Moreover, it was suggested that SOD2 was involved in NEAT1v1-induced parkin expression, and that GABARAP promoted parkin degradation via mitophagy. This study highlights the unprecedented roles of NEAT1v1 in connecting radioresistance and mitophagy in HCC.
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Ryu TH, Subramanian M, Yeom E, Yu K. The prominin-like Gene Expressed in a Subset of Dopaminergic Neurons Regulates Locomotion in Drosophila. Mol Cells 2022; 45:640-648. [PMID: 35993164 PMCID: PMC9448647 DOI: 10.14348/molcells.2022.0006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/15/2022] [Accepted: 05/02/2022] [Indexed: 11/27/2022] Open
Abstract
CD133, also known as prominin-1, was first identified as a biomarker of mammalian cancer and neural stem cells. Previous studies have shown that the prominin-like (promL) gene, an orthologue of mammalian CD133 in Drosophila, plays a role in glucose and lipid metabolism, body growth, and longevity. Because locomotion is required for food sourcing and ultimately the regulation of metabolism, we examined the function of promL in Drosophila locomotion. Both promL mutants and pan-neuronal promL inhibition flies displayed reduced spontaneous locomotor activity. As dopamine is known to modulate locomotion, we also examined the effects of promL inhibition on the dopamine concentration and mRNA expression levels of tyrosine hydroxylase (TH) and DOPA decarboxylase (Ddc), the enzymes responsible for dopamine biosynthesis, in the heads of flies. Compared with those in control flies, the levels of dopamine and the mRNAs encoding TH and Ddc were lower in promL mutant and pan-neuronal promL inhibition flies. In addition, an immunostaining analysis revealed that, compared with control flies, promL mutant and pan-neuronal promL inhibition flies had lower levels of the TH protein in protocerebral anterior medial (PAM) neurons, a subset of dopaminergic neurons. Inhibition of promL in these PAM neurons reduced the locomotor activity of the flies. Overall, these findings indicate that promL expressed in PAM dopaminergic neurons regulates locomotion by controlling dopamine synthesis in Drosophila.
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Affiliation(s)
- Tae Hoon Ryu
- Metabolism and Neurophysiology Research Group, Disease Target Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34113, Korea
| | - Manivannan Subramanian
- Metabolism and Neurophysiology Research Group, Disease Target Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
| | - Eunbyul Yeom
- Metabolism and Neurophysiology Research Group, Disease Target Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea
- School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea
| | - Kweon Yu
- Metabolism and Neurophysiology Research Group, Disease Target Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34113, Korea
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8
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Li H, Wang B, Qi B, Jiang G, Qin M, Yu M. Connexin32 regulates expansion of liver cancer stem cells via the PI3K/Akt signaling pathway. Oncol Rep 2022; 48:166. [PMID: 35894130 PMCID: PMC9351005 DOI: 10.3892/or.2022.8381] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/28/2022] [Indexed: 11/06/2022] Open
Abstract
Liver cancer stem cells (LCSCs) are responsible for liver cancer recurrence, metastasis, and drug resistance. Previous studies by the authors demonstrated that upregulated expression of connexin 32 (Cx32) reversed doxorubicin resistance and reduced invasion and metastasis of liver cancer cells. However, the role of Cx32 in expansion of LCSCs remains unclear. A total of 85 patients were enrolled in the present study and followed-up for 5 years. The expression of Cx32 in hepatocellular carcinoma (HCC) tissues and corresponding paracancerous tissues were detected by immunohistochemistry (IHC). Cx32 was silenced in HepG2 cells and overexpressed in HCCLM3 cells and the stemness of liver cells was examined by detecting the expression of LCSC markers (EpCAM, CD133, Nanog, Oct4, Sox9, c-Myc), sphere formation, and xenograft tumorigenesis. Finally, the effect of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway on Cx32-regulated LCSC expansion was investigated. Cx32 was downregulated in LCSCs and HCC tissues, and predicted poor prognosis in patients with HCC. Overexpression of Cx32 in HCCLM3 cells significantly inhibited LCSC expansion, tumorigenesis, and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway activity. By contrast, silencing of Cx32 in HepG2 cells upregulated expansion of LCSCs and PI3K/Akt pathway activity. Modulating the activity of the PI3K/Akt pathway by SC-79 and LY294002 in HepG2 and HCCLM3 cells, respectively, confirmed that Cx32 could affect the expansion of LCSCs through PI3K/Akt signaling. In conclusion, the present study demonstrated that Cx32 regulated the expansion of LCSCs, and increased expression of Cx32 significantly inhibited the expansion of LCSCs, suggesting that Cx32 may be an optimal target for intervention of HCC.
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Affiliation(s)
- Hongyu Li
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Boying Wang
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Benquan Qi
- Department of Emergency Internal Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Guojun Jiang
- Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Min Qin
- Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
| | - Meiling Yu
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
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Neurospora crassa is a potential source of anti-cancer agents against breast cancer. Breast Cancer 2022; 29:1032-1041. [PMID: 35881300 DOI: 10.1007/s12282-022-01383-9] [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: 05/07/2022] [Accepted: 06/23/2022] [Indexed: 11/02/2022]
Abstract
Fungi are an excellent source of pharmaceuticals including anti-tumor agents. Neurospora crassa generates metabolites with diverse structural classes, however, its potential as an anti-tumor agent source has not been explored. The purpose of this study aimed to investigate the potential of Neurospora crassa mixture against breast cancer. The in vitro T-47D and MDA-MB-231 experiments showed that N. crassa mixture at the concentrations of both 1.7 and 0.85 µg/ml significantly inhibited tumor cell proliferation, migration and invasion, and 3D spheroid formation. However, the inhibition rates of MCF-10A ranged 10-20% at concentrations of 0.85 and 1.7 µg/ml. The mixture at the concentration of 0.85 µg/ml could significantly downregulate the expressions of transcription factors of E2F1 and E2F3, cancer stem cell-related genes of LIN28, HIWI, and CD133, and onco-lncRNA HOTAIR, and increase CASP3 activity in either T-47D or MDA-MD-231 breast cancer cell lines. In vivo breast cancer C3H mouse model results showed that N. crassa mixture significantly inhibited tumor growth. These findings suggest that N. crassa contains an antitumor component(s) against breast cancer invasiveness, which may inhibit the self-renewal and differentiation of breast cancer stem cells possibly by downregulating cancer stem cell-associated and/or transcription factor genes and oncogenes, and promoting apoptosis.
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10
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Ammar OA, El-Missiry MA, Othman AI, Amer ME. Melatonin is a potential oncostatic agent to inhibit HepG2 cell proliferation through multiple pathways. Heliyon 2022; 8:e08837. [PMID: 35141433 PMCID: PMC8814902 DOI: 10.1016/j.heliyon.2022.e08837] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/22/2021] [Accepted: 01/24/2022] [Indexed: 11/25/2022] Open
Abstract
CONTEXT Chemotherapy is a cornerstone in the treatment of hepatocellular carcinoma (HCC). Melatonin is a pineal hormone that targets various cancers, however, its antitumor pathways are still not fully elucidated. OBJECTIVE This study investigated melatonin's antitumor molecular mechanisms to inhibit the proliferation of HepG2 cells. MATERIALS AND METHODS HepG2 Cells were classified into cells without treatment as a control group and cells treated with melatonin (5.4 mmol/L) for 48 h. Proliferating cell nuclear antigen (PCNA) and marker of proliferation Ki-67 were estimated using immunohistochemical analysis. Apoptosis and cell cycle were evaluated using flow cytometric analysis. Apoptotic markers were detected using RT-qPCR assay. Antioxidants and oxidative stress biomarkers were performed using a colorimetric assay. RESULTS Melatonin produced a remarkable steady decrease in the viability of HepG2 cells at a concentration range between 5-20 mmol/L. Melatonin suppressed cell proliferation in the G2/M phase of the cell cycle (34.97 ± 0.92%) and induced apoptosis (12.43 ± 0.73%) through up-regulating p21 and p53 that was confirmed by the reduction of PCNA and Ki-67 expressions. Additionally, melatonin repressed angiogenesis evidenced by the down-regulation of angiopoietin-2, vascular endothelial growth factor receptor-2 expressions (0.42-fold change), and the level of CD133. Moreover, melatonin augmented the oxidative stress manifested by a marked increase of 4-hydroxynonenal levels with a reduction of glutathione content and superoxide dismutase activity. DISCUSSION AND CONCLUSION Melatonin inhibits proliferation and angiogenesis and induced apoptosis and oxidative stress in HepG2 cells. These results indicate the oncostatic effectiveness of melatonin on liver cancer.
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Affiliation(s)
- Omar A. Ammar
- Basic Science Department, Delta University for Science and Technology, Gamasa, Egypt
| | | | - Azza I. Othman
- Zoology Department, Faculty of Science, Mansoura University, Egypt
| | - Maggie E. Amer
- Zoology Department, Faculty of Science, Mansoura University, Egypt
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11
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Arman T, Baron JA, Lynch KD, White LA, Aldan J, Clarke JD. MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period. Toxicology 2021; 464:153021. [PMID: 34740672 PMCID: PMC8629135 DOI: 10.1016/j.tox.2021.153021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/08/2021] [Accepted: 10/29/2021] [Indexed: 12/30/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) causes liver extracellular matrix (ECM) remodeling and is a risk factor for fibrosis and hepatocellular carcinoma (HCC). Microcystin-LR (MCLR) is a hepatotoxin produced by fresh-water cyanobacteria that causes a NASH-like phenotype, liver fibrosis, and is also a risk factor for HCC. The focus of the current study was to investigate and compare hepatic recovery after cessation of MCLR exposure in healthy versus NASH animals. Male Sprague-Dawley rats were fed either a control or a high fat/high cholesterol (HFHC) diet for eight weeks. Animals received either vehicle or 30 μg/kg MCLR (i.p: 2 weeks, alternate days). Animals were euthanized at one of three time points: at the completion of the MCLR exposure period and after 2 and 4 weeks of recovery. Histological staining suggested that after four weeks of recovery the MCLR-exposed HFHC group had less steatosis and more fibrosis compared to the vehicle-exposed HFHC group and MCLR-exposed control group. RNA-Seq analysis revealed dysregulation of ECM genes after MCLR exposure in both control and HFHC groups that persisted only in the HFHC groups during recovery. After 4 weeks of recovery, MCLR hepatotoxicity in pre-existing NASH persistently dysregulated genes related to cellular differentiation and HCC. These data demonstrate impaired hepatic recovery and persistent carcinogenic changes after MCLR toxicity in pre-existing NASH.
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Affiliation(s)
- Tarana Arman
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - J Allen Baron
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - Katherine D Lynch
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - Laura A White
- Washington Animal Disease Diagnostic Laboratory, Washington State University, Pullman, WA, 99164, United States
| | - Johnny Aldan
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States
| | - John D Clarke
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, United States.
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12
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The Natural Pigment Violacein Potentially Suppresses the Proliferation and Stemness of Hepatocellular Carcinoma Cells In Vitro. Int J Mol Sci 2021; 22:ijms221910731. [PMID: 34639072 PMCID: PMC8509727 DOI: 10.3390/ijms221910731] [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: 07/24/2021] [Revised: 09/30/2021] [Accepted: 10/01/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC cells and overcoming drug resistance for improving the treatment of HCC. Violacein is a deep violet-colored indole derivative that is produced by several bacterial strains, including Chromobacterium violaceum, and it possesses numerous pharmacological properties, including antitumor activity. However, the therapeutic effects of violacein and the mechanism underlying its antitumor effect against HCC remain to be elucidated. This study is the first to demonstrate that violacein inhibits the proliferation and stemness of Huh7 and Hep3B HCC cells. The antiproliferative effect of violacein was attributed to cell cycle arrest at the sub-G1 phase and the induction of apoptotic cell death. Violacein induced nuclear condensation, dissipated mitochondrial membrane potential (MMP), increased generation of reactive oxygen species (ROS), activated the caspase cascade, and upregulated p53 and p21. The anticancer effect of violacein on HCC cells was also associated with the downregulation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2 signaling. Violacein not only suppressed the proliferation and formation of tumorspheres of Huh7 and Hep3B cancer stem-like cells but also reduced the expression of key markers of cancer stemness, including CD133, Sox2, Oct4, and Nanog, by inhibiting the signal transducer and activator of transcription 3 (STAT3)/AKT/ERK pathways. These results suggest the therapeutic potential of violacein in effectively suppressing HCC by targeting the proliferation and stemness of HCC cells.
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Liu Y, Zheng C, Huang Y, He M, Xu WW, Li B. Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm (Beijing) 2021; 2:315-340. [PMID: 34766149 PMCID: PMC8554658 DOI: 10.1002/mco2.55] [Citation(s) in RCA: 167] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation-induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial-mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes.
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Affiliation(s)
- Ya‐Ping Liu
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
| | - Can‐Can Zheng
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
| | - Yun‐Na Huang
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering MedicineNational Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouP. R. China
| | - Ming‐Liang He
- Department of Biomedical SciencesCity University of Hong KongHong KongChina
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering MedicineNational Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouP. R. China
| | - Bin Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhouP. R. China
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Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13164237. [PMID: 34439391 PMCID: PMC8392268 DOI: 10.3390/cancers13164237] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/15/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma is a life-threatening disease. Despite many efforts to understand the exact pathogenesis and the signaling pathways involved in its formation, treatment remains unsatisfactory. Currently, an important function in the development of neoplastic diseases and treatment effects is attributed to changes taking place at the epigenetic level. Epigenetic studies revealed modified methylation patterns in HCC, dysfunction of enzymes engaged in the DNA methylation process, the aberrant function of non-coding RNAs, and a set of histone modifications that influence gene expression. The aim of this review is to summarize the current knowledge on the role of epigenetics in the formation of hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy.
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15
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Chen Z, Lu T, Huang L, Wang Z, Yan Z, Guan Y, Hu W, Fan Z, Zhu P. circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF. J Clin Invest 2021; 131:e148020. [PMID: 34403373 DOI: 10.1172/jci148020] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 08/12/2021] [Indexed: 12/24/2022] Open
Abstract
Liver tumor-initiating cells (TICs) are involved in liver tumorigenesis, metastasis, drug resistance and relapse, but the regulatory mechanisms of liver TICs are largely unknown. Here, we have identified a functional circular RNA, termed circRNA activating MAFF (cia-MAF), that is robustly expressed in liver cancer and liver TICs. cia-MAF knockout primary cells and cia-maf knockout liver tumors harbor decreased ratios of TICs, and display impaired liver tumorigenesis, self-renewal and metastatic capacities. In contrast, cia-MAF overexpression drives liver TIC propagation, self-renewal and metastasis. Mechanistically, cia-MAF binds to the MAFF promoter, recruits the TIP60 complex to the MAFF promoter, and finally promotes MAFF expression. Loss of cia-MAF function attenuates the combination between the TIP60 complex and the MAFF promoter. MAFF is highly expressed in liver tumors and liver TICs, and its antisense oligo (ASO) has therapeutic potential in treating liver cancer without MAFA/MAFG gene copy number alterations (CNAs). This study reveal an additional layer for liver TIC regulation as well as circRNA function, and also provide an additional target for eliminating liver TICs, especially for liver tumor without MAFA/MAFG gene CNAs.
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Affiliation(s)
- Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Tiankun Lu
- Key Laboratory of Infection and Immunity, University of Chinese Academy of Sciences, Beijing, China
| | - Lan Huang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhiwei Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhongyi Yan
- School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Yubo Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Wenjing Hu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Zusen Fan
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
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Li Z, Tian J, Du L, Gao Y, Wang Y, You F, Wang L. Anlotinib exerts anti-cancer efficiency on lung cancer stem cells in vitro and in vivo through reducing NF-κB activity. J Cell Mol Med 2021; 25:5547-5559. [PMID: 33955683 PMCID: PMC8184695 DOI: 10.1111/jcmm.16564] [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: 07/13/2020] [Revised: 03/18/2021] [Accepted: 04/09/2021] [Indexed: 02/05/2023] Open
Abstract
Anlotinib is a multi-target tyrosine kinase inhibitor. Previous studies confirmed that anlotinib exerts anti-cancer efficiency. However, the functional roles of anlotinib on cancer stem cells (CSCs) are yet to be elucidated. In this study, lung CSCs were isolated and identified in vitro, and mouse xenografts were established in vivo. MTT assays, tumour sphere formation assays, TdT-mediated dUTP nick-end labelling (TUNEL) staining, Annexin V-FITC/PI staining, immunofluorescence analysis and Western blot were performed to investigate the anti-cancer effects of anlotinib on lung CSCs. The results showed that anlotinib inhibits the growth of lung CSCs in vitro and in vivo. In addition, anlotinib induced apoptosis of these cells along with down-regulated expression level of Bcl-2 whereas up-regulated Bax and cleaved caspase-3 expression. It also sensitized lung CSCs to the cytotoxicity of cisplatin and paclitaxel; the tumour sphere formation and expression levels of multiple stemness-associated markers, such as ALDH1 and CD133, were also decreased. Furthermore, the underlying mechanism indicated that anlotinib reduces the phosphorylated levels of NF-κB p65 and IκB-α in lung CSCs. Taken together, these findings suggested that anlotinib exerts potent anti-cancer effects against lung CSCs through apoptotic induction and stemness phenotypic attenuation. The mechanism could be associated with the suppression of NF-κB activity.
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Affiliation(s)
- Zhuohong Li
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Juncai Tian
- Lung Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.,Department of Respiratory Medicine, The First People's Hospital of Ziyang, Ziyang, China
| | - Lei Du
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ying Gao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yao Wang
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fengming You
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Wang
- Lung Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
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Tiliroside as a CAXII inhibitor suppresses liver cancer development and modulates E2Fs/Caspase-3 axis. Sci Rep 2021; 11:8626. [PMID: 33883691 PMCID: PMC8060393 DOI: 10.1038/s41598-021-88133-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 03/10/2021] [Indexed: 12/29/2022] Open
Abstract
Liver cancer is the fatal cause of cancer deaths worldwide due to its aggressiveness and lack of effective therapies. Tiliroside (C30H26O13) is an active compound extracted from herb plant Tribulus terrestris L., which has been used as alternative therapy in clinic practice. However, its therapeutic use against liver cancer has not been previously reported. Here, we showed that Tiliroside exerted significantly higher anti-proliferation effect on liver cancer cell lines Hep3B and SNU-449 than on liver normal cell THLE-3 cells or NC group, respectively, by using MTS assay. Results from colony formation, immigration and invasion assays support the anticancer efficacy of Tiliroside and its low-toxic property while treating liver normal cell THLE-3. 3D spheroid formation and CD133 expression level also displays its anti-stemness effect. It has been showed that Tiliroside may function as Carbonic anhydrases XII (CAXII) inhibitor and affects apoptotic E2F1/E2F3/Caspase-3 axis by using CAXII esterase activity assay, Human carbonic anhydrase 12 (CA-12) ELISA Kit, quantitative reverse transcription PCR (RT-qPCR) as well as CaspACE Assay System, respectively. In summary, we demonstrate for the first time that Tiliroside suppresses liver cancer development possibly by acting as a novel CAXII inhibitor, which warrant further investigation on its therapeutic implications.
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18
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Microvesicles - promising tiny players' of cancer stem cells targeted liver cancer treatments: The interesting interactions and therapeutic aspects. Pharmacol Res 2021; 169:105609. [PMID: 33852962 DOI: 10.1016/j.phrs.2021.105609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 11/23/2022]
Abstract
Liver cancer is one of the most malignant cancers worldwide with poor prognosis. Intracellular mediators like microvesicles (MVs) and cancer stem cells (CSCs) are considered as potential candidates in liver cancer progression. CSCs receive stimuli from the tumor microenvironment to initiate tumor formation in which it's secreted MVs play a noteworthy role. The phenotypic conversion of tumor cells during epithelial-to-mesenchymal transition (EMT) is a key step in tumor invasion and metastasis which indicates that the diverse cell populations within the primary tumor are in a dynamic balance and can be regulated by cell to cell communication via secreted microvesicles. Thus, in this review, we aim to highlight the evidences that suggest CSCs are crucial for liver cancer development where the microvesicles plays an important part in the maintenance of its stemness properties. In addition, we summarize the existing evidences that support the concept of microvesicles, the tiny particles have a big role behind the rare immortal CSCs which controls the tumor initiation, propagation and metastasis in liver cancer. Identifying interactions between CSCs and microvesicles may offer new insights into precise anti-cancer therapies in the future.
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Asadzadeh Z, Mansoori B, Mohammadi A, Kazemi T, Mokhtarzadeh A, Shanehbandi D, Hemmat N, Derakhshani A, Brunetti O, Safaei S, Aghajani M, Najafi S, Silvestris N, Baradaran B. The combination effect of Prominin1 (CD133) suppression and Oxaliplatin treatment in colorectal cancer therapy. Biomed Pharmacother 2021; 137:111364. [PMID: 33592546 DOI: 10.1016/j.biopha.2021.111364] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is considered one of the leading types of cancer in the world. CD133, as a cancer stem cell marker, has a pivotal role in the development of drug resistance, migration, and stemness properties of CRC cells. This study was designed to check the combined effect of CD133 siRNA and Oxaliplatin on proliferation, migration, apoptosis, and stemness properties of CRC cells in the HT-29 cell line. MTT assay was performed to define the combined effect of CD133 siRNA and Oxaliplatin on the viability of HT-29 cells, and it showed that the combination of CD133 siRNA and Oxaliplatin could reduce the IC50 of this drug from 32.85 to 19.75 nmol. In order to figure out the effect of this combination therapy on CD133 expression at the gene and protein level, qRT-PCR and western blot were exploited, respectively. The results demonstrated that the silencing of CD133 could reduce the relative expression of this marker to about 0.00001 compared to the control group and reduce the protein level to 0.01. The ability of cell migration was tested by wound healing assay as well. Also, colony formation and sphere formation were conducted to assess the stemness properties in the combination group. Flow cytometry was conducted to investigate the apoptosis (15%), cell cycle (about 10% arresting in G0-G1 phase), and surface expression of CD133 in different groups (from 39.3% in the control group to 2.41 in the combination group). Finally, the expression of migration-, and stemness-associated genes were measured by qRT-PCR. We indicated that silencing of CD133 reduces the migration and stemness properties of colorectal cancerous cells. This suppression makes HT-29 cells more sensitive to Oxaliplatin and reduces the effective dose of this chemical drug. Therefore, the suppression of CD133 in combination with Oxaliplatin treatment might be a promising therapeutic approach in the treatment of colorectal cancer.
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Affiliation(s)
- Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
| | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran; Medical Oncology Unit-IRCCS IstitutoTumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit-IRCCS IstitutoTumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Marjan Aghajani
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran
| | - Nicola Silvestris
- Medical Oncology Unit-IRCCS IstitutoTumori "Giovanni Paolo II" of Bari, Bari, Italy; Department of Biomedical Sciences and Human Oncology DIMO-University of Bari, Bari, Italy.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran; Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Golgashtst., 5166/15731 Tabriz, Iran.
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20
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Lee J, Cho Y. Potential roles of stem cell marker genes in axon regeneration. Exp Mol Med 2021; 53:1-7. [PMID: 33446881 PMCID: PMC8080715 DOI: 10.1038/s12276-020-00553-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/16/2020] [Indexed: 01/29/2023] Open
Abstract
Axon regeneration is orchestrated by many genes that are differentially expressed in response to injury. Through a comparative analysis of gene expression profiling, injury-responsive genes that are potential targets for understanding the mechanisms underlying regeneration have been revealed. As the efficiency of axon regeneration in both the peripheral and central nervous systems can be manipulated, we suggest that identifying regeneration-associated genes is a promising approach for developing therapeutic applications in vivo. Here, we review the possible roles of stem cell marker- or stemness-related genes in axon regeneration to gain a better understanding of the regeneration mechanism and to identify targets that can enhance regenerative capacity.
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Affiliation(s)
- Jinyoung Lee
- Laboratory of Axon Regeneration & Degeneration, Department of Life Sciences, Korea University, Anam-ro 145, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Yongcheol Cho
- Laboratory of Axon Regeneration & Degeneration, Department of Life Sciences, Korea University, Anam-ro 145, Seongbuk-gu, Seoul, 02841, Republic of Korea.
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21
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El-Daly SM, Gouhar SA, Gamal-Eldeen AM, Abdel Hamid FF, Ashour MN, Hassan NS. Synergistic Effect of α-Solanine and Cisplatin Induces Apoptosis and Enhances Cell Cycle Arrest in Human Hepatocellular Carcinoma Cells. Anticancer Agents Med Chem 2020; 19:2197-2210. [PMID: 31566136 DOI: 10.2174/1871520619666190930123520] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/01/2019] [Accepted: 06/03/2019] [Indexed: 01/09/2023]
Abstract
AIM The clinical application of cisplatin is limited by severe side effects associated with high applied doses. The synergistic effect of a combination treatment of a low dose of cisplatin with the natural alkaloid α-solanine on human hepatocellular carcinoma cells was evaluated. METHODS HepG2 cells were exposed to low doses of α-solanine and cisplatin, either independently or in combination. The efficiency of this treatment modality was evaluated by investigating cell growth inhibition, cell cycle arrest, and apoptosis enhancement. RESULTS α-solanine synergistically potentiated the effect of cisplatin on cell growth inhibition and significantly induced apoptosis. This synergistic effect was mediated by inducing cell cycle arrest at the G2/M phase, enhancing DNA fragmentation and increasing apoptosis through the activation of caspase 3/7 and/or elevating the expression of the death receptors DR4 and DR5. The induced apoptosis from this combination treatment was also mediated by reducing the expression of the anti-apoptotic mediators Bcl-2 and survivin, as well as by modulating the miR-21 expression. CONCLUSION Our study provides strong evidence that a combination treatment of low doses of α-solanine and cisplatin exerts a synergistic anticancer effect and provides an effective treatment strategy against hepatocellular carcinoma.
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Affiliation(s)
- Sherien M El-Daly
- Medical Biochemistry Department, Medical Research Division, National Research Centre, Dokki, 12622, Cairo, Egypt.,Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki 12622, Cairo, Egypt
| | - Shaimaa A Gouhar
- Medical Biochemistry Department, Medical Research Division, National Research Centre, Dokki, 12622, Cairo, Egypt
| | - Amira M Gamal-Eldeen
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki 12622, Cairo, Egypt.,Biochemistry Department, National Research Centre, Dokki, Cairo, Egypt.,Clinical Laboratory Department, College of Applied Medical Sciences, Taif University, At Taif 26521, Saudi Arabia
| | - Fatma F Abdel Hamid
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Magdi N Ashour
- Medical Biochemistry Department, Medical Research Division, National Research Centre, Dokki, 12622, Cairo, Egypt
| | - Nahla S Hassan
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
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Lee J, Shin JE, Lee B, Kim H, Jeon Y, Ahn SH, Chi SW, Cho Y. The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling. Proc Natl Acad Sci U S A 2020; 117:15955-15966. [PMID: 32554499 PMCID: PMC7355016 DOI: 10.1073/pnas.1920829117] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Axon regeneration is regulated by a neuron-intrinsic transcriptional program that is suppressed during development but that can be reactivated following peripheral nerve injury. Here we identify Prom1, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program. Prom1 expression is developmentally down-regulated, and the genetic deletion of Prom1 in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role of Prom1 in injury-induced regeneration. Elevating prominin-1 levels in cultured DRG neurons or in mice via adeno-associated virus-mediated gene delivery enhances axon regeneration in vitro and in vivo, allowing outgrowth on an inhibitory substrate. Prom1 overexpression induces the consistent down-regulation of cholesterol metabolism-associated genes and a reduction in cellular cholesterol levels in a Smad pathway-dependent manner, which promotes axonal regrowth. We find that prominin-1 interacts with the type I TGF-β receptor ALK4, and that they synergistically induce phosphorylation of Smad2. These results suggest that Prom1 and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.
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Affiliation(s)
- Jinyoung Lee
- Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea
| | - Jung Eun Shin
- Department of Molecular Neuroscience, Dong-A University College of Medicine, 49201 Busan, Republic of Korea
| | - Bohm Lee
- Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea
| | - Hyemin Kim
- Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea
| | - Yewon Jeon
- Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea
| | - Seung Hyun Ahn
- Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea
| | - Sung Wook Chi
- Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea
| | - Yongcheol Cho
- Department of Life Sciences, Korea University, 02841 Seoul, Republic of Korea;
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5-O-Acetyl-Renieramycin T from Blue Sponge Xestospongia sp. Induces Lung Cancer Stem Cell Apoptosis. Mar Drugs 2019; 17:md17020109. [PMID: 30754694 PMCID: PMC6409812 DOI: 10.3390/md17020109] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/06/2019] [Accepted: 02/07/2019] [Indexed: 02/08/2023] Open
Abstract
Lung cancer is one of the most significant cancers as it accounts for almost 1 in 5 cancer deaths worldwide, with an increasing incident rate. Management of the cancer has been shown to frequently fail due to the ability of the cancer cells to resist therapy as well as metastasis. Recent evidence has suggested that the poor response to the current treatment drugs and the ability to undergo metastasis are driven by cancer stem cells (CSCs) within the tumor. The discovery of novel compounds able to suppress CSCs and sensitize the chemotherapeutic response could be beneficial to the improvement of clinical outcomes. Herein, we report for the first time that 5-O-acetyl-renieramycin T isolated from the blue sponge Xestospongia sp. mediated lung cancer cell death via the induction of p53-dependent apoptosis. Importantly, 5-O-acetyl-renieramycin T induced the death of CSCs as represented by the CSC markers CD44 and CD133, while the stem cell transcription factor Nanog was also found to be dramatically decreased in 5-O-acetyl-renieramycin T-treated cells. We also found that such a CSC suppression was due to the ability of the compound to deplete the protein kinase B (AKT) signal. Furthermore, 5-O-acetyl-renieramycin T was able to significantly sensitize cisplatin-mediated apoptosis in the lung cancer cells. Together, the present research findings indicate that this promising compound from the marine sponge is a potential candidate for anti-cancer approaches.
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Xie C, Zhu J, Wang X, Chen J, Geng S, Wu J, Zhong C, Li X. Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway. J Exp Clin Cancer Res 2019; 38:39. [PMID: 30691509 PMCID: PMC6350284 DOI: 10.1186/s13046-019-1052-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 01/22/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Tobacco smoke (TS) critically contributes to the development of hepatocellular carcinoma. Cancer stem cells (CSCs) induced by TS is an early event in the initiation of carcinogenesis. Tumor specific microenvironment including inflammatory factors is key mediator for maintaining the stemness of CSCs through various pathways such as p38 MAPK. However, the mechanisms of inflammatory factors in TS-induced acquisition of liver CSCs properties remain undefined. The aim of this study was to investigate the role of IL-33/p38 axis in long term TS-induced acquisition of hepatic CSCs properties in mouse liver tissues and human liver cells. METHODS BALB/c mice were exposed to TS for 12 weeks, along with or without 1 mg/kg SB203580 (p38 inhibitors) treatment. Histopathological analysis, alterations in the levels of IL-33, liver CSCs markers, EMT-like changes and p38 MAPK activation in liver tissues of mice were analyzed by immunohistochemical staining, immunofluorescence assay and Western blot analysis. Moreover, LO2 immortalized human liver cells were exposed to cigarette smoke extract (CSE) and the tumorsphere formation ability was determined. LO2 cells were further treated with IL-33 or CSE and the expression of phosphorylated p38, liver CSCs markers and EMT-related proteins was examined. RESULTS Long term TS exposure increased the levels of CSCs markers, induced epithelial-to mesenchymal transition (EMT) and inflammatory factor IL-33 expression. Moreover, we showed that p38 MAPK modulated TS-stimulated hepatic CSC-like properties, as evidenced by the findings that long term TS exposure activated p38, and that TS-induced stemness was abolished by p38 inhibition. In addition, data from in vitro model showed that similar to cigarette smoke extract (CSE), IL-33 treatment promoted the activation of p38, increased the levels of liver CSCs markers expression and EMT-like changes. CONCLUSIONS Collectively, these data suggested that IL-33/p38 axis plays an important role in long term TS exposure-induced acquisition of hepatic CSC-like properties.
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Affiliation(s)
- Chunfeng Xie
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Jiangning, Nanjing, 211166 Jiangsu China
| | - Jianyun Zhu
- Suzhou Digestive Diseases and Nutrition Research Center, North District of Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, No. 242 Guangji Road, Suzhou, 215008 Jiangsu China
| | - Xueqi Wang
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Jiangning, Nanjing, 211166 Jiangsu China
| | - Jiaqi Chen
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Jiangning, Nanjing, 211166 Jiangsu China
| | - Shanshan Geng
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Jiangning, Nanjing, 211166 Jiangsu China
| | - Jieshu Wu
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Jiangning, Nanjing, 211166 Jiangsu China
| | - Caiyun Zhong
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Jiangning, Nanjing, 211166 Jiangsu China
- Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166 China
| | - Xiaoting Li
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Jiangning, Nanjing, 211166 Jiangsu China
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25
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Fu C, Wang L, Tian G, Zhang C, Zhao Y, Xu H, Su M, Wang Y. Enhanced anticancer effect of oncostatin M combined with salinomycin in CD133 + HepG2 liver cancer cells. Oncol Lett 2018; 17:1798-1806. [PMID: 30675240 PMCID: PMC6341778 DOI: 10.3892/ol.2018.9796] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 11/02/2018] [Indexed: 12/24/2022] Open
Abstract
Oncostatin M (OSM) induces the differentiation of liver cancer stem cells (LCSCs) and increases sensitivity to the chemotherapeutic agent 5-fluorouracil, whereas salinomycin (Sal) induces apoptosis in cancer stem cells and inhibits the proliferation of liver cancer cells. However, there have been no studies investigating the anticancer effects of combination treatment with OSM and Sal. In the present study, we investigated the synergistic effects of OSM and Sal on LCSCs, the CD133+ subpopulations from HepG2 human liver cancer cells. CD133+ LCSCs were isolated using an immunomagnetic bead technique and identified through colony formation. After incubating with OSM and Sal, the ability of LCSC proliferation and invasion, as well as apoptosis rates were evaluated, and the expression of stemness-related genes was examined by quantitative real-time polymerase chain reaction. Additionally, the secretion of α-fetoprotein (AFP) and albumin (ALB) were analyzed by enzyme-linked immunosorbent assay. Our results indicated that OSM combined with Sal significantly suppressed LCSC proliferation and invasion and induced apoptosis, as determined by flow cytometry and increases in cleaved caspase-3 levels detected by western blotting. The results of the JC-1 staining assay indicated that this effect involved the mitochondrial pathway. Moreover, combination treatment reduced the expression of CD133 in LCSCs and suppressed stemness-related gene expression. Furthermore, the LCSCs produced lower levels of AFP and higher levels of ALB following combination treatment. In all experiments, combination treatment elicited more efficient anticancer effects on LCSCs as compared with single-drug treatment; therefore, our results demonstrated that combined treatment with OSM and Sal inhibited proliferation and induced differentiation and apoptosis in LCSCs, suggesting combined use of OSM and Sal as a therapeutic strategy for liver cancer.
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Affiliation(s)
- Changhao Fu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Lu Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Geer Tian
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Chen Zhang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.,Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen, Fujian 361021, P.R. China
| | - Yuanyuan Zhao
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hao Xu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Manman Su
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
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26
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Zheng H, Zhang Y, Chen Y, Guo P, Wang X, Yuan X, Ge W, Yang R, Yan Q, Yang X, Xi Y. Prominin-like, a homolog of mammalian CD133, suppresses di lp6 and TOR signaling to maintain body size and weight in Drosophila. FASEB J 2018; 33:2646-2658. [PMID: 30307770 DOI: 10.1096/fj.201800123r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
CD133 (AC133/prominin-1) has been identified as a stem cell marker and a putative cancer stem cell marker in many solid tumors. Its biologic function and molecular mechanisms remain largely elusive. Here, we show that a fly mutant for prominin-like, a homolog of mammalian CD133, shows a larger body size and excess weight accompanied with higher fat deposits as compared with the wild type. The expression levels of prominin-like are mediated by ecdysone signaling where its protein levels increase dramatically in the fat body during metamorphosis. Prominin-like mutants exhibit higher Drosophila insulin-like peptide 6 (di lp6) levels during nonfeeding stages and increased Akt/ Drosophila target of rapamycin (dTOR) signaling. On an amino acid-restricted diet, prominin-like mutants exhibit a significantly larger body size than the wild type does, similar to that which occurs upon the activation of the dTOR pathway in the fat body. Our data suggest that prominin-like functions by suppressing TOR and dilp6 signaling to control body size and weight. The identification of the physiologic function of prominin-like in Drosophila may provide valuable insight into the understanding of the metabolic function of CD133 in mammals.-Zheng, H., Zhang, Y., Chen, Y., Guo, P., Wang, X., Yuan, X., Ge, W., Yang, R., Yan, Q., Yang, X., Xi, Y. Prominin-like, a homolog of mammalian CD133, suppresses di lp6 and TOR signaling to maintain body size and weight in Drosophila.
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Affiliation(s)
- Huimei Zheng
- Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Genetics, Zhejiang University, Hangzhou, China.,Department of Genetics, Zhejiang University School of Medicine, Hangzhou, China.,College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Yafei Zhang
- College of Life Sciences, Zhejiang University, Hangzhou, China.,Beijing Genomics Institute, Shanghai, China
| | - Yuchen Chen
- Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Genetics, Zhejiang University, Hangzhou, China.,Department of Genetics, Zhejiang University School of Medicine, Hangzhou, China
| | - Pengfei Guo
- Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Genetics, Zhejiang University, Hangzhou, China.,Department of Genetics, Zhejiang University School of Medicine, Hangzhou, China.,College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Xuexiang Wang
- College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Xin Yuan
- Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Genetics, Zhejiang University, Hangzhou, China.,Department of Genetics, Zhejiang University School of Medicine, Hangzhou, China
| | - Wanzhong Ge
- Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Genetics, Zhejiang University, Hangzhou, China.,Department of Genetics, Zhejiang University School of Medicine, Hangzhou, China
| | - Ru Yang
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China; and
| | - Qingfeng Yan
- College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Xiaohang Yang
- Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Genetics, Zhejiang University, Hangzhou, China.,Department of Genetics, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University-University of Toronto Joint Institute of Genetics and Genomic Medicine, Zhejiang University, Hangzhou, China
| | - Yongmei Xi
- Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Genetics, Zhejiang University, Hangzhou, China.,Department of Genetics, Zhejiang University School of Medicine, Hangzhou, China
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27
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Zhang G, Zhang S, Ren J, Yao C, Zhao Z, Qi X, Zhang X, Wang S, Li L. Salinomycin may inhibit the cancer stem-like populations with increased chemoradioresistance that nasopharyngeal cancer tumorspheres contain. Oncol Lett 2018; 16:2495-2500. [PMID: 30013643 DOI: 10.3892/ol.2018.8923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 11/07/2017] [Indexed: 01/10/2023] Open
Abstract
Tumor recurrence and metastasis of nasopharyngeal cancer (NPC) often result in the failure of treatment due to chemoradioresistance. Cancer stem cells (CSCs) have been observed to drive tumor initiation and tumor chemoradioresistance. Therefore, the poor prognosis of advanced NPC is likely to result from the failure to kill CSCs. Sphere formation may be used as an experimental method to enrich potential CSC subpopulations. At present, there are few reports on NPC tumorspheres. The present study focused on examining the cancer stem-like properties of NPC tumorspheres from NPC cell lines. Western blot analysis revealed that NPC tumorspheres had a higher expression of stem cell markers Nanog homeobox and SRY-box 2, compared with parental cells. It was additionally verified that NPC tumorspheres contained a high aldehyde dehydrogenase (ALDH) enzymatic activity compared with parental cells. ALDH+ cells were amplified by 9- to 10-fold in tumorspheres, compared with parental cells (1.8 vs. 16.9%). The tumorsphere cells exhibited an increased half maximal inhibitory concentration value of >10-fold with cisplatin compared with the control parental cells. Compared with the parental cells, the percentage of side population cells in the tumorsphere cell population increased significantly (10.3 vs. 2.3%; P<0.05). NPC tumorsphere cells demonstrated enhanced resistance to radiation. Further investigation verified that salinomycin inhibited NPC CSCs by selectively targeting its stem cells. Altogether, the data revealed that NPC tumorspheres contain cancer stem-like populations with increased chemoradioresistance. It was suggested that the serum-free culture of NPC cells may provide an appropriate model for researching the sensitivity of CSCs to therapeutic agents. It was additionally revealed that salinomycin is an efficient inhibitor of NPC CSCs, supporting the hypothesis that salinomycin may eliminate CSCs and imply a need for further clinical evaluation.
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Affiliation(s)
- Gong Zhang
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Shuping Zhang
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Jinjin Ren
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Chunxiao Yao
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Zhongren Zhao
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Xiurong Qi
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Xiaofeng Zhang
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Shuye Wang
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
| | - Lei Li
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, Shanxi 030012, P.R. China
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28
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Moghadam AR, Patrad E, Tafsiri E, Peng W, Fangman B, Pluard TJ, Accurso A, Salacz M, Shah K, Ricke B, Bi D, Kimura K, Graves L, Najad MK, Dolatkhah R, Sanaat Z, Yazdi M, Tavakolinia N, Mazani M, Amani M, Ghavami S, Gartell R, Reilly C, Naima Z, Esfandyari T, Farassati F. Ral signaling pathway in health and cancer. Cancer Med 2017; 6:2998-3013. [PMID: 29047224 PMCID: PMC5727330 DOI: 10.1002/cam4.1105] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 04/10/2017] [Accepted: 04/14/2017] [Indexed: 12/12/2022] Open
Abstract
The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.
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Affiliation(s)
- Adel Rezaei Moghadam
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Elham Patrad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Elham Tafsiri
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Warner Peng
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Benjamin Fangman
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Timothy J Pluard
- Saint Luke's HospitalUniversity of Missouri at Kansas CityKansas CityMissouri
| | - Anthony Accurso
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Michael Salacz
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kushal Shah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Brandon Ricke
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Danse Bi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Kyle Kimura
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Leland Graves
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Marzieh Khajoie Najad
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Roya Dolatkhah
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zohreh Sanaat
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mina Yazdi
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Naeimeh Tavakolinia
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Mohammad Mazani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Mojtaba Amani
- Pasteur Institute of IranTehranIran
- Ardabil University of Medical Sciences, BiochemistryArdabilIran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell ScienceUniversity of ManitobaWinnipegCanada
| | - Robyn Gartell
- Department of Pediatrics, Columbia Presbyterian Medical CenterNew YorkNew York
| | - Colleen Reilly
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Zaid Naima
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Tuba Esfandyari
- Department of Medicine, Molecular Medicine LaboratoryThe University of Kansas Medical SchoolKansas CityKansas
| | - Faris Farassati
- Research Service (151)Kansas City Veteran Affairs Medical Center & Midwest Biomedical Research Foundation4801 E Linwood BlvdKansas CityMissouri64128‐2226
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29
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Castelli G, Pelosi E, Testa U. Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells. Cancers (Basel) 2017; 9:cancers9090127. [PMID: 28930164 PMCID: PMC5615342 DOI: 10.3390/cancers9090127] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 12/15/2022] Open
Abstract
Liver cancer is the second most common cause of cancer-related death. The major forms of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Both these tumors develop against a background of cirrhotic liver, non-alcoholic fatty liver disease, chronic liver damage and fibrosis. HCC is a heterogeneous disease which usually develops within liver cirrhosis related to various etiologies: hepatitis B virus (HBV) infection (frequent in Asia and Africa), hepatitis C virus (HCV), chronic alcohol abuse, or metabolic syndrome (frequent in Western countries). In cirrhosis, hepatocarcinogenesis is a multi-step process where pre-cancerous dysplastic macronodules transform progressively into HCC. The patterns of genomic alterations observed in these tumors were recently identified and were instrumental for the identification of potential targeted therapies that could improve patient care. Liver cancer stem cells are a small subset of undifferentiated liver tumor cells, responsible for cancer initiation, metastasis, relapse and chemoresistance, enriched and isolated according to immunophenotypic and functional properties: cell surface proteins (CD133, CD90, CD44, EpCAM, OV-6, CD13, CD24, DLK1, α2δ1, ICAM-1 and CD47); the functional markers corresponding to side population, high aldehyde dehydrogenase (ALDH) activity and autofluorescence. The identification and definition of liver cancer stem cells requires both immunophenotypic and functional properties.
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Affiliation(s)
- Germana Castelli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00141, Italy.
| | - Elvira Pelosi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00141, Italy.
| | - Ugo Testa
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00141, Italy.
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30
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In Vitro Anticancer Effect of Gedunin on Human Teratocarcinomal (NTERA-2) Cancer Stem-Like Cells. BIOMED RESEARCH INTERNATIONAL 2017; 2017:2413197. [PMID: 28680880 PMCID: PMC5478822 DOI: 10.1155/2017/2413197] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 05/09/2017] [Indexed: 12/02/2022]
Abstract
Gedunin is one of the major compounds found in the neem tree (Azadirachta indica). In the present study, antiproliferative potential of gedunin was evaluated in human embryonal carcinoma cells (NTERA-2, a cancer stem cell model) and peripheral blood mononuclear cells (PBMCs), using Sulforhodamine (SRB) and WST-1 assays, respectively. The effects of gedunin on expression of heat shock protein 90 (HSP90), its cochaperone Cdc37, and HSP client proteins (AKT, ErbB2, and HSF1) were evaluated by real-time PCR. Effects of gedunin on apoptosis were evaluated by (a) apoptosis associated morphological changes, (b) caspase 3/7 expression, (c) DNA fragmentation, (d) TUNEL assay, and (e) real-time PCR of apoptosis related genes (Bax, p53, and survivin). Gedunin showed a promising antiproliferative effect in NTERA-2 cells with IC50 values of 14.59, 8.49, and 6.55 μg/mL at 24, 48, and 72 h after incubations, respectively, while exerting a minimal effect on PBMCs. Expression of HSP90, its client proteins, and survivin was inhibited and Bax and p53 were upregulated by gedunin. Apoptosis related morphological changes, DNA fragmentation, and increased caspase 3/7 activities confirmed the proapoptotic effects of gedunin. Collectively, results indicate that gedunin may be a good drug lead for treatment of chemo and radiotherapy resistant cancer stem cells.
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31
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Lee SH, Hyun SK, Kim HB, Kang CD, Kim SH. Potential Role of CD133 Expression in the Susceptibility of Human Liver Cancer Stem-Like Cells to TRAIL. Oncol Res 2017; 24:495-509. [PMID: 28281970 PMCID: PMC7838688 DOI: 10.3727/096504016x14685034103950] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies, with a poor prognosis and high recurrence rate. In the present study, we identified CD133, one of the markers of cancer stem cells, as a novel molecular target of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In four human HCC cell lines established from primary HCC tumors, we found that CD133-high human liver cancer stem-like cells (CD133hi) derived from the SNU-475 cell line were highly susceptible to TRAIL compared to other HCC cell lines with a small population of CD133. CD133hi SNU-475 cells showed upregulation of TRAIL receptor DR5 and stemness-related genes such as c-Myc and ABC transporters compared to their CD133-low (CD133lo) cells. Hypersensitivity of CD133hi cells to TRAIL was associated with c-Myc-mediated upregulation of DR5 and downregulation of c-FLIPL in the cells. Knockdown of CD133 expression in CD133hi cells resulted in the downregulation of c-Myc, and depletion of c-Myc caused a decrease in the cell surface expression of DR5 and an increase in the expression of c-FLIPL and, consequently, attenuated TRAIL-induced cytotoxicity and apoptosis of CD133hi cells. These results suggest that TRAIL may provide a new strategy for CD133hi CSCs of HCC-targeted therapies and, potentially, for therapies of other CD133-expressing types of cancer.
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Affiliation(s)
- Su-Hoon Lee
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea
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32
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n-Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in Glioblastoma. Int J Mol Sci 2017; 18:ijms18020372. [PMID: 28208648 PMCID: PMC5343907 DOI: 10.3390/ijms18020372] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 02/06/2017] [Indexed: 01/16/2023] Open
Abstract
Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor. Due to its highly recurrent rate and poor prognosis, the overall survival time with this type of tumor is only 20–21 months. Recent knowledge suggests that its recurrence is in part due to the presence of cancer stem cells (CSCs), which display radioresistant, chemoresistant, self-renewal and tumorigenic potential. Enhancers of Zeste 2 (EZH2) and AXL receptor tyrosine kinase (AXL) are both highly expressed in GBM. Additionally, they are an essential regulator involved in CSCs maintenance, migration, invasion, epithelial-to-mesenchymal transition (EMT), stemness, metastasis and patient survival. In this study, we used a small molecule, n-butylidenephthalide (BP), to assess the anti-GBM stem-like cells potential, and then tried to find out the associated genes involved with regulation in migration and invasion. We demonstrated that BP reduced the expression of AXL and stemness related genes in a dose-dependent manner. The migratory and invasive capabilities of GBM stem-like cells could be reduced by AXL/EZH2. Finally, in the overexpression of AXL, EZH2 and Sox2 by transfection in GBM stem-like cells, we found that AXL/EZH2/TGF-β1, but not Sox2, might be a key regulator in tumor invasion, migration and EMT. These results might help in the development of a new anticancer compound and can be a target for treating GBM.
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33
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Gao XM, Zhang R, Dong QZ, Qin LX. Properties and feasibility of using cancer stem cells in clinical cancer treatment. Cancer Biol Med 2016; 13:489-495. [PMID: 28154781 PMCID: PMC5250607 DOI: 10.20892/j.issn.2095-3941.2016.0076] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 10/24/2016] [Indexed: 02/07/2023] Open
Abstract
Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells (CSCs). The characteristics of this subgroup of cells include self-renewal, tumorigenesis, multiple differentiation and high invasiveness, metastasis, and drug resistance potential. Many studies have demonstrated that CSCs play important roles in tumor growth, spread and metastatic relapse after treatment, and are closely related to the prognosis of patients. From a therapeutic viewpoint, deep insights into the CSCs biology, development of specific therapeutic strategies for targeting CSCs, and characterization of their microenvironment could be an ideal way to combat cancer.
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Affiliation(s)
- Xiao-Mei Gao
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Rui Zhang
- Department of General Surgery, Huashan Hospital and Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Qiong-Zhu Dong
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
- Department of General Surgery, Huashan Hospital and Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Lun-Xiu Qin
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
- Department of General Surgery, Huashan Hospital and Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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The Progress and Prospects of Putative Biomarkers for Liver Cancer Stem Cells in Hepatocellular Carcinoma. Stem Cells Int 2016; 2016:7614971. [PMID: 27610139 PMCID: PMC5005617 DOI: 10.1155/2016/7614971] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 06/06/2016] [Accepted: 07/04/2016] [Indexed: 01/30/2023] Open
Abstract
Accumulating evidence suggests that hepatocellular carcinoma (HCC) is organized by liver cancer stem cells (LCSCs), which are a subset of cells with “stem-like” characteristics. Identification of the LCSCs is a fundamental and important problem in HCC research. LCSCs have been investigated by various stem cell biomarkers. There is still lack of consensus regarding the existence of a “global” marker for LCSCs in HCC. In this review article, we summarize the progress and prospects of putative biomarkers for LCSCs in the past decades, which is essential to develop future therapies targeting CSCs and to predict prognosis and curative effect of these therapies.
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Nomura A, Banerjee S, Chugh R, Dudeja V, Yamamoto M, Vickers SM, Saluja AK. CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer. Oncotarget 2016; 6:8313-22. [PMID: 25829252 PMCID: PMC4480754 DOI: 10.18632/oncotarget.3228] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 01/27/2015] [Indexed: 12/31/2022] Open
Abstract
CD133 has been implicated as a cancer stem cell (CSC) surface marker in several malignancies including pancreatic cancer. However, the functional role of this surface glycoprotein in the cancer stem cell remains elusive. In this study, we determined that CD133 overexpression induced “stemness” properties in MIA-PaCa2 cells along with increased tumorigenicity, tumor progression, and metastasis in vivo. Additionally, CD133 expression induced epithelial-mesenchymal transition (EMT) and increased in vitro invasion. EMT induction and increased invasiveness were mediated by NF-κB activation, as inhibition of NF-κB mitigated these effects. This study showed that CD133 expression contributes to pancreatic cancer “stemness,” tumorigenicity, EMT induction, invasion, and metastasis.
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Affiliation(s)
- Alice Nomura
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Sulagna Banerjee
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Rohit Chugh
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Vikas Dudeja
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Masato Yamamoto
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Selwyn M Vickers
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Ashok K Saluja
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
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Canter RJ, Grossenbacher SK, Ames E, Murphy WJ. Immune targeting of cancer stem cells in gastrointestinal oncology. J Gastrointest Oncol 2016; 7:S1-S10. [PMID: 27034806 DOI: 10.3978/j.issn.2078-6891.2015.066] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis postulates that a sub-population of quiescent cells exist within tumors which are resistant to conventional cytotoxic/anti-proliferative therapies. It is these CSCs which then seed tumor relapse, even in cases of apparent complete response to systemic therapy. Therefore, therapies, such as immunotherapy, which add a specific anti-CSC strategy to standard cytoreductive treatments may provide a promising new direction for future cancer therapies. CSCs are an attractive target for immune therapies since, unlike chemotherapy or radiotherapy, immune effector cells do not specifically require target cells to be proliferating in order to effectively kill them. Although recent advances have been made in the development of novel systemic and targeted therapies for advanced gastro-intestinal (GI) malignancies, there remains an unmet need for durable new therapies for these refractory malignancies. Novel immunotherapeutic strategies targeting CSCs are in pre-clinical and clinical development across the spectrum of the immune system, including strategies utilizing adaptive immune cell-based effectors, innate immune effectors, as well as vaccine approaches. Lastly, since important CSC functions are affected by the tumor microenvironment, targeting of both cellular (myeloid derived suppressor cells and tumor-associated macrophages) and sub-cellular (cytokines, chemokines, and PD1/PDL1) components of the tumor microenvironment is under investigation in the immune targeting of CSCs. These efforts are adding to the significant optimism about the potential utility of immunotherapy to overcome cancer resistance mechanisms and cure greater numbers of patients with advanced malignancy.
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Affiliation(s)
- Robert J Canter
- 1 Division of Surgical Oncology, Department of Surgery, 2 Laboratory of Cancer Immunology, Department of Dermatology, 3 Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817, USA
| | - Steven K Grossenbacher
- 1 Division of Surgical Oncology, Department of Surgery, 2 Laboratory of Cancer Immunology, Department of Dermatology, 3 Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817, USA
| | - Erik Ames
- 1 Division of Surgical Oncology, Department of Surgery, 2 Laboratory of Cancer Immunology, Department of Dermatology, 3 Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817, USA
| | - William J Murphy
- 1 Division of Surgical Oncology, Department of Surgery, 2 Laboratory of Cancer Immunology, Department of Dermatology, 3 Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817, USA
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Crosstalk-eliminated quantitative determination of aflatoxin B1-induced hepatocellular cancer stem cells based on concurrent monitoring of CD133, CD44, and aldehyde dehydrogenase1. Toxicol Lett 2015; 243:31-9. [PMID: 26739636 DOI: 10.1016/j.toxlet.2015.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 12/14/2015] [Accepted: 12/21/2015] [Indexed: 01/22/2023]
Abstract
Cancer stem cells (CSCs), known as tumor initiating cells, have become a critically important issue for cancer therapy. Although much research has demonstrated the induction of hepato cellular carcinoma by aflatoxin B1, the formation of hepatocellular CSCs and their quantitative determination is hardly reported. In this work, it was found that hepatocellular CSCs were produced from HepG2 cells by aflatoxin B1-induced mutation, and their amount was quantitatively determined using crosstalk-eliminated multicolor cellular imaging based on quantum dot (Qdot) nanoprobes and an acousto-optical tunable filter (AOTF). Hepatocellular CSCs were acquired via magnetic bead-based sorting and observed using concurrent detection of three different markers: CD133, CD44, and aldehyde dehydrogenase1 (ALDH1). The DNA mutation of HepG2 cells caused by aflatoxin B1 was quantitatively observed via absorbance spectra of aflatoxin B1-8, 9-epoxide-DNA adducts. The percentages of hepatocellular CSCs formed in the entire HepG2 cells were determined to be 9.77±0.65%, 10.9±1.39%, 11.4±1.32%, and 12.8±0.7%, respectively, at 0 μM, 5 μM, 10 μM, and 20 μM of aflatoxin B1. The results matched well with those obtained utilizing flow cytometry. This study demonstrates that aflatoxin mediated mutation induced the conversion of hepatic cancer cell to hepatic CSCs by using a Qdot based constructed multicolor cellular imaging system.
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38
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Zhu CP, Wang AQ, Zhang HH, Wan XS, Yang XB, Chen SG, Zhao HT. Research progress and prospects of markers for liver cancer stem cells. World J Gastroenterol 2015; 21:12190-12196. [PMID: 26576103 PMCID: PMC4641136 DOI: 10.3748/wjg.v21.i42.12190] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/10/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is a common malignancy and surgery is the main treatment strategy. However, the prognosis is still poor because of high frequencies of postoperative recurrence and metastasis. In recent years, cancer stem cell (CSC) theory has evolved with the concept of stem cells, and has been applied to oncological research. According to cancer stem cell theory, liver cancer can be radically cured only by eradication of liver cancer stem cells (LCSCs). This notion has lead to the isolation and identification of LCSCs, which has become a highly researched area. Analysis of LCSC markers is considered to be the primary method for identification of LCSCs. Here, we provide an overview of the current research progress and prospects of surface markers for LCSCs.
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39
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Tso JL, Yang S, Menjivar JC, Yamada K, Zhang Y, Hong I, Bui Y, Stream A, McBride WH, Liau LM, Nelson SF, Cloughesy TF, Yong WH, Lai A, Tso CL. Bone morphogenetic protein 7 sensitizes O6-methylguanine methyltransferase expressing-glioblastoma stem cells to clinically relevant dose of temozolomide. Mol Cancer 2015; 14:189. [PMID: 26546412 PMCID: PMC4636799 DOI: 10.1186/s12943-015-0459-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 10/20/2015] [Indexed: 12/21/2022] Open
Abstract
Background Temozolomide (TMZ) is an oral DNA-alkylating agent used for treating patients with glioblastoma. However, therapeutic benefits of TMZ can be compromised by the expression of O6-methylguanine methyltransferase (MGMT) in tumor tissue. Here we used MGMT-expressing glioblastoma stem cells (GSC) lines as a model for investigating the molecular mechanism underlying TMZ resistance, while aiming to explore a new treatment strategy designed to possibly overcome resistance to the clinically relevant dose of TMZ (35 μM). Methods MGMT-expressing GSC cultures are resistant to TMZ, and IC50 (half maximal inhibitory concentration) is estimated at around 500 μM. Clonogenic GSC surviving 500 μM TMZ (GSC-500 μM TMZ), were isolated. Molecular signatures were identified via comparative analysis of expression microarray against parental GSC (GSC-parental). The recombinant protein of top downregulated signature was used as a single agent or in combination with TMZ, for evaluating therapeutic effects of treatment of GSC. Results The molecular signatures characterized an activation of protective stress responses in GSC-500 μM TMZ, mainly including biotransformation/detoxification of xenobiotics, blocked endoplasmic reticulum stress-mediated apoptosis, epithelial-to-mesenchymal transition (EMT), and inhibited growth/differentiation. Bone morphogenetic protein 7 (BMP7) was identified as the top down-regulated gene in GSC-500 μM TMZ. Although augmenting BMP7 signaling in GSC by exogenous BMP7 treatment did not effectively stop GSC growth, it markedly sensitized both GSC-500 μM TMZ and GSC-parental to 35 μM TMZ treatment, leading to loss of self-renewal and migration capacity. BMP7 treatment induced senescence of GSC cultures and suppressed mRNA expression of CD133, MGMT, and ATP-binding cassette drug efflux transporters (ABCB1, ABCG2), as well as reconfigured transcriptional profiles in GSC by downregulating genes associated with EMT/migration/invasion, stemness, inflammation/immune response, and cell proliferation/tumorigenesis. BMP7 treatment significantly prolonged survival time of animals intracranially inoculated with GSC when compared to those untreated or treated with TMZ alone (p = 0.0017), whereas combination of two agents further extended animal survival compared to BMP7 alone (p = 0.0489). Conclusions These data support the view that reduced endogenous BMP7 expression/signaling in GSC may contribute to maintained stemness, EMT, and chemoresistant phenotype, suggesting that BMP7 treatment may provide a novel strategy in combination with TMZ for an effective treatment of glioblastoma exhibiting unmethylated MGMT. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0459-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jonathan L Tso
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Shuai Yang
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.
| | - Jimmy C Menjivar
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Kazunari Yamada
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Department of Advanced Molecular and Cell Therapy, Kyushu University Hospital, Higashiku, Fukuoka, Japan.
| | - Yibei Zhang
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Department of Orthopedics, Zhongshan Hospital, Xiamen University, Xiamen, China.
| | - Irene Hong
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Yvonne Bui
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Alexandra Stream
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
| | - William H McBride
- Department of Radiation-Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. .,Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA.
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA.
| | - Stanley F Nelson
- Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA.
| | - Timothy F Cloughesy
- Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA.
| | - William H Yong
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA.
| | - Albert Lai
- Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA.
| | - Cho-Lea Tso
- Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA.
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LIU YANMIN, LI XUANFEI, LIU HAO, WU XIAOLING. Ultrasound-targeted microbubble destruction-mediated downregulation of CD133 inhibits epithelial-mesenchymal transition, stemness and migratory ability of liver cancer stem cells. Oncol Rep 2015; 34:2977-86. [DOI: 10.3892/or.2015.4270] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 07/29/2015] [Indexed: 11/06/2022] Open
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41
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Wang F, Dai W, Wang Y, Shen M, Chen K, Cheng P, Zhang Y, Wang C, Li J, Zheng Y, Lu J, Yang J, Zhu R, Zhang H, Zhou Y, Xu L, Guo C. The synergistic in vitro and in vivo antitumor effect of combination therapy with salinomycin and 5-fluorouracil against hepatocellular carcinoma. PLoS One 2014; 9:e97414. [PMID: 24816638 PMCID: PMC4016361 DOI: 10.1371/journal.pone.0097414] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 04/17/2014] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the few cancers in which a continuous increase in incidence has been observed over several years. Drug resistance is a major problem in the treatment of HCC. In the present study, we used salinomycin (Sal) and 5-fluorouracil (5-FU) combination therapy on HCC cell lines Huh7, LM3 and SMMC-7721 and nude mice subcutaneously tumor model to study whether Sal could increase the sensitivity of hepatoma cells to the traditional chemotherapeutic agent such as 5-FU. The combination of Sal and 5-FU resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. Sal reversed the 5-FU-induced increase in CD133(+) EPCAM(+) cells, epithelial-mesenchymal transition and activation of the Wnt/β-catenin signaling pathway. The combination of Sal and 5-FU may provide us with a new approach to reverse drug resistant for the treatment of patients with HCC.
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Affiliation(s)
- Fan Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Yugang Wang
- Department of Gastroenterology, Shanghai Tongren Hospital, Jiaotong University of Medicine, Shanghai, PR China
| | - Miao Shen
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Ping Cheng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Yan Zhang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Chengfen Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Jing Yang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Rong Zhu
- Department of Gastroenterology, Clinical Medicine of Shanghai Tenth People’s Hospital, Nanjing Medical University, Shanghai, PR China
| | - Huawei Zhang
- Department of Gastroenterology, The First Hospital Affiliated to Suzhou University, Suzhou, PR China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
| | - Ling Xu
- Department of Gastroenterology, Shanghai Tongren Hospital, Jiaotong University of Medicine, Shanghai, PR China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University of Medicine, Shanghai, PR China
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Sukowati CHC, Tiribelli C. The biological implication of cancer stem cells in hepatocellular carcinoma: a possible target for future therapy. Expert Rev Gastroenterol Hepatol 2013; 7:749-757. [PMID: 24161136 DOI: 10.1586/17474124.2013.846826] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Recent studies indicated the importance of stem cells in cancer, including in hepatocellular carcinoma. The presence of the stem cells and cancer stem cells in liver diseases is associated with the initiation, maintenance, metastasis and chemoresistance. Since hepatocellular carcinoma is a heterogeneous disease with a wide variety of prognostic types, which may limit the efficiency of standardized therapy, the understanding of the source of the cancer, alteration in important molecular signaling pathways and interaction between cancer cells and other cells types will be important in defining future, tailored treatment strategies.
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PKH(high) cells within clonal human nephrospheres provide a purified adult renal stem cell population. Stem Cell Res 2013; 11:1163-77. [PMID: 24012544 DOI: 10.1016/j.scr.2013.08.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 08/02/2013] [Accepted: 08/03/2013] [Indexed: 01/09/2023] Open
Abstract
The existence and identification of adult renal stem cells is a controversial issue. In this study, renal stem cells were identified from cultures of clonal human nephrospheres. The cultured nephrospheres exhibited the activation of stem cell pathways and contained cells at different levels of maturation. In each nephrosphere the presence of 1.12-1.25 cells mirroring stem cell properties was calculated. The nephrosphere cells were able to generate three-dimensional tubular structures in 3D cultures and in vivo. In clonal human nephrospheres a PKH(high) phenotype was isolated using PKH26 epifluorescence, which can identify quiescent cells within the nephrospheres. The PKH(high) cells, capable of self-renewal and of generating a differentiated epithelial, endothelial and podocytic progeny, can also survive in vivo maintaining the undifferentiated status. The PKH(high) status, together with a CD133(+)/CD24(-) phenotype, identified a homogeneous cell population displaying in vitro self-renewal and multipotency capacity. The resident adult renal stem cell population isolated from nephrospheres can be used for the study of mechanisms that regulate self-renewal and differentiation in adult renal tissue as well as in renal pathological conditions.
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44
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Low glucose promotes CD133mAb-elicited cell death via inhibition of autophagy in hepatocarcinoma cells. Cancer Lett 2013; 336:204-12. [PMID: 23652197 DOI: 10.1016/j.canlet.2013.04.031] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Revised: 04/14/2013] [Accepted: 04/29/2013] [Indexed: 02/07/2023]
Abstract
CD133 on cancer stem cells is a potential therapeutic target. In this study, CD133 antibody (CD133mAb) treatment resulted in cell death in hepatoma LM3, HepG2, Hep3B and Huh-7 cells, especially under low glucose condition. The treatment also inhibited formation of spheroids, colonies, and xenograft tumors. Ectopic CD133 enabled hepatocyte L02 to be suppressed by CD133mAb and increased spheroid formation. CD133mAb caused cell death in primary HCC cells and sensitized them to Doxorubicin and Cisplatin. The antibody effect was attributed to suppressing autophagy and promoting necrotic cell death. Therefore, targeting CD133 under low glucose condition is a potential therapeutic approach for hepatocarcinomas.
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