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An J, Hu X, Liu F. Current understanding of cancer stem cells: Immune evasion and targeted immunotherapy in gastrointestinal malignancies. Front Oncol 2023; 13:1114621. [PMID: 36910604 PMCID: PMC9996315 DOI: 10.3389/fonc.2023.1114621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
As a relatively rare population of cancer cells existing in the tumor microenvironment, cancer stem cells (CSCs) possess properties of immune privilege to evade the attack of immune system, regulated by the microenvironment of CSCs, the so-called CSCs niche. The bidirectional interaction of CSCs with tumor microenvironment (TME) components favors an immunosuppressive shelter for CSCs' survival and maintenance. Gastrointestinal cancer stem cells (GCSCs) are broadly regarded to be intimately involved in tumor initiation, progression, metastasis and recurrence, with elevated tumor resistance to conventional therapies, which pose a major hindrance to the clinical efficacy for treated patients with gastrointestinal malignancies. Thus, a multitude of efforts have been made to combat and eradicate GCSCs within the tumor mass. Among diverse methods of targeting CSCs in gastrointestinal malignancies, immunotherapy represents a promising strategy. And the better understanding of GCSCs immunomodulation and immunoresistance mechanisms is beneficial to guide and design novel GCSCs-specific immunotherapies with enhanced immune response and clinical efficacy. In this review, we have gathered available and updated information to present an overview of the immunoevasion features harbored by cancer stem cells, and we focus on the description of immune escape strategies utilized by CSCs and microenvironmental regulations underlying CSCs immuno-suppression in the context of gastrointestinal malignancies. Importantly, this review offers deep insights into recent advances of CSC-targeting immunotherapeutic approaches in gastrointestinal cancers.
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Affiliation(s)
- Junyi An
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohua Hu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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2
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Vainshelbaum NM, Giuliani A, Salmina K, Pjanova D, Erenpreisa J. The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction. Int J Mol Sci 2022; 23:ijms232314930. [PMID: 36499258 PMCID: PMC9736112 DOI: 10.3390/ijms232314930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/18/2022] [Accepted: 11/26/2022] [Indexed: 12/02/2022] Open
Abstract
The expression of gametogenesis-related (GG) genes and proteins, as well as whole genome duplications (WGD), are the hallmarks of cancer related to poor prognosis. Currently, it is not clear if these hallmarks are random processes associated only with genome instability or are programmatically linked. Our goal was to elucidate this via a thorough bioinformatics analysis of 1474 GG genes in the context of WGD. We examined their association in protein-protein interaction and coexpression networks, and their phylostratigraphic profiles from publicly available patient tumour data. The results show that GG genes are upregulated in most WGD-enriched somatic cancers at the transcriptome level and reveal robust GG gene expression at the protein level, as well as the ability to associate into correlation networks and enrich the reproductive modules. GG gene phylostratigraphy displayed in WGD+ cancers an attractor of early eukaryotic origin for DNA recombination and meiosis, and one relative to oocyte maturation and embryogenesis from early multicellular organisms. The upregulation of cancer-testis genes emerging with mammalian placentation was also associated with WGD. In general, the results suggest the role of polyploidy for soma-germ transition accessing latent cancer attractors in the human genome network, which appear as pre-formed along the whole Evolution of Life.
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Affiliation(s)
- Ninel M. Vainshelbaum
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia
- Faculty of Biology, The University of Latvia, LV-1586 Riga, Latvia
- Correspondence: (N.M.V.); (J.E.)
| | - Alessandro Giuliani
- Environmen and Health Department, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Kristine Salmina
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia
| | - Dace Pjanova
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia
| | - Jekaterina Erenpreisa
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia
- Correspondence: (N.M.V.); (J.E.)
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Liao M, Du H, Wang B, Huang J, Huang D, Tong G. Anticancer Effect of Polyphyllin I in Suppressing Stem Cell-Like Properties of Hepatocellular Carcinoma via the AKT/GSK-3 β/ β-Catenin Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4031008. [PMID: 36317061 PMCID: PMC9617736 DOI: 10.1155/2022/4031008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/29/2022] [Accepted: 09/28/2022] [Indexed: 12/24/2022]
Abstract
Polyphyllin I (PPI), also called Chong Lou saponin I, is a steroidal saponin isolated from the rhizome of Paris polyphylla. PPI has been demonstrated to have strong anticancer activity. However, its effect on the stemness of liver cancer stem cells (LCSCs) is not completely understood. Herein, we aimed to investigate the effect of PPI on the stem cell-like features of LCSCs and hepatocellular carcinoma (HCC). LCSCs were enriched in a serum-free medium and treated with PPI, sorafenib (Sora), or PPI and Sora. Several endpoints, including spheroid formation and differentiation, cell proliferation, surface markers of LCSCs, PPI binding targets, and stemness-associated protein expression, were evaluated. Immunofluorescence staining, quantitative real-time polymerase chain reaction, siRNA transfection, and coimmunoprecipitation ubiquitination assays were conducted for in-depth mechanistic studies. Evaluation of in vivo antitumor efficacy demonstrated that PPI effectively inhibited the proliferation of liver cancer cells and the self-renewal and differentiation of LCSCs. Flow cytometry indicated that PPI suppressed the expression of the stem cell surface markers EpCAM and CD13. Molecular docking showed a high affinity between PPI and proteins of the Wnt/β-catenin signaling pathway, including AKT, GSK-3β, and β-catenin, with the binding energies of -5.51, -5.32, and -5.40 kcal/mol, respectively, which suggested that PPI might regulate the Wnt/β-catenin signaling pathway to affect the stem cell-like properties of HCC. Further ex vivo experiments implied that PPI activated the AKT/GSK-3β-mediated ubiquitin proteasomal degradation of β-catenin and subsequently attenuated the prooncogenic effect of LCSCs. Finally, the anticancer property of PPI was confirmed in vivo. It was found that PPI inhibited the tumor growth in an HCC cell line xenograft model. Taken together, molecular docking analysis and experimental data highlighted the novel function of PPI in suppressing the stem cell-like characteristics of LCSCs via the AKT/GSK-3β/β-catenin signaling pathway.
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Affiliation(s)
- Mianmian Liao
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Haiyan Du
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Bing Wang
- Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Jinzhen Huang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Danping Huang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- Department of Integrated Traditional Chinese and Western Medicine, School of Clinical Medicine of Guangdong Pharmaceuticcal University, Guangzhou, China
| | - Guangdong Tong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
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4
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Guizhen Z, Guanchang J, Liwen L, Huifen W, Zhigang R, Ranran S, Zujiang Y. The tumor microenvironment of hepatocellular carcinoma and its targeting strategy by CAR-T cell immunotherapy. Front Endocrinol (Lausanne) 2022; 13:918869. [PMID: 36093115 PMCID: PMC9452721 DOI: 10.3389/fendo.2022.918869] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/05/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, which ranks sixth in cancer incidence and third in mortality. Although great strides have been made in novel therapy for HCC, such as immunotherapy, the prognosis remains less than satisfactory. Increasing evidence demonstrates that the tumor immune microenvironment (TME) exerts a significant role in the evolution of HCC and has a non-negligible impact on the efficacy of HCC treatment. In the past two decades, the success in hematological malignancies made by chimeric antigen receptor-modified T (CAR-T) cell therapy leveraging it holds great promise for cancer treatment. However, in the face of a hostile TME in solid tumors like HCC, the efficacy of CAR-T cells will be greatly compromised. Here, we provide an overview of TME features in HCC, discuss recent advances and challenges of CAR-T immunotherapy in HCC.
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Affiliation(s)
- Zhang Guizhen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ji Guanchang
- Department of Urology People’s Hospital of Puyang, Puyang, China
| | - Liu Liwen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Wang Huifen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ren Zhigang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sun Ranran
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yu Zujiang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
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Hu X, Chen R, Wei Q, Xu X. The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We? Int J Biol Sci 2022; 18:536-551. [PMID: 35002508 PMCID: PMC8741863 DOI: 10.7150/ijbs.64537] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in early diagnosis and heterogeneity are obstacles to effective treatment, especially for advanced HCC. Liver transplantation (LT) is considered the best therapy for HCC. Although many biomarkers are being proposed, alpha-fetoprotein (AFP), which was identified over 60 years ago, remains the most utilized. Recently, much hope has been placed in the immunogenicity of AFP to develop novel therapies, such as AFP vaccines and AFP-specific adoptive T-cell transfer (ACT). This review summarizes the performance of AFP as a biomarker for HCC diagnosis and prognosis, as well as its correlation with molecular classes. In addition, the role of AFP in LT is also described. Finally, we highlight the mechanism and application prospects of two immune therapies (AFP vaccine and ACT) for HCC. In general, our review points out the prevalence of AFP in HCC, accompanied by some controversies and novel directions for future research.
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Affiliation(s)
- Xin Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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Zhou X, Xie X, Liu T, Chen S, Wang Y, Zhang J, Wang S, Wang Y, Dou S, Qi R, Kang N, Zhang D, Jin X, Cui R, Jiang H. REC8 enhances stemness and promotes metastasis of colorectal cancer through BTK/Akt/β-catenin signaling pathway. Transl Oncol 2021; 15:101305. [PMID: 34890967 DOI: 10.1016/j.tranon.2021.101305] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer/testis antigens (CTAs) are often aberrantly expressed in cancer stem cells (CSCs) which are responsible for tumor metastasis. Rec8 meiotic recombination protein (REC8), a member of CTAs, shares distinct roles in various cancers, while its contribution to CSCs and colorectal cancer (CRC) remains unclear. We found that overexpression of REC8 facilitated the migration and invasion of CRC cells (DLD-1 and SW480 cells) in vitro and promoted the liver metastasis of CRC in vivo. Moreover, REC8 is highly expressed in CRC stem-like cells and is required for the maintenance of CSC stemness. Mechanistic studies suggested that REC8 mediated through the activation of Bruton tyrosine kinase (BTK). Inhibition of BTK by ibrutinib not only suppressed the migration and invasion-promoting ability, but also declined the increased expression of p-BTK, p-Akt, β-catenin, and CSC markers upon REC8 overexpression. Importantly, high expression of REC8 in cancerous tissues was related to advanced clinical stage and lymph node metastasis of 62 CRC patients, and REC8 was enriched in the cancerous cells positive for CSC markers. Collectively, our results indicate that REC8 promotes CRC metastasis by increasing cell stemness through BTK/Akt/β-catenin pathway.
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Affiliation(s)
- Xue Zhou
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Xiaoli Xie
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Ting Liu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Shengxiong Chen
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yijun Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Jiuna Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Shuling Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Yongjuan Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Shiying Dou
- Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ran Qi
- Department of General Practice, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ning Kang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Dongxuan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Xiaoxu Jin
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Ruolin Cui
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China
| | - Huiqing Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China.
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Proteomic Signatures of Diffuse and Intestinal Subtypes of Gastric Cancer. Cancers (Basel) 2021; 13:cancers13235930. [PMID: 34885041 PMCID: PMC8656738 DOI: 10.3390/cancers13235930] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/20/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is a leading cause of death from cancer globally. Gastric cancer is classified into intestinal, diffuse and indeterminate subtypes based on histology according to the Laurén classification. The intestinal and diffuse subtypes, although different in histology, demographics and outcomes, are still treated in the same fashion. This study was designed to discover proteomic signatures of diffuse and intestinal subtypes. Mass spectrometry-based proteomics using tandem mass tags (TMT)-based multiplexed analysis was used to identify proteins in tumor tissues from patients with diffuse or intestinal gastric cancer with adjacent normal tissue control. A total of 7448 or 4846 proteins were identified from intestinal or diffuse subtype, respectively. This quantitative mass spectrometric analysis defined a proteomic signature of differential expression across the two subtypes, which included gremlin1 (GREM1), bcl-2-associated athanogene 2 (BAG2), olfactomedin 4 (OLFM4), thyroid hormone receptor interacting protein 6 (TRIP6) and melanoma-associated antigen 9 (MAGE-A9) proteins. Although GREM1, BAG2, OLFM4, TRIP6 and MAGE-A9 have all been previously implicated in tumor progression and metastasis, they have not been linked to intestinal or diffuse subtypes of gastric cancer. Using immunohistochemical labelling of a tissue microarray comprising of 124 cases of gastric cancer, we validated the proteomic signature obtained by mass spectrometry in the discovery cohort. Our findings should help investigate the pathogenesis of these gastric cancer subtypes and potentially lead to strategies for early diagnosis and treatment.
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Wu SC, Münger K. Role and Clinical Utility of Cancer/Testis Antigens in Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13225690. [PMID: 34830845 PMCID: PMC8616139 DOI: 10.3390/cancers13225690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/03/2021] [Accepted: 11/11/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer/testis (CT) antigens exhibit selective expression predominantly in immunoprivileged tissues in non-pathological contexts but are aberrantly expressed in diverse cancers. Due to their expression pattern, they have historically been attractive targets for immunotherapies. A growing number of studies implicate CT antigens in almost all hallmarks of cancer, suggesting that they may act as cancer drivers. CT antigens are expressed in head and neck squamous cell carcinomas. However, their role in the pathogenesis of these cancers remains poorly studied. Given that CT antigens hold intriguing potential as therapeutic targets and as biomarkers for prognosis and that they can provide novel insights into oncogenic mechanisms, their further study in the context of head and squamous cell carcinoma is warranted.
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Affiliation(s)
- Sharon Changshan Wu
- Molecular Microbiology Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA;
| | - Karl Münger
- Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
- Correspondence:
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Oh C, Kim HR, Oh S, Ko JY, Kim Y, Kang K, Yang Y, Kim J, Park JH, Roe JS, Yoo KH. Epigenetic Upregulation of MAGE-A Isoforms Promotes Breast Cancer Cell Aggressiveness. Cancers (Basel) 2021; 13:cancers13133176. [PMID: 34202157 PMCID: PMC8268034 DOI: 10.3390/cancers13133176] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/14/2021] [Accepted: 06/21/2021] [Indexed: 01/28/2023] Open
Abstract
Simple Summary Breast cancer is a heterogeneous disease that has complex causes and mechanisms of development. Currently, patient treatment options depend on the breast cancer molecular subtype, which is classified based on the presence or absence of hormone receptors and HER2. However, this classification system has limitations in terms of predicting responsiveness to anticancer drugs and patient outcomes. In this study, we present a new approach to classifying molecular breast cancer subtypes: it is based on changes in histone modifications in the promoter region of the MAGEA12 locus, which we found related closely to MAGEA12 expression and MAGEA12-associated malignancy of breast cancer cells. Abstract After decades-long efforts to diagnose and treat breast cancer, the management strategy that has proved most successful to date is molecular-subtype-specific inhibition of the hormone receptors and HER2 that are expressed by individual cancers. Melanoma-associated antigen (MAGE) proteins comprise >40 highly conserved members that contain the MAGE homology domain. They are often overexpressed in multiple cancers and contribute to cancer progression and metastasis. However, it remains unclear whether the biological activity arising from MAGE gene expression is associated with breast cancer subtypes. In this study, we analyzed the RNA-sequencing (RNA-seq) data of 70 breast cancer cell lines and found that MAGEA12 and MAGEA3 were highly expressed in a subset of these lines. Significantly, MAGEA12 and MAGEA3 expression levels were independent of hormone receptor expression levels but were closely associated with markers of active histone modifications. This indicates that overexpression of these genes is attributable to epigenetic deregulation. RNA-seq of MAGEA12-depleted cells was then used to identify 382 candidate targets of MAGEA12 that were downregulated by MAGEA12 depletion. Furthermore, our gain-of-function experiments showed that MAGEA12 overexpression promoted aggressive behaviors of malignant breast cancer cells, including enhancing their cell migration and invasion. These changes were associated with increased epigenetic deregulation of the MAGEA12 signature genes. Thus, MAGEA12 may play an important role in breast cancer malignancy. Taken together, our findings suggest that MAGEA12 could be a promising therapeutic target in breast cancer, and its overexpression and epigenetic changes could serve as subtype classification biomarkers.
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Affiliation(s)
- Chaeun Oh
- Laboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (C.O.); (S.O.)
| | - Hwa-Ryeon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea;
| | - Sumin Oh
- Laboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (C.O.); (S.O.)
- Research Institute of Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
| | - Je Yeong Ko
- Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (J.Y.K.); (Y.K.); (Y.Y.); (J.K.); (J.H.P.)
| | - Yesol Kim
- Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (J.Y.K.); (Y.K.); (Y.Y.); (J.K.); (J.H.P.)
| | - Keunsoo Kang
- Department of Microbiology, College of Science & Technology, Dankook University, Cheonan 31116, Korea;
| | - Young Yang
- Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (J.Y.K.); (Y.K.); (Y.Y.); (J.K.); (J.H.P.)
| | - Jongmin Kim
- Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (J.Y.K.); (Y.K.); (Y.Y.); (J.K.); (J.H.P.)
| | - Jong Hoon Park
- Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (J.Y.K.); (Y.K.); (Y.Y.); (J.K.); (J.H.P.)
| | - Jae-Seok Roe
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea;
- Correspondence: (J.-S.R.); (K.H.Y.); Tel.: +82-2-2123-2700 (J.-S.R.); +82-2-2077-7836 (K.H.Y.)
| | - Kyung Hyun Yoo
- Laboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; (C.O.); (S.O.)
- Research Institute of Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
- Correspondence: (J.-S.R.); (K.H.Y.); Tel.: +82-2-2123-2700 (J.-S.R.); +82-2-2077-7836 (K.H.Y.)
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Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials. Cancers (Basel) 2021; 13:cancers13020271. [PMID: 33450845 PMCID: PMC7828372 DOI: 10.3390/cancers13020271] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 12/13/2022] Open
Abstract
The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials.
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Li J, Zhu Y. Recent Advances in Liver Cancer Stem Cells: Non-coding RNAs, Oncogenes and Oncoproteins. Front Cell Dev Biol 2020; 8:548335. [PMID: 33117795 PMCID: PMC7575754 DOI: 10.3389/fcell.2020.548335] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, with high morbidity, relapse, metastasis and mortality rates. Although liver surgical resection, transplantation, chemotherapy, radiotherapy and some molecular targeted therapeutics may prolong the survival of HCC patients to a certain degree, the curative effect is still poor, primarily because of tumor recurrence and the drug resistance of HCC cells. Liver cancer stem cells (LCSCs), also known as liver tumor-initiating cells, represent one small subset of cancer cells that are responsible for disease recurrence, drug resistance and death. Therefore, understanding the regulatory mechanism of LCSCs in HCC is of vital importance. Thus, new studies that present gene regulation strategies to control LCSC differentiation and replication are under development. In this review, we provide an update on the latest advances in experimental studies on non-coding RNAs (ncRNAs), oncogenes and oncoproteins. All the articles addressed the crosstalk between different ncRNAs, oncogenes and oncoproteins, as well as their upstream and downstream products targeting LCSCs. In this review, we summarize three pathways, the Wnt/β-catenin signaling pathway, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, and interleukin 6/Janus kinase 2/signal transducer and activator of transcription 3 (IL6/JAK2/STAT3) signaling pathway, and their targeting gene, c-Myc. Furthermore, we conclude that octamer 4 (OCT4) and Nanog are two important functional genes that play a pivotal role in LCSC regulation and HCC prognosis.
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Affiliation(s)
- Juan Li
- Department of Radiotherapy Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ying Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Liver Disease Center of Integrated Traditional and Western Medicine, Institute of Integrative Medicine, Dalian Medical University, Dalian, China
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12
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Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol 2020; 26:1580-1593. [PMID: 32327907 PMCID: PMC7167409 DOI: 10.3748/wjg.v26.i14.1580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/22/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.
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MESH Headings
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Cancer Vaccines/administration & dosage
- Combined Modality Therapy/methods
- Dendritic Cells/immunology
- Drug Resistance, Neoplasm/immunology
- Gastrointestinal Neoplasms/immunology
- Gastrointestinal Neoplasms/pathology
- Gastrointestinal Neoplasms/therapy
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Innate/drug effects
- Immunity, Innate/immunology
- Immunotherapy/methods
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/prevention & control
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Tumor Escape/drug effects
- Tumor Escape/immunology
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Irina Alexiu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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13
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Cui J, Gong M, Fang S, Hu C, Wang Y, Zhang J, Tang N, He Y. All-trans retinoic acid reverses malignant biological behavior of hepatocarcinoma cells by regulating miR-200 family members. Genes Dis 2020; 8:509-520. [PMID: 34179313 PMCID: PMC8209308 DOI: 10.1016/j.gendis.2019.12.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/10/2019] [Accepted: 12/31/2019] [Indexed: 02/07/2023] Open
Abstract
As a potential chemo-therapeutic agent, all-trans retinoic acid (ATRA) can significantly reverse epithelial-mesenchymal transition (EMT) of hepal-6 hepatocarcinoma cell line in vitro, but the mechanism is unclear. The expression profile of microRNA-200 (miR-200) families is different in hepatocellular carcinoma. In this study, we found that ATRA treatment could up-regulate the expression of miR-200a-3p, 200c-3p, and 141-3p, which were involved in ATRA regulated proliferation and apoptosis of hepal-6 cell, but not colony formation. Meanwhile, miR-200a-3p, 200c-3p, and 141-3p could recovery ATRA inhibited migration and invasion abilities of hepal-6 cells at various levels. miR-200a-3p and 200c-3p prevented ATRA from inducing the differentiation and hepatic functions of hepal-6 cells. Antagomir specific for miR-200a-3p and 200c-3p down-regulated the expression of CK18, but only miR-200a-3p antagomir played prominent role in regulating the expression of these mesenchymal markers, N-Cadherin, Snail and Twist. The transcriptional activities of 8 transcription factors were up-regulated and 35 transcription factors were down-regulated by ATRA. Compared with ATRA group, inhibition of miR-200a-3p, 200c-3p, and 141-3p significantly strengthened the expression of Fra1/Jun (AP1), Ets1/PEA3, Brn3, and Zeb1/AREB6 at varying degrees. Therefore, this result suggested that ATRA may suppress EMT through down-regulating miR-200a-3p, 200c-3p and 141-3p related transcription factors. miR-200 and their downstream genes might be the potentially specific targets for the treatment of hepatocarcinoma.
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Affiliation(s)
- Jiejie Cui
- Department of Pediatric Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China.,Puyang People's Hospital, Puyang, Henan Province, 457000, PR China
| | - Mengjia Gong
- Department of Pediatric Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China
| | - Shuyu Fang
- Department of Pediatric Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China
| | - Chaoqun Hu
- Department of Pediatric Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China
| | - Yi Wang
- Department of Pediatric Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China
| | - Jingfang Zhang
- Puyang People's Hospital, Puyang, Henan Province, 457000, PR China
| | - Ni Tang
- Department of Pediatric Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China
| | - Yun He
- Department of Pediatric Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China
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Expression dynamics of Mage family genes during self-renewal and differentiation of mouse pluripotent stem and teratocarcinoma cells. Oncotarget 2019; 10:3248-3266. [PMID: 31143371 PMCID: PMC6524934 DOI: 10.18632/oncotarget.26933] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 04/29/2019] [Indexed: 12/28/2022] Open
Abstract
The biological roles of cancer-testis antigens of the Melanoma antigen (Mage) family in mammalian development, stem cell differentiation and carcinogenesis are largely unknown. In order to understand the involvement of the Mage family genes in maintenance of normal and cancer stem cells, the expression patterns of Mage-a, Mage-b, Mage-d, Mage-e, Mage-h and Mage-l gene subfamilies were analyzed during the self-renewal and differentiation of mouse pluripotent stem and teratocarcinoma cells. Clustering analysis based on the gene expression profiles of undifferentiated and differentiating cell populations revealed strong correlations between Mage expression patterns and differentiation and malignant states. Gene co-expression analysis disclosed the potential contributions of Mage family members in self-renewal and differentiation of pluripotent stem and teratocarcinoma cells. Two gene clusters including Mage-a4 and Mage-a8, Mageb1, Mage-d1, Mage-d2, Mage-e1, Mage-l2 were identified as functional antagonists with opposing roles in the regulation of proliferation and differentiation of mouse pluripotent stem and teratocarcinoma cells. The identified aberrant expression patterns of Mage-a2, Mage-a6, Mage-b4, Mageb-16 and Mage-h1 in teratocarcinoma cells can be considered as specific teratocarcinoma biomarkers promoted the malignant phenotype. Our study first provides a model for the involvement of Mage family members in regulatory networks during the self-renewal and early differentiation of normal and cancerous stem cells for further research of the predicted functional modules and the development of new cancer treatment strategies.
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