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Das A, Yilmaz O, Yilmaz O, Deshpande V. SOX17: a new therapeutic target for immune evasion of colorectal cancer. J Clin Pathol 2025:jcp-2024-209878. [PMID: 40350244 DOI: 10.1136/jcp-2024-209878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 05/14/2025]
Abstract
Despite advances in cancer immunotherapies across various cancers, survival outcomes in colorectal cancer (CRC) with these agents remain largely unsatisfactory despite the high tumour burden. Colorectal stem cells (CSCs), especially LGR5+ CSCs, are the significant drivers in CRC initiation, progression and resistance to conventional therapies. Although native immune surveillance is sufficient to combat early tumour formation, CRC evades early immune detection with its well-documented adenoma-to-carcinoma sequence. The exact mechanism underlying this phenomenon still needs to be better understood. SRY-related HMG box gene 17 (SOX17), a transcription factor that specifies embryonic gut formation, is increasingly recognised as a significant factor in CRC tumourigenesis. However, its role as a tumour suppressor or oncogene is still debated. Evidence from a recent study highlighted the critical role of SOX17 in reshaping the tumour immune ecosystem through the simultaneous inhibition of CD8+ T cells and selective suppression of LGR5 expression in CSCs through transcriptional repression, thereby facilitating disease progression. Given its role in immune evasion, SOX17 could be a promising marker in personalised therapy. Additionally, SOX17 could play a role in the diagnostic arena, potentially identifying dysplasia in the gastrointestinal tract. Future clinical, basic and genetic studies focusing on SOX17 are needed to ascertain its mechanistic role in tumour immunomodulation in CRC and diagnosing preneoplastic lesions in the gastrointestinal tract.
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Affiliation(s)
- Avash Das
- Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Omer Yilmaz
- Harvard Medical School, Boston, Massachusetts, USA
| | - Osman Yilmaz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Vikram Deshpande
- Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Zhou K, Ma X, Yan T, Zheng H, Xie S, Guo L, Lu R. Stemness-Relevant Gene Signature for Chemotherapeutic Response and Prognosis Prediction in Ovarian Cancer. Stem Cells Int 2025; 2025:2505812. [PMID: 40182754 PMCID: PMC11968171 DOI: 10.1155/sci/2505812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 02/05/2025] [Accepted: 02/21/2025] [Indexed: 04/05/2025] Open
Abstract
Background: Ovarian cancer (OC) stands as the leading cause of cancer-related deaths among women, globally, owing to metastasis and acquired chemoresistance. Cancer stem cells (CSCs) are accountable for tumor initiation and exhibit resistance to chemotherapy and radiotherapy. Identifying stemness-related biomarkers that can aid in the stratification of risk and the response to chemotherapy for OC is feasible and critical. Methods: Gene expression and clinical data of patients with OC were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Four thousand three hundred seventeen stemness-related genes (SRGs) were acquired from the StemChecker database. TCGA was used as the training dataset, while GSE30161 served as validation dataset. Univariate Cox regression analysis was used to identify overall survival (OS)-related SRGs, and multivariate Cox regression analysis and random survival forest analysis were used for generating stemness-relevant prognostic model. Kaplan-Meier plots were used to visualize survival functions. Receiver operating characteristic (ROC) curves were used to assess the prognostic predictive ability of SRG-based features. Associations between signature score, tumor immune phenotype, and response to chemotherapy were analyzed via TIMER 2.0 and oncoPredict R package, respectively. A cohort of Shanghai Cancer Center was employed to verify the predictive robustness of the signature with respect to chemotherapy response. Results: Seven SRGs (actin-binding Rho activating C-terminal like (ABRACL), growth factor receptor bound protein 7 (GRB7), Lin-28 homolog B (LIN28B), lipolysis stimulated lipoprotein receptor (LSR), neuromedin U (NMU), Solute Carrier Family 4 Member 11 (SLC4A11), and thymocyte selection associated family member 2 (THEMIS2)) were found to have excellent predictive potential for patient survival. Patients in the high stemness risk group presented a poorer prognosis (p < 0.0001), and patients with lower stemness scores were more likely to benefit from chemotherapy. Several tumorigenesis pathways, such as mitotic spindle and glycolysis, were enriched in the high stemness risk group. Tumor with high-risk scores tended to be in a status of relatively high tumor infiltration of CD4+ T cells, neutrophils, and macrophages, while tumor with low-risk scores tended to be in a status of relatively high tumor infiltration of CD8+ T cells. Conclusions: The stemness-relevant prognostic gene signature has the potential to serve as a clinically helpful biomarker for guiding the management of OC patients.
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Affiliation(s)
- Kaixia Zhou
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaolu Ma
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Tianqing Yan
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Pan Y, Yuan C, Zeng C, Sun C, Xia L, Wang G, Chen X, Zhang B, Liu J, Ding ZY. Cancer stem cells and niches: challenges in immunotherapy resistance. Mol Cancer 2025; 24:52. [PMID: 39994696 PMCID: PMC11852583 DOI: 10.1186/s12943-025-02265-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 02/06/2025] [Indexed: 02/26/2025] Open
Abstract
Cancer stem cells (CSCs) are central to tumor progression, metastasis, immune evasion, and therapeutic resistance. Characterized by remarkable self-renewal and adaptability, CSCs can transition dynamically between stem-like and differentiated states in response to external stimuli, a process termed "CSC plasticity." This adaptability underpins their resilience to therapies, including immune checkpoint inhibitors and adoptive cell therapies (ACT). Beyond intrinsic properties, CSCs reside in a specialized microenvironment-the CSC niche-which provides immune-privileged protection, sustains their stemness, and fosters immune suppression. This review highlights the critical role of CSCs and their niche in driving immunotherapy resistance, emphasizing the need for integrative approaches to overcome these challenges.
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Affiliation(s)
- Yonglong Pan
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Cellular Signaling laboratory, Key laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Chaoyi Yuan
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chenglong Zeng
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chaoyang Sun
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center, Key Laboratory of the MOE, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Limin Xia
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Guihua Wang
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Tongji Hospital, GI Cancer Research Institute, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Jianfeng Liu
- Cellular Signaling laboratory, Key laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
| | - Ze-Yang Ding
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Chernosky NM, Tamagno I, Polak KL, Chan ER, Yuan X, Jackson MW. Toll-Like receptor 3-mediated interferon-β production is suppressed by oncostatin m and a broader epithelial-mesenchymal transition program. Breast Cancer Res 2024; 26:167. [PMID: 39593161 PMCID: PMC11590466 DOI: 10.1186/s13058-024-01918-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Patients with Triple Negative Breast Cancer (TNBC) currently lack targeted therapies, and consequently face higher mortality rates when compared to patients with other breast cancer subtypes. The tumor microenvironment (TME) cytokine Oncostatin M (OSM) reprograms TNBC cells to a more stem-like/mesenchymal state, conferring aggressive cancer cell properties such as enhanced migration and invasion, increased tumor-initiating capacity, and intrinsic resistance to the current standards of care. In contrast to OSM, Interferon-β (IFN-β) promotes a more differentiated, epithelial cell phenotype in addition to its role as an activator of anti-tumor immunity. Importantly, OSM suppresses the production of IFN-β, although the mechanism of IFN-β suppression has not yet been elucidated. METHODS IFN-β production and downstream autocrine signaling were assessed via quantitative real-time PCR (qRT-PCR) and Western blotting in TNBC cells following exposure to OSM. RNA-sequencing (RNA-seq) was used to assess an IFN-β metagene signature, and to assess the expression of innate immune sensors, which are upstream activators of IFN-β. Cell migration was assessed using an in vitro chemotaxis assay. Additionally, TNBC cells were exposed to TGF-β1, Snail, and Zeb1, and IFN-β production and downstream autocrine signaling were assessed via RNA-seq, qRT-PCR, and Western blotting. RESULTS Here, we identify the repression of Toll-like Receptor 3 (TLR3), an innate immune sensor, as the key molecular event linking OSM signaling and the repression of IFN-β transcription, production, and autocrine IFN signaling. Moreover, we demonstrate that additional epithelial-mesenchymal transition-inducing factors, such as TGF-β1, Snail, and Zeb1, similarly suppress TLR3-mediated IFN-β production and signaling. CONCLUSIONS Our findings provide a novel insight into the regulation of TLR3 and IFN-β production in TNBC cells, which are known indicators of treatment responses to DNA-damaging therapies. Furthermore, strategies to stimulate TLR3 in order to increase IFN-β within the TME may be ineffective in stem-like/mesenchymal cells, as TLR3 is strongly repressed. Rather, we propose that therapies targeting OSM or OSM receptor would reverse the stem-like/mesenchymal program and restore TLR3-mediated IFN-β production within the TME, facilitating improved responses to current therapies.
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Affiliation(s)
- Noah M Chernosky
- Department of Pathology Case, Western Reserve University, Cleveland, OH, 44106, USA
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA
| | - Ilaria Tamagno
- Department of Pathology Case, Western Reserve University, Cleveland, OH, 44106, USA
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA
| | - Kelsey L Polak
- Department of Pathology Case, Western Reserve University, Cleveland, OH, 44106, USA
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA
| | - E Ricky Chan
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA
- Cleveland Institute for Computational Biology, Cleveland, OH, 44106, USA
| | - Xueer Yuan
- Department of Pathology Case, Western Reserve University, Cleveland, OH, 44106, USA
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA
| | - Mark W Jackson
- Department of Pathology Case, Western Reserve University, Cleveland, OH, 44106, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA.
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Malla R, Jyosthsna K, Rani G, Purnachandra Nagaraju G. CD44/PD-L1-mediated networks in drug resistance and immune evasion of breast cancer stem cells: Promising targets of natural compounds. Int Immunopharmacol 2024; 138:112613. [PMID: 38959542 DOI: 10.1016/j.intimp.2024.112613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 06/28/2024] [Accepted: 06/30/2024] [Indexed: 07/05/2024]
Abstract
Cancer stem cells (CSCs) significantly interfere with immunotherapy, leading to challenges such as low response rates and acquired resistance. PD-L1 expression is associated with the CSC population's overexpression of CD44. Mounting evidence suggests that the breast cancer stem cell (BCSC) marker CD44 and the immune checkpoint PD-L1 contribute to treatment failure through their networks. Natural compounds can overcome therapy resistance in breast cancer by targeting mechanisms underlying resistance in BCSCs. This review provides an updated insight into the CD44 and PD-L1 networks of BCSCs in mediating metastasis and immune evasion. The review critically examines existing literature, providing a comprehensive understanding of the topic and emphasizing the impact of natural flavones on the signaling pathways of BCSCs. Additionally, the review discusses the potential of natural compounds in targeting CD44 and PD-L1 in breast cancer (BC). Natural compounds consistently show potential in targeting regulatory mechanisms of BCSCs, inducing loss of stemness, and promoting differentiation. They offer a promising approach for developing alternative therapeutic strategies to manage breast cancer.
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Affiliation(s)
- RamaRao Malla
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, School of Science, GITAM (Deemed to be University), Visakhapatnam 530045, Andhra Pradesh, India; Department of Biochemistry and Bioinformatics, School of Science, GITAM (Deemed to be University), Visakhapatnam 530045, Andhra Pradesh, India.
| | - Kattula Jyosthsna
- Department of Biotechnology, School of Science, GITAM (Deemed to be University), Visakhapatnam 530045, Andhra Pradesh, India
| | - G Rani
- Department of Biotechnology, School of Science, GITAM (Deemed to be University), Visakhapatnam 530045, Andhra Pradesh, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA
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Han H, He T, Wu Y, He T, Zhou W. Multidimensional analysis of tumor stem cells: from biological properties, metabolic adaptations to immune escape mechanisms. Front Cell Dev Biol 2024; 12:1441081. [PMID: 39184916 PMCID: PMC11341543 DOI: 10.3389/fcell.2024.1441081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/25/2024] [Indexed: 08/27/2024] Open
Abstract
As a key factor in tumorigenesis, progression, recurrence and metastasis, the biological properties, metabolic adaptations and immune escape mechanisms of CSCs are the focus of current oncological research. CSCs possess self-renewal, multidirectional differentiation and tumorigenicity, and their mechanisms of action can be elucidated by the clonal evolution, hierarchical model and the dynamic CSCs model, of which the dynamic model is widely recognized due to its better explanation of the function and origin of CSCs. The origin hypothesis of CSCs involves cell-cell fusion, horizontal gene transfer, genomic instability and microenvironmental regulation, which together shape the diversity of CSCs. In terms of classification, CSCs include primary CSCs (pri-CSCs), precancerous stem cells (pre-CSCs), migratory CSCs (mig-CSCs), and chemo-radiotherapy-resistant CSCs (cr-CSCs and rr-CSCs), with each type playing a specific role in tumor progression. Surface markers of CSCs, such as CD24, CD34, CD44, CD90, CD133, CD166, EpCAM, and LGR5, offer the possibility of identifying, isolating, and targeting CSCs, but the instability and heterogeneity of their expression increase the difficulty of treatment. CSCs have adapted to their survival needs through metabolic reprogramming, showing the ability to flexibly switch between glycolysis and oxidative phosphorylation (OXPHOS), as well as adjustments to amino acid and lipid metabolism. The Warburg effect typifies their metabolic profiles, and altered glutamine and fatty acid metabolism further contributes to the rapid proliferation and survival of CSCs. CSCs are able to maintain their stemness by regulating the metabolic networks to maintain their stemness characteristics, enhance antioxidant defences, and adapt to therapeutic stress. Immune escape is another strategy for CSCs to maintain their survival, and CSCs can effectively evade immune surveillance through mechanisms such as up-regulating PD-L1 expression and promoting the formation of an immunosuppressive microenvironment. Together, these properties reveal the multidimensional complexity of CSCs, underscoring the importance of a deeper understanding of the biology of CSCs for the development of more effective tumor therapeutic strategies. In the future, therapies targeting CSCs will focus on precise identification of surface markers, intervention of metabolic pathways, and overcoming immune escape, with the aim of improving the relevance and efficacy of cancer treatments, and ultimately improving patient prognosis.
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Affiliation(s)
- Han Han
- Department of Biochemistry and Molecular Biology, Shenyang Medical College, Shenyang City, China
| | - Ting He
- Department of Pathogen Biology, Shenyang Medical College, Shenyang City, China
| | - Yingfan Wu
- Department of Pathogen Biology, Shenyang Medical College, Shenyang City, China
| | - Tianmei He
- Department of Pathogen Biology, Shenyang Medical College, Shenyang City, China
| | - Weiqiang Zhou
- Department of Pathogen Biology, Shenyang Medical College, Shenyang City, China
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7
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Ali SM, Adnan Y, Ahmad Z, Chawla T, Ali SMA. Significant Association of PD-L1 With CD44 Expression and Patient Survival: Avenues for Immunotherapy and Cancer Stem Cells Downregulation in Pancreatic Cancers. J Cancer Epidemiol 2024; 2024:3448648. [PMID: 39148690 PMCID: PMC11325009 DOI: 10.1155/2024/3448648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/19/2024] [Accepted: 06/24/2024] [Indexed: 08/17/2024] Open
Abstract
Background: Pancreatic cancers are known for their aggressive nature. This aggressiveness may be attributed to the presence of cancer stem cells (CSCs), which promote relapse, metastasis, and resistance to chemotherapy. Targeting CSCs is essential to reverse this aggressiveness in pancreatic malignancies. Literature highlights the association of PD-L1 expression with CSCs in various cancers, suggesting immunotherapy as a promising therapeutic approach. This study is aimed at investigating the potential of immunotherapy in pancreatic cancers by examining its association with selected CSC marker expression. Method: A retrospective cohort study was conducted involving 56 patients with confirmed diagnoses of pancreatic cancers at Aga Khan University Hospital from January 2015 to October 2022. After exclusions, based on refusal to provide consent or incomplete follow-up data, 38 patients were enrolled in the study. Immunohistochemistry was performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue samples to assess the expression of CSC markers (CD133, CD44, and L1CAM) and immune checkpoint inhibitor marker (PD-L1). Statistical analysis was employed to determine associations between marker expression, clinical factors, and overall survival. Results: The study revealed that 86.8% of pancreatic cancer cases exhibited positive PD-L1 expression. Moreover, a significant association of PD-L1 expression was observed with the presence of CD44 protein (p = 0.030), as well as with the overall survival of patients (p = 0.023). Conclusion: Our findings show a significant association of PD-L1 with CD44 marker expression as well as patient survival. This research shows the potential to serve as the foundation for investigating the efficacy of immunotherapy in reducing CD44-expressing CSCs in pancreatic cancer, potentially enhancing patient outcomes.
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Affiliation(s)
| | - Yumna Adnan
- Department of Surgery Aga Khan University Hospital, Karachi, Pakistan
| | - Zubair Ahmad
- Consultant Histopathologist Sultan Qaboos Comprehensive Cancer Care and Research Centre, Seeb, Oman
- Department of Pathology and Laboratory Medicine Aga Khan University Hospital, Karachi, Pakistan
| | - Tabish Chawla
- Department of Surgery Aga Khan University Hospital, Karachi, Pakistan
| | - S M Adnan Ali
- Department of Surgery Aga Khan University Hospital, Karachi, Pakistan
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Zou Z, Luo T, Wang X, Wang B, Li Q. Exploring the interplay between triple-negative breast cancer stem cells and tumor microenvironment for effective therapeutic strategies. J Cell Physiol 2024; 239:e31278. [PMID: 38807378 DOI: 10.1002/jcp.31278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/28/2024] [Accepted: 04/05/2024] [Indexed: 05/30/2024]
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic malignancy with poor treatment outcomes. The interaction between the tumor microenvironment (TME) and breast cancer stem cells (BCSCs) plays an important role in the development of TNBC. Owing to their ability of self-renewal and multidirectional differentiation, BCSCs maintain tumor growth, drive metastatic colonization, and facilitate the development of drug resistance. TME is the main factor regulating the phenotype and metastasis of BCSCs. Immune cells, cancer-related fibroblasts (CAFs), cytokines, mesenchymal cells, endothelial cells, and extracellular matrix within the TME form a complex communication network, exert highly selective pressure on the tumor, and provide a conducive environment for the formation of BCSC niches. Tumor growth and metastasis can be controlled by targeting the TME to eliminate BCSC niches or targeting BCSCs to modify the TME. These approaches may improve the treatment outcomes and possess great application potential in clinical settings. In this review, we summarized the relationship between BCSCs and the progression and drug resistance of TNBC, especially focusing on the interaction between BCSCs and TME. In addition, we discussed therapeutic strategies that target the TME to inhibit or eliminate BCSCs, providing valuable insights into the clinical treatment of TNBC.
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Affiliation(s)
- Zhuoling Zou
- Queen Mary College, Nanchang University, Nanchang, Jiangxi, China
| | - Tinglan Luo
- Department of Oncology, The Seventh People's Hospital of Chongqing (Affiliated Central Hospital of Chongqing University of Technology), Chongqing, China
| | - Xinyuan Wang
- Department of Clinical Medicine, The Second Clinical College of Chongqing Medicine University, Chongqing, China
| | - Bin Wang
- Department of Oncology, The Seventh People's Hospital of Chongqing (Affiliated Central Hospital of Chongqing University of Technology), Chongqing, China
| | - Qing Li
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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9
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Saw PE, Liu Q, Wong PP, Song E. Cancer stem cell mimicry for immune evasion and therapeutic resistance. Cell Stem Cell 2024; 31:1101-1112. [PMID: 38925125 DOI: 10.1016/j.stem.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 03/11/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024]
Abstract
Cancer stem cells (CSCs) are heterogeneous, possess self-renewal attributes, and orchestrate important crosstalk in tumors. We propose that the CSC state represents "mimicry" by cancer cells that leads to phenotypic plasticity. CSC mimicry is suggested as CSCs can impersonate immune cells, vasculo-endothelia, or lymphangiogenic cells to support cancer growth. CSCs facilitate both paracrine and juxtracrine signaling to prime tumor-associated immune and stromal cells to adopt pro-tumoral phenotypes, driving therapeutic resistance. Here, we outline the ingenuity of CSCs' mimicry in their quest to evade immune detection, which leads to immunotherapeutic resistance, and highlight CSC-mimicry-targeted therapeutic strategies for robust immunotherapy.
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Affiliation(s)
- Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China
| | - Qiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping-Pui Wong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Zenith Institute of Medical Sciences, Guangzhou 510120, China.
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10
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Li X, Zhang C, Yue W, Jiang Y. Modulatory effects of cancer stem cell-derived extracellular vesicles on the tumor immune microenvironment. Front Immunol 2024; 15:1362120. [PMID: 38962016 PMCID: PMC11219812 DOI: 10.3389/fimmu.2024.1362120] [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: 12/27/2023] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
Cancer stem cells (CSCs), accounting for only a minor cell proportion (< 1%) within tumors, have profound implications in tumor initiation, metastasis, recurrence, and treatment resistance due to their inherent ability of self-renewal, multi-lineage differentiation, and tumor-initiating potential. In recent years, accumulating studies indicate that CSCs and tumor immune microenvironment act reciprocally in driving tumor progression and diminishing the efficacy of cancer therapies. Extracellular vesicles (EVs), pivotal mediators of intercellular communications, build indispensable biological connections between CSCs and immune cells. By transferring bioactive molecules, including proteins, nucleic acids, and lipids, EVs can exert mutual influence on both CSCs and immune cells. This interaction plays a significant role in reshaping the tumor immune microenvironment, creating conditions favorable for the sustenance and propagation of CSCs. Deciphering the intricate interplay between CSCs and immune cells would provide valuable insights into the mechanisms of CSCs being more susceptible to immune escape. This review will highlight the EV-mediated communications between CSCs and each immune cell lineage in the tumor microenvironment and explore potential therapeutic opportunities.
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Affiliation(s)
- Xinyu Li
- Department of Animal Science, College of Animal Science, Hebei North University, Zhangjiakou, Hebei, China
- Department of Gynecology and Obstetrics, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Cuilian Zhang
- Reproductive Medicine Center, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, China
| | - Wei Yue
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China
| | - Yuening Jiang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China
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11
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Yang K, Yi T. Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy. Front Mol Biosci 2024; 10:1297611. [PMID: 38455361 PMCID: PMC10918437 DOI: 10.3389/fmolb.2023.1297611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/14/2023] [Indexed: 03/09/2024] Open
Abstract
The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.
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Affiliation(s)
- Kangqi Yang
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Tuo Yi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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12
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Su X, Fu C, Liu F, Bian R, Jing P. T-cell exhaustion prediction algorithm in tumor microenvironment for evaluating prognostic stratification and immunotherapy effect of esophageal cancer. ENVIRONMENTAL TOXICOLOGY 2024; 39:592-611. [PMID: 37493251 DOI: 10.1002/tox.23887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/01/2023] [Accepted: 06/29/2023] [Indexed: 07/27/2023]
Abstract
Esophageal cancer (EC) is a common digestive malignancy that ranks sixth in cancer deaths, with a 5-year survival rate of 15%-25%. As a result, reliable prognostic biomarkers are required to accurately predict the prognosis of EC. T-cell exhaustion (TEX) is associated with poorer prognosis and immune infiltration in EC. In this study, nine risk genes were finally screened to constitute the prognostic model using least absolute shrinkage and selection operator analysis. Patients were divided into two groups based on the expression of the TEX-related genes: high-risk group and low-risk group. The expression of TEX-related genes differed significantly between the two groups. The findings revealed that the risk model developed was highly related to the clinical prognosis and amount of immune cell infiltration in EC patients. It was also significantly correlated with the therapeutic sensitivity of multiple chemotherapeutic agents in EC patients. Subsequently, we successfully constructed drug-resistant cell lines KYSE480/CDDP-R and KYSE180/CDDP-R to verify the correlation between PD-1 and drug resistance in EC. Then, we examined the mRNA and protein expression levels of PD-1 in parental and drug-resistant cells using qPCR and WB. It was found that the expression level of PD-1 was significantly increased in the plasma red of drug-resistant cells. Next, we knocked down PD-1 in drug-resistant cells and found that the resistance of EC cells to CDDP was significantly reduced. And the proportion of apoptotic cells in cells treated with 6 μM CDDP for 24 h was significantly in increase. The TEX-based risk model achieved good prediction results for prognosis prediction in EC patients. And it was also significantly associated with the level of immune cell infiltration and drug therapy sensitivity of EC patients. Additionally, the downregulation of PD-1 may be associated with increased drug sensitivity in EC and enhanced T-cell infiltration. The high-risk group had lower TIDE scores, indicating that the high-risk group benefits more after receiving immunotherapy. Thus, the TEX-based risk model can be used as a novel tumor prognostic biomarker.
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Affiliation(s)
- Xiangyu Su
- School of Medicine, Southeast University, Nanjing, China
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Chenchun Fu
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Fei Liu
- Department of Oncology, Luhe People's Hospital of Nanjing, Nanjing, China
| | - Rongrong Bian
- Department of Oncology, Luhe People's Hospital of Nanjing, Nanjing, China
| | - Ping Jing
- Department of Gastroenterology, Luhe People's Hospital of Nanjing, Nanjing, China
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13
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Zhao Q, Zong H, Zhu P, Su C, Tang W, Chen Z, Jin S. Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs. Exp Hematol Oncol 2024; 13:6. [PMID: 38254219 PMCID: PMC10802076 DOI: 10.1186/s40164-024-00474-x] [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: 09/28/2023] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.
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Affiliation(s)
- Qi Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chang Su
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wenxue Tang
- The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jing‑ba Road, Zhengzhou, 450014, China.
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Shuiling Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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14
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Mahanti K, Bhattacharyya S. Rough neighborhood: Intricacies of cancer stem cells and infiltrating immune cell interaction in tumor microenvironment and potential in therapeutic targeting. Transl Res 2023; 265:S1931-5244(23)00176-7. [PMID: 39491179 DOI: 10.1016/j.trsl.2023.10.003] [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: 08/16/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 11/05/2024]
Abstract
Ongoing research on cellular heterogeneity of Cancer stem cells (CSCs) and its synergistic involvement with tumor milieu reveals enormous complexity, resulting in diverse hindrance in immune therapy. CSCs has captured attention for their contribution in shaping of tumor microenvironment and as target for therapeutic intervention. Recent studies have highlighted cell-extrinsic and intrinsic mechanisms of reciprocal interaction between tumor stroma constituents and CSCs. Therapeutic targeting requires an in-depth understanding of the underlying mechanisms involved with the rate limiting factors in tumor aggressiveness and pinpoint role of CSCs. Some of the major constituents of tumor microenvironment includes resident and infiltrating immune cell, both innate and adaptive. Some of these immune cells play crucial role as adjustors of tumor immune response. Tumor-adjustor immune cell interaction confer plasticity and features enabling tumor growth and metastasis in one hand and on the other hand blunts anti-tumor immunity. Detail understanding of CSC and TME resident immune cells interaction can shape new avenues for cancer immune therapy. In this review, we have tried to summarize the development of knowledge on cellular, molecular and functional interaction between CSCs and tumor microenvironment immune cells, highlighting immune-mediated therapeutic strategies aimed at CSCs. We also discussed developing a potential CSC and TME targeted therapeutic avenue.
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Affiliation(s)
- Krishna Mahanti
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India
| | - Sankar Bhattacharyya
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India.
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15
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Lučić I, Kurtović M, Mlinarić M, Piteša N, Čipak Gašparović A, Sabol M, Milković L. Deciphering Common Traits of Breast and Ovarian Cancer Stem Cells and Possible Therapeutic Approaches. Int J Mol Sci 2023; 24:10683. [PMID: 37445860 DOI: 10.3390/ijms241310683] [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: 05/06/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.
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Affiliation(s)
- Ivan Lučić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Matea Kurtović
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Monika Mlinarić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Nikolina Piteša
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Ana Čipak Gašparović
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Lidija Milković
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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Nahas GR, Sherman LS, Sinha G, El Far MH, Petryna A, Munoz SM, Silverio KA, Shaker M, Neopane P, Mariotti V, Rameshwar P. Increased expression of musashi 1 on breast cancer cells has implication to understand dormancy and survival in bone marrow. Aging (Albany NY) 2023; 15:3230-3248. [PMID: 36996499 PMCID: PMC10449290 DOI: 10.18632/aging.204620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 03/13/2023] [Indexed: 03/31/2023]
Abstract
Breast cancer (BC) stem cells (CSCs) resist treatment and can exist as dormant cells in tissues such as the bone marrow (BM). Years before clinical diagnosis, BC cells (BCCs) could migrate from the primary site where the BM niche cells facilitate dedifferentiation into CSCs. Additionally, dedifferentiation could occur by cell autonomous methods. Here we studied the role of Msi 1, a RNA-binding protein, Musashi I (Msi 1). We also analyzed its relationship with the T-cell inhibitory molecule programmed death-ligand 1 (PD-L1) in CSCs. PD-L1 is an immune checkpoint that is a target in immune therapy for cancers. Msi 1 can support BCC growth through stabilization of oncogenic transcripts and modulation of stem cell-related gene expression. We reported on a role for Msi 1 to maintain CSCs. This seemed to occur by the differentiation of CSCs to more matured BCCs. This correlated with increased transition from cycling quiescence and reduced expression of stem cell-linked genes. CSCs co-expressed Msi 1 and PD-L1. Msi 1 knockdown led to a significant decrease in CSCs with undetectable PD-L1. This study has implications for Msi 1 as a therapeutic target, in combination with immune checkpoint inhibitor. Such treatment could also prevent dedifferentiation of breast cancer to CSCs, and to reverse tumor dormancy. The proposed combined treatment might be appropriate for other solid tumors.
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Affiliation(s)
- George R. Nahas
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Lauren S. Sherman
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Garima Sinha
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Markos H. El Far
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Andrew Petryna
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Steven M. Munoz
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Kimberly A. Silverio
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Maran Shaker
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
- Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ 07103, USA
| | - Pujan Neopane
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Veronica Mariotti
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Pranela Rameshwar
- Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
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17
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TRUONG NC, HUYNH NT, PHAM KD, PHAM PV. Roles of cancer stem cells in cancer immune surveillance. MINERVA BIOTECHNOLOGY AND BIOMOLECULAR RESEARCH 2023. [DOI: 10.23736/s2724-542x.23.02944-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
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18
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Montoyo-Pujol YG, García-Escolano M, Ponce JJ, Delgado-García S, Martín TA, Ballester H, Castellón-Molla E, Martínez-Peinado P, Pascual-García S, Sempere-Ortells JM, Peiró G. Variable Intrinsic Expression of Immunoregulatory Biomarkers in Breast Cancer Cell Lines, Mammospheres, and Co-Cultures. Int J Mol Sci 2023; 24:4478. [PMID: 36901916 PMCID: PMC10003642 DOI: 10.3390/ijms24054478] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 02/13/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Advances in immunotherapy have increased interest in knowing the role of the immune system in breast cancer (BC) pathogenesis. Therefore, immune checkpoints (IC) and other pathways related to immune regulation, such as JAK2 and FoXO1, have emerged as potential targets for BC treatment. However, their intrinsic gene expression in vitro has not been extensively studied in this neoplasia. Thus, we evaluated the mRNA expression of tumor-cell-intrinsic CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FoXO1 in different BC cell lines, derived mammospheres, and co-cultures with peripheral blood mononuclear cells (PBMCs) by real-time quantitative polymerase chain reaction (qRT-PCR). Our results showed that intrinsic CTLA-4, CD274 (PD-L1), and PDCD1LG2 (PD-L2) were highly expressed in triple-negative cell lines, while CD276 was predominantly overexpressed in luminal cell lines. In contrast, JAK2 and FoXO1 were under-expressed. Moreover, high levels of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), and JAK2 were found after mammosphere formation. Finally, the interaction between BC cell lines and peripheral blood mononuclear cells (PBMCs) stimulates the intrinsic expression of CTLA-4, PCDC1 (PD1), CD274 (PD-L1), and PDCD1LG2 (PD-L2). In conclusion, the intrinsic expression of immunoregulatory genes seems very dynamic, depending on BC phenotype, culture conditions, and tumor-immune cell interactions.
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Affiliation(s)
- Yoel Genaro Montoyo-Pujol
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Medical Oncology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Marta García-Escolano
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - José J. Ponce
- Medical Oncology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Silvia Delgado-García
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Tina Aurora Martín
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Hortensia Ballester
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Elena Castellón-Molla
- Pathology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Pascual Martínez-Peinado
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
| | - Sandra Pascual-García
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
| | - José Miguel Sempere-Ortells
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Gloria Peiró
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Pathology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
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19
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IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance? Biomedicines 2023; 11:biomedicines11010229. [PMID: 36672737 PMCID: PMC9855361 DOI: 10.3390/biomedicines11010229] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Insulin-like growth factor 2 (IGF2) is upregulated in both childhood and adult malignancies. Its overexpression is associated with resistance to chemotherapy and worse prognosis. However, our understanding of its physiological and pathological role is lagging behind what we know about IGF1. Dysregulation of the expression and function of IGF2 receptors, insulin receptor isoform A (IR-A), insulin growth factor receptor 1 (IGF1R), and their downstream signaling effectors drive cancer initiation and progression. The involvement of IGF2 in carcinogenesis depends on its ability to link high energy intake, increase cell proliferation, and suppress apoptosis to cancer risk, and this is likely the key mechanism bridging insulin resistance to cancer. New aspects are emerging regarding the role of IGF2 in promoting cancer metastasis by promoting evasion from immune destruction. This review provides a perspective on IGF2 and an update on recent research findings. Specifically, we focus on studies providing compelling evidence that IGF2 is not only a major factor in primary tumor development, but it also plays a crucial role in cancer spread, immune evasion, and resistance to therapies. Further studies are needed in order to find new therapeutic approaches to target IGF2 action.
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20
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Alwosaibai K, Aalmri S, Mashhour M, Ghandorah S, Alshangiti A, Azam F, Selwi W, Gharaibeh L, Alatawi Y, Alruwaii Z, Alsaab HO. PD-L1 is highly expressed in ovarian cancer and associated with cancer stem cells populations expressing CD44 and other stem cell markers. BMC Cancer 2023; 23:13. [PMID: 36604635 PMCID: PMC9814309 DOI: 10.1186/s12885-022-10404-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 12/05/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors, including PD-L1 (programmed death ligand-1) inhibitors have well documented anticancer therapeutic effect in most types of cancers but its use in the treatment of ovarian cancer is not yet proven. The aim of our study is to explore the predictive biomarkers in ovarian cancer and its association with the outcomes. We have investigated the role of PD-L1 expressions in the tumor microenvironment cells including immune cells and cancer stem cells in different types of ovarian cancer. METHODS A total of 119 surgical archived ovarian cancer samples were collected from the pathology department at King Fahad Specialist Hospital, Dammam, Saudi Arabia that included serous carcinomas, clear cell carcinomas, mucinous carcinomas, endometrioid carcinomas, and granulosa cell tumors. Immunohistochemistry (IHC) staining was performed using (i) PD-L1 antibodies to detect PD-L1 expressions; (ii) CD8 and CD4 to detect Tumor Infiltrating Lymphocytes (TILs); and (iii) CD44, LGR5, and ALDH2 to detect stem cell markers. The clinicopathological data were collected from patients' medical record to investigate the association with PD-L1, TILs, and stem cells expressions. RESULTS We report high PD-L1 expressions in 47.8% of ovarian cancer samples. PD-L1 expressions were detected in different types of epithelial ovarian cancer and were not associated with poor prognosis of ovarian cancer. However, determining the expression levels of TILs in the ovarian cancer tissues found that 81% (n = 97) of ovarian cancer samples have TILs that express both of CD8 and CD4 and significantly associated with high PD-L1 expressions. Interestingly, we have found that ovarian cancer tissues with high expressions of PD-L1 were associated with high expressions of stem cells expressing CD44 and LGR5. CONCLUSIONS PD-L1 is highly expressed in the serous type of ovarian carcinomas and the overall expression of PD-L1 is not associated with poor survival rate. Furthermore, PD-L1 expressions are strongly associated with TILs and stem cell markers in ovarian cancer. Inhibiting the PD-L1 using immune checkpoint inhibitors might downregulate stem cell population that known to be associated with cancer recurrence.
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Affiliation(s)
- Kholoud Alwosaibai
- grid.415280.a0000 0004 0402 3867Research Center, Biomedical Research Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Salmah Aalmri
- grid.415280.a0000 0004 0402 3867Research Center, Biomedical Research Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Miral Mashhour
- grid.415280.a0000 0004 0402 3867Department of Pathology and Lab Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Salim Ghandorah
- grid.415280.a0000 0004 0402 3867Department of Pathology and Lab Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Abdulraheem Alshangiti
- grid.415280.a0000 0004 0402 3867Department of Medical Oncology, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Faisal Azam
- grid.415280.a0000 0004 0402 3867Department of Medical Oncology, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Waleed Selwi
- grid.415280.a0000 0004 0402 3867Department of Medical Oncology, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Lubna Gharaibeh
- grid.116345.40000000406441915Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
| | - Yasser Alatawi
- grid.440760.10000 0004 0419 5685Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Zainab Alruwaii
- Department of Anatomic Pathology, Dammam Regional Laboratory and Blood Bank, Dammam, Saudi Arabia
| | - Hashem O. Alsaab
- grid.412895.30000 0004 0419 5255Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O BOX 11099, Taif, Saudi Arabia
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21
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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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22
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Gu Y, Bobrin V, Zhang D, Sun B, Ng CK, Chen SPR, Gu W, Monteiro MJ. RGD-Coated Polymer Nanoworms for Enriching Cancer Stem Cells. Cancers (Basel) 2022; 15:cancers15010234. [PMID: 36612229 PMCID: PMC9818073 DOI: 10.3390/cancers15010234] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/24/2022] [Accepted: 12/25/2022] [Indexed: 01/04/2023] Open
Abstract
Cancer stem cells (CSCs) are primarily responsible for tumour drug resistance and metastasis; thus, targeting CSCs can be a promising approach to stop cancer recurrence. However, CSCs are small in numbers and readily differentiate into matured cancer cells, making the study of their biological features, including therapeutic targets, difficult. The use of three-dimensional (3D) culture systems to enrich CSCs has some limitations, including low sphere forming efficiency, enzymatic digestion that may damage surface proteins, and more importantly no means to sustain the stem properties. A responsive 3D polymer extracellular matrix (ECM) system coated with RGD was used to enrich CSCs, sustain stemness and avoid enzymatic dissociation. RGD was used as a targeting motif and a ligand to bind integrin receptors. We found that the system was able to increase sphere forming efficiency, promote the growth of spheric cells, and maintain stemness-associated properties compared to the current 3D culture. We showed that continuous culture for three generations of colon tumour spheroid led to the stem marker CD24 gradually increasing. Furthermore, the new system could enhance the cancer cell sphere forming ability for the difficult triple negative breast cancer cells, MBA-MD-231. The key stem gene expression for colon cancer also increased with the new system. Further studies indicated that the concentration of RGD, especially at high doses, could inhibit stemness. Taken together, our data demonstrate that our RGD-based ECM system can facilitate the enrichment of CSCs and now allow for the investigation of new therapeutic approaches for colorectal cancer or other cancers.
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Affiliation(s)
- Yushu Gu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Valentin Bobrin
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Dayong Zhang
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
- Department of Clinical Medicine, Zhejiang University City College, Hangzhou 310015, China
| | - Bing Sun
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Chun Ki Ng
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Sung-Po R. Chen
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
| | - Wenyi Gu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
- Correspondence: (W.G.); (M.J.M.)
| | - Michael J. Monteiro
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane, QLD 4072, Australia
- Correspondence: (W.G.); (M.J.M.)
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23
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Lee-Theilen M, Fadini DD, Hadhoud JR, van Dongen F, Kroll G, Rolle U, Fiegel HC. Hepatoblastoma Cancer Stem Cells Express PD-L1, Reveal Plasticity and Can Emerge upon Chemotherapy. Cancers (Basel) 2022; 14:5825. [PMID: 36497307 PMCID: PMC9736435 DOI: 10.3390/cancers14235825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
The biology of cancer stem cells (CSCs) of pediatric cancers, such as hepatoblastoma, is sparsely explored. This is mainly due to the very immature nature of these tumors, which complicates the distinction of CSCs from the other tumor cells. Previously, we identified a CSC population in hepatoblastoma cell lines expressing the CSC markers CD34 and CD90, cell surface Vimentin (csVimentin) and binding of OV-6. In this study, we detected the co-expression of the immune escape factor PD-L1 in the CSC population, whereas the other tumor cells remained negative. FACS data revealed that non-CSCs give rise to CSCs, reflecting plasticity of CSCs and non-CSCs in hepatoblastoma as seen in other tumors. When we treated cells with cisplatin and decitabine, a new CD34+/lowOV-6lowCD90+ population emerged that lacked csVimentin and PD-L1 expression. Expression analyses showed that this new CSC subset shared similar pluripotency and EMT features with the already-known CSCs. FACS results further revealed that this subset is also generated from non-CSCs. In conclusion, we showed that hepatoblastoma CSCs express PD-L1 and that the biology of hepatoblastoma CSCs is of a plastic nature. Chemotherapeutic treatment leads to another CSC subset, which is highly chemoresistant and could be responsible for a poor prognosis after postoperative chemotherapy.
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Affiliation(s)
- Mieun Lee-Theilen
- Department of Pediatric Surgery and Pediatric Urology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany
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24
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Qi Y, Zou H, Zhao X, Kapeleris J, Monteiro M, Li F, Xu ZP, Deng Y, Wu Y, Tang Y, Gu W. Inhibition of colon cancer K-RasG13D mutation reduces cancer cell proliferation but promotes stemness and inflammation via RAS/ERK pathway. Front Pharmacol 2022; 13:996053. [PMID: 36386200 PMCID: PMC9650442 DOI: 10.3389/fphar.2022.996053] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 10/13/2022] [Indexed: 11/28/2022] Open
Abstract
K-Ras is a well-studied oncogene, and its mutation is frequently found in epithelial cancers like pancreas, lung, and colorectal cancers. Cancer cells harboring K-Ras mutations are difficult to treat due to the drug resistance and metastasis properties. Cancer stem cells (CSCs) are believed the major cause of chemotherapeutic resistance and responsible for tumor recurrence and metastasis. But how K-Ras mutation affects CSCs and inflammation is not clear. Here, we compared two colon cancer cell lines, HCT-116 and HT-29, with the former being K-RasG13D mutant and the latter being wildtype. We found that HCT-116 cells treated with a K-Ras mutation inhibitor S7333 formed significantly more tumor spheroids than the untreated control, while the wild type of HT-29 cells remained unchanged. However, the size of tumor spheroids was smaller than the untreated controls, indicating their proliferation was suppressed after S7333 treatment. Consistent with this, the expressions of stem genes Lgr5 and CD133 significantly increased and the expression of self-renewal gene TGF-β1 also increased. The flow cytometry analysis indicated that the expression of stem surface marker CD133 increased in the treated HCT-116 cells. To understand the pathway through which the G13D mutation induced the effects, we studied both RAS/ERK and PI3K/Akt pathways using specific inhibitors SCH772984 and BEZ235. The results indicated that RAS/ERK rather than PI3K/Akt pathway was involved. As CSCs play the initial role in cancer development and the inflammation is a vital step during tumor initiation, we analyzed the correlation between increased stemness and inflammation. We found a close correlation of increased Lgr5 and CD133 with proinflammatory factors like IL-17, IL-22, and IL-23. Together, our findings suggest that K-RasG13D mutation promotes cancer cell growth but decreases cancer stemness and inflammation thus tumorigenesis and metastasis potential in colon cancer. Inhibition of this mutation reverses the process. Therefore, care needs be taken when employing targeted therapies to K-RasG13D mutations in clinics.
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Affiliation(s)
- Yan Qi
- Department of Pathology, Central People’s Hospital of Zhanjiang and Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Brisbane, QLD, Australia
| | - Hong Zou
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Brisbane, QLD, Australia
- Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - XiaoHui Zhao
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Brisbane, QLD, Australia
| | - Joanna Kapeleris
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Brisbane, QLD, Australia
| | - Michael Monteiro
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Brisbane, QLD, Australia
| | - Feng Li
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhi Ping Xu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Brisbane, QLD, Australia
| | - Yizhen Deng
- Gillion Biotherapeutics Ltd., Guangzhou Huangpu Industrial Zoon, Guangzhou, China
| | - Yanheng Wu
- Gillion Biotherapeutics Ltd., Guangzhou Huangpu Industrial Zoon, Guangzhou, China
| | - Ying Tang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Ying Tang, ; Wenyi Gu,
| | - Wenyi Gu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Brisbane, QLD, Australia
- Gillion Biotherapeutics Ltd., Guangzhou Huangpu Industrial Zoon, Guangzhou, China
- *Correspondence: Ying Tang, ; Wenyi Gu,
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25
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Gupta G, Merhej G, Saravanan S, Chen H. Cancer resistance to immunotherapy: What is the role of cancer stem cells? CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:981-994. [PMID: 36627890 PMCID: PMC9771758 DOI: 10.20517/cdr.2022.19] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 08/08/2022] [Accepted: 09/19/2022] [Indexed: 11/06/2022]
Abstract
Immunotherapy is an emerging form of cancer therapy that is associated with promising outcomes. However, most cancer patients either do not respond to immunotherapy or develop resistance to treatment. The resistance to immunotherapy is poorly understood compared to chemotherapy and radiotherapy. Since immunotherapy targets cells within the tumor microenvironment, understanding the behavior and interactions of different cells within that environment is essential to adequately understand both therapy options and therapy resistance. This review focuses on reviewing and analyzing the special features of cancer stem cells (CSCs), which we believe may contribute to cancer resistance to immunotherapy. The mechanisms are classified into three main categories: mechanisms related to surface markers which are differentially expressed on CSCs and help CSCs escape from immune surveillance and immune cells killing; mechanisms related to CSC-released cytokines which can recruit immune cells and tame hostile immune responses; and mechanisms related to CSC metabolites which modulate the activities of infiltrated immune cells in the tumor microenvironment. This review also discusses progress made in targeting CSCs with immunotherapy and the prospect of developing novel cancer therapies.
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Affiliation(s)
| | | | | | - Hexin Chen
- Correspondence to: Dr. Hexin Chen, Department of Biological Science, University of South Carolina, 715 Sumter Street, PSC621, Columbia, SC 29205, USA. E-mail:
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26
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Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L, Wang S. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol 2022; 13:964442. [PMID: 36177034 PMCID: PMC9513184 DOI: 10.3389/fimmu.2022.964442] [Citation(s) in RCA: 257] [Impact Index Per Article: 85.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Programmed cell death protein-1 (PD-1) is a checkpoint receptor expressed on the surface of various immune cells. PD-L1, the natural receptor for PD-1, is mainly expressed in tumor cells. Studies have indicated that PD-1 and PD-L1 are closely associated with the progression of human cancers and are promising biomarkers for cancer therapy. Moreover, the interaction of PD-1 and PD-L1 is one of the important mechanism by which human tumors generate immune escape. This article provides a review on the role of PD-L1/PD-1, mechanisms of immune response and resistance, as well as immune-related adverse events in the treatment of anti-PD-1/PD-L1 immunotherapy in human cancers. Moreover, we summarized a large number of clinical trials to successfully reveal that PD-1/PD-L1 Immune-checkpoint inhibitors have manifested promising therapeutic effects, which have been evaluated from different perspectives, including overall survival, objective effective rate and medium progression-free survival. Finally, we pointed out the current problems faced by PD-1/PD-L1 Immune-checkpoint inhibitors and its future prospects. Although PD-1/PD-L1 immune checkpoint inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. Combination therapy and predictive models based on integrated biomarker determination theory may be the future directions for the application of PD-1/PD-L1 Immune-checkpoint inhibitors in treating human cancers.
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Affiliation(s)
- Qing Tang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yun Chen
- Department of Organ Transplantation, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaojuan Li
- Institute of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shunqin Long
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yao Shi
- Department of Cerebrovascular Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaya Yu
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Wanyin Wu
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Sumei Wang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
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27
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Wang L, Jin Z, Master RP, Maharjan CK, Carelock ME, Reccoppa TBA, Kim MC, Kolb R, Zhang W. Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications. Cancers (Basel) 2022; 14:3287. [PMID: 35805056 PMCID: PMC9265870 DOI: 10.3390/cancers14133287] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/02/2022] [Accepted: 07/02/2022] [Indexed: 02/01/2023] Open
Abstract
Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.
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Affiliation(s)
- Lei Wang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Immunology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Zeng Jin
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Cancer Biology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Rohan P. Master
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Chandra K. Maharjan
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Madison E. Carelock
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Cancer Biology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Tiffany B. A. Reccoppa
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Department of Biology, College of Liberal Arts & Sciences, University of Florida, Gainesville, FL 32610, USA
| | - Myung-Chul Kim
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
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28
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Vien LT, Nga NT, Hue PTK, Kha THB, Hoang NH, Hue PT, Thien PN, Huang CYF, Van Kiem P, Thao DT. A New Liposomal Formulation of Hydrogenated Anacardic Acid to Improve Activities Against Cancer Stem Cells. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221105696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Anacardic acid (AA) is a natural active ingredient that accounts for 65% of the liquid extract from the shell of the cashew nut. Due to the stronger cytotoxic activity of hydrogenated AA (HAA) against NTERA-2 cancer stem cells (CSCs) than AA itself, HAA was co-conjugated with CD133 monoclonal antibody (mAb^CD133) into nanoliposomal particles (AMC). This nanoliposomal complex is expected to improved HAA activities against CSCs based on the targeting capacity of mAb^CD133 toward CD133, a typical CSCs’ surface marker. AMC was manufactured with a mean size of 100.9 nm, a zeta potential of −40.7 mV, and a PDI of 0.283. We report a 100% encapsulation efficiency of HAA into liposomes and a 90.7% conjugation efficiency with mAb^CD133. The penetration of AMC into NTERA-2 CSCs after 2 h was 83.7%. The AMC complex inhibited NTERA-2 growth with an IC50 (inhibition concentration at 50%) value of 75.83 ± 6.70 µM, showing the targeting ability and lower toxicity (IC50 > 100 µM) on healthy cells. The AMC nanoparticles also demonstrated significant potential apoptotic induction by activating caspase 3 activity by up to 2.57 and 2.06 folds compared to that of the negative control at 20 and 4 µM, respectively. This induction was significant improvement in comparison with that of unconjugated HAA ( P < .05). AMC presented a clear effect on the solid structure of NTERA-2 spheroids and significantly suppressed the proliferation of CSCs in the 3D tumorspheres with an IC50 = 64.25 ± 3.15 µM, compared to the free form with an IC50 = 82.22 ± 0.65 µM ( P < .05). Therefore, this nanoliposomal complex exhibits promising capacities as an effective material against NTERA-2 CSCs.
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Affiliation(s)
- Le Tri Vien
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Health Research and Educational Development in Central Highlands, Pleiku City, Gia Lai, Vietnam
| | - Nguyen Thi Nga
- Institute of Biotechnology, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Phung Thi Kim Hue
- Institute of Health Research and Educational Development in Central Highlands, Pleiku City, Gia Lai, Vietnam
| | | | | | - Pham Thi Hue
- Huynh Man Dat High School for the Gifted, Kien Giang, Vietnam
| | - Pham Ngoc Thien
- Huynh Man Dat High School for the Gifted, Kien Giang, Vietnam
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Phan Van Kiem
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Do Thi Thao
- Institute of Biotechnology, Vietnam Academy of Science and Technology, Hanoi, Vietnam
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29
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Ruiu R, Di Lorenzo A, Cavallo F, Conti L. Are Cancer Stem Cells a Suitable Target for Breast Cancer Immunotherapy? Front Oncol 2022; 12:877384. [PMID: 35530300 PMCID: PMC9069673 DOI: 10.3389/fonc.2022.877384] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/21/2022] [Indexed: 11/13/2022] Open
Abstract
There is substantial evidence to suggest that complete tumor eradication relies on the effective elimination of cancer stem cells (CSCs). CSCs have been widely described as mediators of resistance to conventional therapies, including chemo- and radiotherapy, as well as of tumor metastasization and relapse in different tumor types, including breast cancer. However, the resistant phenotype of CSCs makes their targeting a tough task, and immunotherapy may therefore be an interesting option. Nevertheless, although immunotherapeutic approaches to cancer treatment have generated great enthusiasm due to recent success in clinics, breast cancer treatment mostly relies on standard approaches. In this context, we review the existing literature on the immunological properties of breast CSC and immunotherapeutic approaches to them. We will thus attempt to clarify whether there is room for the immunotargeting of breast CSCs in the current landscape of breast cancer therapies. Finally, we will provide our opinion on the CSC-targeting immunotherapeutic strategies that could prospectively be attempted.
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Affiliation(s)
| | | | - Federica Cavallo
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
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30
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Xu C, Jin G, Wu H, Cui W, Wang YH, Manne RK, Wang G, Zhang W, Zhang X, Han F, Cai Z, Pan BS, Hsu CC, Liu Y, Zhang A, Long J, Zou H, Wang S, Ma X, Duan J, Wang B, Liu W, Lan H, Xiong Q, Xue G, Chen Z, Xu Z, Furth ME, Haigh Molina S, Lu Y, Xie D, Bian XW, Lin HK. SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling. J Clin Invest 2022; 132:141797. [PMID: 35229723 PMCID: PMC8884909 DOI: 10.1172/jci141797] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 01/12/2022] [Indexed: 12/25/2022] Open
Abstract
Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/– tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint–initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.
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Affiliation(s)
- Chuan Xu
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.,Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China.,Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Guoxiang Jin
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.,Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China.,Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hong Wu
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China.,Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Wei Cui
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China.,School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Yu-Hui Wang
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Rajesh Kumar Manne
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Guihua Wang
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Weina Zhang
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Xian Zhang
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Fei Han
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Zhen Cai
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Bo-Syong Pan
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Che-Chia Hsu
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Yiqiang Liu
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Anmei Zhang
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Jie Long
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Hongbo Zou
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China.,Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shuang Wang
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China.,Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaodan Ma
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jinling Duan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Bin Wang
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Weihui Liu
- Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Haitao Lan
- Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qing Xiong
- Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gang Xue
- Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Zhongzhu Chen
- Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, Chongqing, China
| | - Zhigang Xu
- Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, Chongqing, China
| | - Mark E Furth
- Wake Forest Innovations, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA
| | - Sarah Haigh Molina
- Wake Forest Innovations, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA
| | - Yong Lu
- Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Dan Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Hui-Kuan Lin
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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31
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Singh D, Khan MA, Siddique HR. Specific targeting of cancer stem cells by immunotherapy: A possible stratagem to restrain cancer recurrence and metastasis. Biochem Pharmacol 2022; 198:114955. [PMID: 35181312 DOI: 10.1016/j.bcp.2022.114955] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
Abstract
Cancer stem cells (CSCs), the tumor-initiating cells playing a crucial role in cancer progression, recurrence, and metastasis, have the intrinsic property of self-renewal and therapy resistance. The tumorigenic properties of these cells include generation of cellular heterogeneity and immuno-suppressive tumor microenvironment (TME), conferring them the capability to resist a variety of anti-cancer therapeutics. Further, CSCs possess several unique immunological properties that help them escape recognition by the innate and adaptive immune system and shape a TME into a pro-tumorigenic and immunosuppressive landscape. In this context, immunotherapy is considered one of the best therapeutic options for eliminating CSCs to halt cancer recurrence and metastasis. In this review, we discuss the various immunomodulatory properties of CSCs and the interaction of CSCs with the immune system enabling immune evasion. In addition, we also highlight the present research update on immunotherapeutic targeting of CSCs and the possible further scope of research on this topic. We believe that a deeper understanding of CSCs' immunological properties and the crosstalk between CSCs and the immune system can develop better innovative immune-therapeutics and enhance the efficacy of current therapy-resistant cancer treatments.
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Affiliation(s)
- Deepti Singh
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Mohammad Afsar Khan
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Hifzur R Siddique
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India.
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32
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Lewuillon C, Laguillaumie MO, Quesnel B, Idziorek T, Touil Y, Lemonnier L. Put in a “Ca2+ll” to Acute Myeloid Leukemia. Cells 2022; 11:cells11030543. [PMID: 35159351 PMCID: PMC8834247 DOI: 10.3390/cells11030543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/28/2022] [Accepted: 02/01/2022] [Indexed: 02/05/2023] Open
Abstract
Acute myeloid leukemia (AML) is a clonal disorder characterized by genetic aberrations in myeloid primitive cells (blasts) which lead to their defective maturation/function and their proliferation in the bone marrow (BM) and blood of affected individuals. Current intensive chemotherapy protocols result in complete remission in 50% to 80% of AML patients depending on their age and the AML type involved. While alterations in calcium signaling have been extensively studied in solid tumors, little is known about the role of calcium in most hematologic malignancies, including AML. Our purpose with this review is to raise awareness about this issue and to present (i) the role of calcium signaling in AML cell proliferation and differentiation and in the quiescence of hematopoietic stem cells; (ii) the interplay between mitochondria, metabolism, and oxidative stress; (iii) the effect of the BM microenvironment on AML cell fate; and finally (iv) the mechanism by which chemotherapeutic treatments modify calcium homeostasis in AML cells.
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Affiliation(s)
- Clara Lewuillon
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Marie-Océane Laguillaumie
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Bruno Quesnel
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Thierry Idziorek
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Yasmine Touil
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (C.L.); (M.-O.L.); (B.Q.); (T.I.); (Y.T.)
| | - Loïc Lemonnier
- Univ. Lille, Inserm, U1003—PHYCEL—Physiologie Cellulaire, F-59000 Lille, France
- Laboratory of Excellence, Ion Channels Science and Therapeutics, F-59655 Villeneuve d’Ascq, France
- Correspondence:
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33
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Cao L, Bridle KR, Shrestha R, Prithviraj P, Crawford DHG, Jayachandran A. CD73 and PD-L1 as Potential Therapeutic Targets in Gallbladder Cancer. Int J Mol Sci 2022; 23:ijms23031565. [PMID: 35163489 PMCID: PMC8836068 DOI: 10.3390/ijms23031565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/21/2022] [Accepted: 01/28/2022] [Indexed: 12/24/2022] Open
Abstract
Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract cancers with a dismal prognosis. Ongoing clinical trials are evaluating a few selected immune checkpoint inhibitors (ICIs) as monotherapy for the treatment of GBC patients. However, only a subset of patients benefits from these treatments. To improve ICI therapy response, molecular mechanisms that confer resistance to immune checkpoint (IC) blockade needs to be explored. Epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs) have been implicated as key processes that confer ICI treatment resistance. However, in GBC the EMT-CSC-IC axis has not yet been clearly elucidated. This study aims to examine the aberrant expression of ICs associated with CSC and EMT. We successfully enriched CSCs by utilizing a 3-dimensional culture system and established a reversible EMT model with human GBC NOZ cell line. Notably, ICs CD73 and PD-L1 were closely associated with both CSC and EMT phenotypes. Knockdown of CD73 or PD-L1 reduced the proliferative and motile abilities of both adherent monolayers and anchorage-free spheroids. In conclusion, blocking CD73 and PD-L1 offer a promising therapeutic strategy for targeting highly aggressive populations with CSC and EMT phenotype to improve GBC patient prognosis.
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Affiliation(s)
- Lu Cao
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Kim R. Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Ritu Shrestha
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | | | - Darrell H. G. Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Aparna Jayachandran
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (L.C.); (K.R.B.); (R.S.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia;
- Correspondence:
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34
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Jovanovic MZ, Geller DA, Gajovic NM, Jurisevic MM, Arsenijevic NN, Jovanovic MM, Supic GM, Vojvodic DV, Jovanovic IP. Dual blockage of PD-L/PD-1 and IL33/ST2 axes slows tumor growth and improves antitumor immunity by boosting NK cells. Life Sci 2022; 289:120214. [PMID: 34890591 DOI: 10.1016/j.lfs.2021.120214] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/11/2021] [Accepted: 12/01/2021] [Indexed: 12/09/2022]
Abstract
AIMS Although separate blockage of either IL33/ST2 or PD-L/PD-1 axes has been shown to be beneficial in many tumors, co-blockage of IL33/ST2 and PD-L/PD-1 hasn't been studied yet. MAIN METHODS 4T1 breast cancer and CT26 colon cancer were inducted in BALB/C wild type (WT) and BALB/C ST2 knockout mice, after which mice underwent anti PD-1 and anti IL-33 treatment. KEY FINDINGS Co-blockage of IL33/ST2 and PD-L/PD-1 delayed tumor appearance and slowed tumor growth. Enhanced NK cell cytotoxicity against 4T1 tumor cells in ST2 knockout anti-PD-1 treated mice was associated with overexpression of miRNA-150 and miRNA-155, upregulation of NFκB and STAT3, increased expression of activation markers and decreased expression of immunosuppressive markers in splenic and primary tumor derived NK cells. NK cells from ST2 knockout anti-PD-1 treated mice tend to proliferate more and are less prone to apoptosis. Accumulation of immunosuppressive myeloid derived suppressor cells and regulatory T cells was significantly impaired in spleen and primary tumor of ST2 knockout anti-PD-1 treated mice. SIGNIFICANCE Co-blockage of IL3/ST2 and PD-L/PD-1 axes impedes tumor progression more efficiently than single blockage of either axes, thus offering potential new approach to immunotherapy of tumors.
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Affiliation(s)
- Marina Z Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia
| | - David A Geller
- Department of Surgery, University of Pittsburgh, 3459 Fifth Avenue, UPMC Montefiore, 7 South Pittsburgh, PA 15213 2582, USA.
| | - Nevena M Gajovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia
| | - Milena M Jurisevic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, SvetozaraMarkovica 69, 34000 Kragujevac, Serbia.
| | - Nebojsa N Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia
| | - Milan M Jovanovic
- Department of Abdominal Surgery, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia.
| | - Gordana M Supic
- Institute for Medical Research, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia; Medical Faculty of Military Medical Academy, University of Defense, Crnotravska 17, 11000 Belgrade, Serbia.
| | - Danilo V Vojvodic
- Institute for Medical Research, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia; Medical Faculty of Military Medical Academy, University of Defense, Crnotravska 17, 11000 Belgrade, Serbia.
| | - Ivan P Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia.
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Odri GA, Tchicaya-Bouanga J, Yoon DJY, Modrowski D. Metastatic Progression of Osteosarcomas: A Review of Current Knowledge of Environmental versus Oncogenic Drivers. Cancers (Basel) 2022; 14:cancers14020360. [PMID: 35053522 PMCID: PMC8774233 DOI: 10.3390/cancers14020360] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Osteosarcomas are heterogeneous bone tumors with complex genetic and chromosomic alterations. The numerous patients with metastatic osteosarcoma have a very poor prognosis, and only those who can have full surgical resection of the primary tumor and of all the macro metastasis can survive. Despite the recent improvements in prediction and early detection of metastasis, big efforts are still required to understand the specific mechanisms of osteosarcoma metastatic progression, in order to reveal novel therapeutic targets. Abstract Metastases of osteosarcomas are heterogeneous. They may grow simultaneously with the primary tumor, during treatment or shortly after, or a long time after the end of the treatment. They occur mainly in lungs but also in bone and various soft tissues. They can have the same histology as the primary tumor or show a shift towards a different differentiation path. However, the metastatic capacities of osteosarcoma cells can be predicted by gene and microRNA signatures. Despite the identification of numerous metastasis-promoting/predicting factors, there is no efficient therapeutic strategy to reduce the number of patients developing a metastatic disease or to cure these metastatic patients, except surgery. Indeed, these patients are generally resistant to the classical chemo- and to immuno-therapy. Hence, the knowledge of specific mechanisms should be extended to reveal novel therapeutic approaches. Recent studies that used DNA and RNA sequencing technologies highlighted complex relations between primary and secondary tumors. The reported results also supported a hierarchical organization of the tumor cell clones, suggesting that cancer stem cells are involved. Because of their chemoresistance, their plasticity, and their ability to modulate the immune environment, the osteosarcoma stem cells could be important players in the metastatic process.
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Affiliation(s)
- Guillaume Anthony Odri
- INSERM UMR 1132, Biologie de l’os et du Cartilage (BIOSCAR), Lariboisière Hospital, UFR de Médecine, Faculté de Santé, University of Paris, 75010 Paris, France; (J.T.-B.); (D.J.Y.Y.); (D.M.)
- Service de Chirurgie Orthopédique et Traumatologique, DMU Locomotion, Lariboisière Hospital, 75010 Paris, France
- Correspondence:
| | - Joëlle Tchicaya-Bouanga
- INSERM UMR 1132, Biologie de l’os et du Cartilage (BIOSCAR), Lariboisière Hospital, UFR de Médecine, Faculté de Santé, University of Paris, 75010 Paris, France; (J.T.-B.); (D.J.Y.Y.); (D.M.)
| | - Diane Ji Yun Yoon
- INSERM UMR 1132, Biologie de l’os et du Cartilage (BIOSCAR), Lariboisière Hospital, UFR de Médecine, Faculté de Santé, University of Paris, 75010 Paris, France; (J.T.-B.); (D.J.Y.Y.); (D.M.)
- Service de Chirurgie Orthopédique et Traumatologique, DMU Locomotion, Lariboisière Hospital, 75010 Paris, France
| | - Dominique Modrowski
- INSERM UMR 1132, Biologie de l’os et du Cartilage (BIOSCAR), Lariboisière Hospital, UFR de Médecine, Faculté de Santé, University of Paris, 75010 Paris, France; (J.T.-B.); (D.J.Y.Y.); (D.M.)
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Wang M, Chen S, Ao D. Targeting DNA repair pathway in cancer: Mechanisms and clinical application. MedComm (Beijing) 2021; 2:654-691. [PMID: 34977872 PMCID: PMC8706759 DOI: 10.1002/mco2.103] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 02/05/2023] Open
Abstract
Over the last decades, the growing understanding on DNA damage response (DDR) pathways has broadened the therapeutic landscape in oncology. It is becoming increasingly clear that the genomic instability of cells resulted from deficient DNA damage response contributes to the occurrence of cancer. One the other hand, these defects could also be exploited as a therapeutic opportunity, which is preferentially more deleterious in tumor cells than in normal cells. An expanding repertoire of DDR-targeting agents has rapidly expanded to inhibitors of multiple members involved in DDR pathways, including PARP, ATM, ATR, CHK1, WEE1, and DNA-PK. In this review, we sought to summarize the complex network of DNA repair machinery in cancer cells and discuss the underlying mechanism for the application of DDR inhibitors in cancer. With the past preclinical evidence and ongoing clinical trials, we also provide an overview of the history and current landscape of DDR inhibitors in cancer treatment, with special focus on the combination of DDR-targeted therapies with other cancer treatment strategies.
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Affiliation(s)
- Manni Wang
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Siyuan Chen
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Danyi Ao
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
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37
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Cao J, Bhatnagar S, Wang J, Qi X, Prabha S, Panyam J. Cancer stem cells and strategies for targeted drug delivery. Drug Deliv Transl Res 2021; 11:1779-1805. [PMID: 33095384 PMCID: PMC8062588 DOI: 10.1007/s13346-020-00863-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2020] [Indexed: 12/23/2022]
Abstract
Cancer stem cells (CSCs) are a small proportion of cancer cells with high tumorigenic activity, self-renewal ability, and multilineage differentiation potential. Standard anti-tumor therapies including conventional chemotherapy, radiation therapy, and molecularly targeted therapies are not effective against CSCs, and often lead to enrichment of CSCs that can result in tumor relapse. Therefore, it is hypothesized that targeting CSCs is key to increasing the efficacy of cancer therapies. In this review, CSC properties including CSC markers, their role in tumor growth, invasiveness, metastasis, and drug resistance, as well as CSC microenvironment are discussed. Further, CSC-targeted strategies including the use of targeted drug delivery systems are examined.
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Affiliation(s)
- Jin Cao
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Shubhmita Bhatnagar
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
- School of Pharmacy, Temple University, Philadelphia, PA, 19140, USA
| | - Jiawei Wang
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
- College of Pharmacy, University of Texas at Austin, Austin, TX, 78712, USA
| | - Xueyong Qi
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Swayam Prabha
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
- Cancer Research & Molecular Biology and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Jayanth Panyam
- College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
- School of Pharmacy, Temple University, Philadelphia, PA, 19140, USA.
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38
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Yadollahi P, Jeon YK, Ng WL, Choi I. Current understanding of cancer-intrinsic PD-L1: regulation of expression and its protumoral activity. BMB Rep 2021. [PMID: 33298250 PMCID: PMC7851443 DOI: 10.5483/bmbrep.2021.54.1.241] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
In the last decade, we have witnessed an unprecedented clinical success in cancer immunotherapies targeting the programmed cell-death ligand 1 (PD-L1) and programmed cell-death 1 (PD-1) pathway. Besides the fact that PD-L1 plays a key role in immune regulation in tumor microenvironment, recently a plethora of reports has suggested a new perspective of non-immunological functions of PD-L1 in the regulation of cancer intrinsic activities including mesenchymal transition, glucose and lipid metabolism, stemness, and autophagy. Here we review the current understanding on the regulation of expression and intrinsic protumoral activity of cancer-intrinsic PD-L1.
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Affiliation(s)
- Pedram Yadollahi
- Innovative Therapeutic Research Institute, Inje University, Busan 47397; Department of Microbiology and Immunology, Inje University College of Medicine, Busan 47392, Korea
| | - You-Kyoung Jeon
- Innovative Therapeutic Research Institute, Inje University, Busan 47397; Department of Microbiology and Immunology, Inje University College of Medicine, Busan 47392, Korea
| | - Wooi Loon Ng
- Innovative Therapeutic Research Institute, Inje University, Busan 47397, Korea
| | - Inhak Choi
- Innovative Therapeutic Research Institute, Inje University, Busan 47397; Department of Microbiology and Immunology, Inje University College of Medicine, Busan 47392, Korea
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39
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The Immune Privilege of Cancer Stem Cells: A Key to Understanding Tumor Immune Escape and Therapy Failure. Cells 2021; 10:cells10092361. [PMID: 34572009 PMCID: PMC8469208 DOI: 10.3390/cells10092361] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/04/2021] [Accepted: 09/06/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The immune privileged status of CSCs is induced and preserved by various mechanisms that directly affect them (e.g., the downregulation of the major histocompatibility complex class I) and indirectly are induced in the host immune cells (e.g., activation of immune suppressive cells). Therefore, deeper insights into the immuno-biology of CSCs are essential in our pursuit to find new therapeutic opportunities that eradicate cancer (stem) cells. Here, we review and discuss the ability of CSCs to evade the innate and adaptive immune system, as we offer a view of the immunotherapeutic strategies adopted to potentiate and address specific subsets of (engineered) immune cells against CSCs.
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40
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Wang C, Li Y, Jia L, Kim JK, Li J, Deng P, Zhang W, Krebsbach PH, Wang CY. CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance. Cell Stem Cell 2021; 28:1597-1613.e7. [PMID: 33945793 PMCID: PMC8419062 DOI: 10.1016/j.stem.2021.04.011] [Citation(s) in RCA: 194] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/22/2021] [Accepted: 04/12/2021] [Indexed: 01/19/2023]
Abstract
Immunosurveillance is a critical mechanism guarding against tumor development and progression. Checkpoint inhibitors have shown significant success in cancer treatment, but expression of key factors such as PD-L1 in putative cancer stem cell (CSC) populations in squamous cell carcinoma has been inconclusive, suggesting that CSCs may have developed other mechanisms to escape immune surveillance. Here we show that CSCs upregulate the immune checkpoint molecule CD276 (B7-H3) to evade host immune responses. CD276 is highly expressed by CSCs in mouse and human head and neck squamous cell carcinoma (HNSCC) and can be used to prospectively isolate tumorigenic CSCs. Anti-CD276 antibodies eliminate CSCs in a CD8+ T cell-dependent manner, inhibiting tumor growth and lymph node metastases in a mouse HNSCC model. Single-cell RNA sequencing (RNA-seq) showed that CD276 blockade remodels SCC heterogeneity and reduces epithelial-mesenchymal transition. These results show that CSCs utilize CD276 for immune escape and suggest that targeting CD276 may reduce CSCs in HNSCC.
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Affiliation(s)
- Cheng Wang
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA
| | - Yang Li
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA
| | - Lingfei Jia
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA
| | - Jin koo Kim
- Division of Constitutive and Regenerative Sciences, School of Dentistry, UCLA, Los Angeles, CA 90095, USA
| | - Jiong Li
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA
| | - Peng Deng
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA
| | - Wuchang Zhang
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA
| | - Paul H. Krebsbach
- Division of Constitutive and Regenerative Sciences, School of Dentistry, UCLA, Los Angeles, CA 90095, USA
| | - Cun-Yu Wang
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA,Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA 90095, USA,Lead contact,Correspondence:
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41
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Abstract
Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.
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Affiliation(s)
- Defne Bayik
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Justin D Lathia
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, USA.
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42
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Khan S, Suryavanshi M, Kaur J, Nayak D, Khurana A, Manchanda RK, Tandon C, Tandon S. Stem cell therapy: A paradigm shift in breast cancer treatment. World J Stem Cells 2021; 13:841-860. [PMID: 34367480 PMCID: PMC8316873 DOI: 10.4252/wjsc.v13.i7.841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/30/2021] [Accepted: 06/17/2021] [Indexed: 02/07/2023] Open
Abstract
As per the latest Globocan statistics, the high prevalence rate of breast cancer in low- and middle-income countries has led to it becoming the most common cancer to be diagnosed, hence posing a major public health challenge. As per this data, more than 11.7% of the estimated new cancer cases in 2020 were due to breast cancer. A small but significant subpopulation of cells with self- renewing ability are present in the tumor stroma and have been given the nomenclature of cancer stem cells (CSCs). These cells display a high degree of plasticity owing to their ability to transition from the slowly cycling quiescent phase to the actively proliferating phenotype. This attribute of CSCs allows them to differentiate into various cell types having diverse functions. Breast CSCs have a pivotal role in development, metastasis, treatment resistance and relapse of breast cancers. This review focuses on the pathways regulating breast CSC maintenance and the current strategies that are being explored for directing the development of novel, targeted, therapeutic approaches for limiting and eradicating this aberrant stem cell population.
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Affiliation(s)
- Sabiha Khan
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
| | - Moushumi Suryavanshi
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi 110085, India
| | - Jasamrit Kaur
- Department of Chemistry, Goswami Ganesh Dutta Sanatan Dharma College, Chandigarh 160030, India
| | - Debadatta Nayak
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | - Anil Khurana
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | | | - Chanderdeep Tandon
- Amity Institute of Biotechnology, Amity University, Noida 201313, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
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43
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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44
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Mokhtari RB, Sambi M, Qorri B, Baluch N, Ashayeri N, Kumar S, Cheng HLM, Yeger H, Das B, Szewczuk MR. The Next-Generation of Combination Cancer Immunotherapy: Epigenetic Immunomodulators Transmogrify Immune Training to Enhance Immunotherapy. Cancers (Basel) 2021; 13:3596. [PMID: 34298809 PMCID: PMC8305317 DOI: 10.3390/cancers13143596] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy harnesses the immune system by targeting tumor cells that express antigens recognized by immune system cells, thus leading to tumor rejection. These tumor-associated antigens include tumor-specific shared antigens, differentiation antigens, protein products of mutated genes and rearrangements unique to tumor cells, overexpressed tissue-specific antigens, and exogenous viral proteins. However, the development of effective therapeutic approaches has proven difficult, mainly because these tumor antigens are shielded, and cells primarily express self-derived antigens. Despite innovative and notable advances in immunotherapy, challenges associated with variable patient response rates and efficacy on select tumors minimize the overall effectiveness of immunotherapy. Variations observed in response rates to immunotherapy are due to multiple factors, including adaptative resistance, competency, and a diversity of individual immune systems, including cancer stem cells in the tumor microenvironment, composition of the gut microbiota, and broad limitations of current immunotherapeutic approaches. New approaches are positioned to improve the immune response and increase the efficacy of immunotherapies, highlighting the challenges that the current global COVID-19 pandemic places on the present state of immunotherapy.
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Affiliation(s)
- Reza Bayat Mokhtari
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
- Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, M2D2, University of Massachusetts, Lowell, MA 01852, USA;
| | - Manpreet Sambi
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
| | - Bessi Qorri
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
| | - Narges Baluch
- Department of Immunology and Allergy, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada;
| | - Neda Ashayeri
- Division of Hematology & Oncology, Department of Pediatrics, Ali-Asghar Children Hospital, Iran University of Medical Science, Tehran 1449614535, Iran;
| | - Sushil Kumar
- QPS, Holdings LLC, Pencader Corporate Center, 110 Executive Drive, Newark, DE 19702, USA;
| | - Hai-Ling Margaret Cheng
- The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5G 1M1, Canada;
- Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Herman Yeger
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada;
| | - Bikul Das
- Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, M2D2, University of Massachusetts, Lowell, MA 01852, USA;
- KaviKrishna Laboratory, Department of Cancer and Stem Cell Biology, GBP, Indian Institute of Technology, Guwahati 781039, India
| | - Myron R. Szewczuk
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
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45
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Erkisa M, Sariman M, Geyik OG, Geyik CG, Stanojkovic T, Ulukay E. Natural Products as a Promising Therapeutic Strategy to Target Cancer Stem Cells. Curr Med Chem 2021; 29:741-783. [PMID: 34182899 DOI: 10.2174/0929867328666210628131409] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/02/2021] [Accepted: 03/02/2021] [Indexed: 11/22/2022]
Abstract
Cancer is still a deadly disease, and its treatment desperately needs to be managed in a very sophisticated way through fast-developing novel strategies. Most of the cancer cases eventually develop into recurrencies, for which cancer stem cells (CSCs) are thought to be responsible. They are considered as a subpopulation of all cancer cells of tumor tissue with aberrant regulation of self-renewal, unbalanced proliferation, and cell death properties. Moreover, CSCs show a serious degree of resistance to chemotherapy or radiotherapy and immune surveillance as well. Therefore, new classes of drugs are rushing into the market each year, which makes the cost of therapy increase dramatically. Natural products are also becoming a new research area as a diverse chemical library to suppress CSCs. Some of the products even show promise in this regard. So, the near future could witness the introduction of natural products as a source of new chemotherapy modalities, which may result in the development of novel anticancer drugs. They could also be a reasonably-priced alternative to highly expensive current treatments. Nowadays, considering the effects of natural compounds on targeting surface markers, signaling pathways, apoptosis, and escape from immunosurveillance have been a highly intriguing area in preclinical and clinical research. In this review, we present scientific advances regarding their potential use in the inhibition of CSCs and the mechanisms by which they kill the CSCs.
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Affiliation(s)
- Merve Erkisa
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Melda Sariman
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Oyku Gonul Geyik
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Caner Geyik Geyik
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Tatjana Stanojkovic
- Experimental Oncology Deparment, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Pasterova 14. Serbia
| | - Engin Ulukay
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
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46
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Prognostic Role of Immune Checkpoint Regulators in Cholangiocarcinoma: A Pilot Study. J Clin Med 2021; 10:jcm10102191. [PMID: 34069452 PMCID: PMC8159105 DOI: 10.3390/jcm10102191] [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: 03/24/2021] [Revised: 04/30/2021] [Accepted: 05/14/2021] [Indexed: 12/11/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a hepatobiliary malignancy associated with steadily increasing incidence and poor prognosis. Ongoing clinical trials are assessing the effectiveness and safety of a few immune checkpoint inhibitors (ICIs) in CCA patients. However, these ICI treatments as monotherapies may be effective for a proportion of patients with CCA. The prevalence and distribution of other immune checkpoints (ICs) in CCA remain unclear. In this pilot study, we screened databases of CCA patients for the expression of 19 ICs and assessed the prognostic significance of these ICs in CCA patients. Notably, expression of immune modulator IDO1 and PD-L1 were linked with poor overall survival, while FASLG and NT5E were related to both worse overall survival and progression-free survival. We also identified immune modulators IDO1, FASLG, CD80, HAVCR2, NT5E, CTLA-4, LGALS9, VTCN1 and TNFRSF14 that synergized with PD-L1 and correlated with worse patient outcomes. In vitro studies revealed that the expression of ICs was closely linked with aggressive CCA subpopulations, such as cancer stem cells and cells undergoing TGF-β and TNF-α-mediated epithelial-to-mesenchymal transition. These findings suggest that the aforementioned IC molecules may serve as potential prognostic biomarkers and drug targets in CCA patients, leading to lasting and durable treatment outcomes.
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47
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Sun W, Zhang Q, Wang R, Li Y, Sun Y, Yang L. Targeting DNA Damage Repair for Immune Checkpoint Inhibition: Mechanisms and Potential Clinical Applications. Front Oncol 2021; 11:648687. [PMID: 34026622 PMCID: PMC8137908 DOI: 10.3389/fonc.2021.648687] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 03/30/2021] [Indexed: 12/26/2022] Open
Abstract
DNA damage repair (DDR) pathways play an essential role in maintaining genomic integrity. DDR dysfunction leads to accumulated DNA damage, predisposition to cancer, and high sensitivity to chemotherapy and radiotherapy. Recent studies have demonstrated that DDR status is associated with response to immune checkpoint inhibitors (ICIs). Among the DDR pathways, mismatch repair is one of the most recognized predictive biomarkers for ICIs. Furthermore, preclinical and early clinical studies suggest the rationale of combining agents targeting the DDR pathways, such as poly (ADP-ribose) polymerase (PARP) inhibitors, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, and ataxia telangiectasia and rad3-related (ATR) kinase inhibitors, with ICIs. In the present review, we describe the predictive role of DDR pathways in ICIs and summarize the advances in potential combination strategies of novel agents targeting DDR with ICIs for cancer treatment.
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Affiliation(s)
- Wei Sun
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Zhang
- Department of Ultrasonic Diagnosis, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Runkun Wang
- Department of Oncology, The First People's hospital of Guangshui, Hubei, China
| | - Yang Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue Sun
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lin Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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48
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Frank MH, Wilson BJ, Gold JS, Frank NY. Clinical Implications of Colorectal Cancer Stem Cells in the Age of Single-Cell Omics and Targeted Therapies. Gastroenterology 2021; 160:1947-1960. [PMID: 33617889 PMCID: PMC8215897 DOI: 10.1053/j.gastro.2020.12.080] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/30/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
The cancer stem cell (CSC) concept emerged from the recognition of inherent tumor heterogeneity and suggests that within a given tumor, in analogy to normal tissues, there exists a cellular hierarchy composed of a minority of more primitive cells with enhanced longevity (ie, CSCs) that give rise to shorter-lived, more differentiated cells (ie, cancer bulk populations), which on their own are not capable of tumor perpetuation. CSCs can be responsible for cancer therapeutic resistance to conventional, targeted, and immunotherapeutic treatment modalities, and for cancer progression through CSC-intrinsic molecular mechanisms. The existence of CSCs in colorectal cancer (CRC) was first established through demonstration of enhanced clonogenicity and tumor-forming capacity of this cell subset in human-to-mouse tumor xenotransplantation experiments and subsequently confirmed through lineage-tracing studies in mice. Surface markers for CRC CSC identification and their prospective isolation are now established. Therefore, the application of single-cell omics technologies to CSC characterization, including whole-genome sequencing, RNA sequencing, and epigenetic analyses, opens unprecedented opportunities to discover novel targetable molecular pathways and hence to develop novel strategies for CRC eradication. We review recent advances in this field and discuss the potential implications of next-generation CSC analyses for currently approved and experimental targeted CRC therapies.
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Affiliation(s)
- Markus H. Frank
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;,Department of Dermatology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts;,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts;,School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
| | - Brian J. Wilson
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts
| | - Jason S. Gold
- Department of Surgery, Veterans Affairs Boston Healthcare System, Boston, Massachusetts;,Department of Surgery, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Natasha Y. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts;,Department of Medicine, Veterans Affairs Boston Healthcare System, Boston, Massachusetts;,Division of Genetics, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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49
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Xing Y, Liu J, Sun S, Ming T, Wang Y, Luo J, Xiao G, Li X, Xie J, Cai X. New electrochemical method for programmed death-ligand 1 detection based on a paper-based microfluidic aptasensor. Bioelectrochemistry 2021; 140:107789. [PMID: 33677221 DOI: 10.1016/j.bioelechem.2021.107789] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/02/2021] [Accepted: 02/13/2021] [Indexed: 12/22/2022]
Abstract
As programmed death-ligand 1 (PD-L1) is considered a referenced therapeutic biomarker, a rapid and low-cost method to detect PD-L1 in body fluids is necessary. In this work, a paper-based microfluidic aptasensor for label-free electrochemical detection of PD-L1 in liquids was fabricated. The aptasensor integrates a reaction cell and a three-electrode system, and a differential pulse voltammetry electrochemical method was adopted. PD-L1 aptamer with a low equilibrium dissociation constant was used as a biorecognition molecule. To bind the aptamer and assist in the electrochemical measurement, nanocomposites were synthesized and used to modify the working electrode, which was composed of an amine-functionalized single-walled carbon nanotube, new methylene blue and gold nanoparticles. The basic performance of the aptasensor was tested in phosphate-buffered saline: the linear range was between 10 pg mL-1 and 2.5 ng mL-1, and the detection limit was 10 pg mL-1 (signal/noise = 3). Moreover, the aptasensor was used for the detection of serum samples and compared with an enzyme linked immunosorbent assay (ELISA). The results showed that the aptasensor provides a new low-cost, portable and highly sensitive detection method for PD-L1, as an alternative to ELISA.
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Affiliation(s)
- Yu Xing
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Juntao Liu
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Shuai Sun
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Tao Ming
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Yang Wang
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Jinping Luo
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Guihua Xiao
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Xinrong Li
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Jingyu Xie
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Xinxia Cai
- State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
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50
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Aramini B, Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Morandi U, Dominici M, Haider KH. Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. Oncotarget 2021; 12:230-250. [PMID: 33613850 PMCID: PMC7869576 DOI: 10.18632/oncotarget.27870] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D'Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
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