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1
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Li Y, Liu X, Dong Y, Zhou Y. Angiogenesis causes and vasculogenic mimicry formation in the context of cancer stem cells. Biochim Biophys Acta Rev Cancer 2025; 1880:189323. [PMID: 40239849 DOI: 10.1016/j.bbcan.2025.189323] [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: 11/14/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/18/2025]
Abstract
Tumor occurrence, development, invasion, and metastasis are regulated by multiple mechanisms. Among these, angiogenesis promotes tumor progression mainly by supplying tumor tissue and providing channels for tumor metastasis. Cancer stem cells (CSCs) are another important factor affecting tumor progression by involving in tumor initiation and development, while remaining insensitive to conventional antitumor treatments. Among treatment strategies for them, owing to the existence of alternative angiogenic pathways or the risk of damaging normal stem cells, the clinical effect is not ideal. Angiogenesis and CSCs may influence each other in this process. Tumor angiogenesis can support CSC self-renewal by providing a suitable microenvironment, whereas CSCs can regulate tumor neovascularization and mediate drug resistance to anti-angiogenic therapy. This review summarized the role of vascular niche formed by angiogenesis in CSC self-renewal and stemness maintenance, and the function of CSCs in endothelial progenitor cell differentiation and pro-angiogenic factor upregulation. We also elucidated the malignant loop between CSCs and angiogenesis promoting tumor progression. Additionally, we summarized and proposed therapeutic targets, including blocking tumor-derived endothelial differentiation, inhibiting pro-angiogenic factor upregulation, and directly targeting endothelial-like cells comprising CSCs. And we analyzed the feasibility of these strategies to identify more effective methods to improve tumor treatment.
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Affiliation(s)
- Ying Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Xiaofang Liu
- Department of Anus and Intestine Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Yaodong Dong
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
| | - Yingying Zhou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
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2
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Magesh V, Sekar R, AlZahrani A, Balasubramanian R, Abdelsalam SA, Rajendran P. HES1 in cancer: a key player in tumorigenesis and its prognostic significance. Mol Genet Genomics 2025; 300:49. [PMID: 40392313 DOI: 10.1007/s00438-025-02259-1] [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: 02/09/2025] [Accepted: 05/07/2025] [Indexed: 05/22/2025]
Abstract
The dysregulation of transcriptional regulators is a critical feature in the progression of many malignancies. Hairy and enhancer of split homolog-1 (HES1), a member of the basic helix-loop-helix (bHLH) gene family, has emerged as a key player in tumorigenesis due to its regulatory roles in multiple cellular pathways. This review aims to systematically explore the relevance of HES1 in cancer development, emphasizing its activation through major signaling pathways such as Notch, Hedgehog, hypoxia, and Wnt, and its contribution to advanced tumor progression. Numerous studies have demonstrated that HES1 upregulates genes associated with stemness, proliferation, and metastasis, and its expression correlates with poor clinicopathological features, including enhanced tumor proliferation, self-renewal, migration, metastasis, and drug resistance. Furthermore, HES1 has been frequently identified as a downstream effector of critical oncogenic pathways, further consolidating its role in aggressive cancers. Based on current evidence, HES1 holds promise as both a prognostic biomarker and a potential therapeutic target in various lethal malignancies. A deeper understanding of HES1's molecular mechanisms could pave the way for the development of targeted interventions aimed at improving cancer outcomes.
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Affiliation(s)
| | - Ramya Sekar
- Department of Oral & Maxillofacial Pathology and Oral Microbiology, Meenakshi Ammal Dental College and Hospital, Meenakshi Academy of Higher Education and Research (Deemed to Be University), Chennai, Tamil Nadu, India
| | - Abdullah AlZahrani
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
| | | | - Salaheldin Abdelraouf Abdelsalam
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Zoology, Faculty of Science, Assiut University, Assiut 71515, Egypt
| | - Peramaiyan Rajendran
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia.
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, Tamil Nadu, India.
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3
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Handschin C, Shalhoub H, Mazet A, Guyon C, Dusserre N, Boutet-Robinet E, Oliveira H, Guillermet-Guibert J. Biotechnological advances in 3D modeling of cancer initiation. Examples from pancreatic cancer research and beyond. Biofabrication 2025; 17:022008. [PMID: 40018875 DOI: 10.1088/1758-5090/adb51c] [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: 07/19/2024] [Accepted: 02/12/2025] [Indexed: 03/01/2025]
Abstract
In recent years, biofabrication technologies have garnered significant attention within the scientific community for their potential to create advancedin vitrocancer models. While these technologies have been predominantly applied to model advanced stages of cancer, there exists a pressing need to develop pertinent, reproducible, and sensitive 3D models that mimic cancer initiation lesions within their native tissue microenvironment. Such models hold profound relevance for comprehending the intricacies of cancer initiation, to devise novel strategies for early intervention, and/or to conduct sophisticated toxicology assessments of putative carcinogens. Here, we will explain the pivotal factors that must be faithfully recapitulated when constructing these models, with a specific focus on early pancreatic cancer lesions. By synthesizing the current state of research in this field, we will provide insights into recent advances and breakthroughs. Additionally, we will delineate the key technological and biological challenges that necessitate resolution in future endeavors, thereby paving the way for more accurate and insightfulin vitrocancer initiation models.
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Affiliation(s)
- C Handschin
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - H Shalhoub
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
| | - A Mazet
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - C Guyon
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
| | - N Dusserre
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - E Boutet-Robinet
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
| | - H Oliveira
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - J Guillermet-Guibert
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
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Horta M, Soares P, Leite Pereira C, Lima RT. Emerging Approaches in Glioblastoma Treatment: Modulating the Extracellular Matrix Through Nanotechnology. Pharmaceutics 2025; 17:142. [PMID: 40006509 PMCID: PMC11859630 DOI: 10.3390/pharmaceutics17020142] [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: 12/21/2024] [Revised: 01/10/2025] [Accepted: 01/16/2025] [Indexed: 02/27/2025] Open
Abstract
Glioblastoma's (GB) complex tumor microenvironment (TME) promotes its progression and resistance to therapy. A critical component of TME is the extracellular matrix (ECM), which plays a pivotal role in promoting the tumor's invasive behavior and aggressiveness. Nanotechnology holds significant promise for GB treatment, with the potential to address challenges posed by both the blood-brain barrier and the GB ECM. By enabling targeted delivery of therapeutic and diagnostic agents, nanotechnology offers the prospect of improving treatment efficacy and diagnostic accuracy at the tumor site. This review provides a comprehensive exploration of GB, including its epidemiology, classification, and current treatment strategies, alongside the intricacies of its TME. It highlights nanotechnology-based strategies, focusing on nanoparticle formulations such as liposomes, polymeric nanoparticles, and gold nanoparticles, which have shown promise in GB therapy. Furthermore, it explores how different emerging nanotechnology strategies modulate the ECM to overcome the challenges posed by its high density, which restricts drug distribution within GB tumors. By emphasizing the intersection of nanotechnology and GB ECM, this review underscores an innovative approach to advancing GB treatment. It addresses the limitations of current therapies, identifies new research avenues, and emphasizes the potential of nanotechnology to improve patient outcomes.
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Affiliation(s)
- Miguel Horta
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.H.); (P.S.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FMUP—Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Paula Soares
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.H.); (P.S.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FMUP—Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Catarina Leite Pereira
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.H.); (P.S.)
- INEB—Instituto Nacional de Engenharia Biomédica, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
| | - Raquel T. Lima
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.H.); (P.S.)
- IPATIMUP—Instituto de Patologia e Imunologia Molecular, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FMUP—Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
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Guo T, Zhang S, Zeng W, Liang Y, Xie J, Liu S, Qiu Y, Fu Y, Ou Y, Ma K, Wang B, Gu W, Duan Y. Isolation and identification of patient-derived liver cancer stem cells and development of personalized treatment strategies. J Transl Med 2024; 22:1036. [PMID: 39558364 PMCID: PMC11575129 DOI: 10.1186/s12967-024-05870-9] [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: 08/24/2024] [Accepted: 11/10/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Liver cancer stem cells (LCSCs) are thought to drive the metastasis and recurrence, however, the heterogeneity of molecular markers of LCSCs has hindered the development of effective methods to isolate them. METHODS This study introduced an effective approach to isolate and culture LCSCs from human primary liver cancer (HPLC), leveraging mouse embryonic fibroblasts (MEFs) as feeder cells in conjunction with using defined medium. Isolated LCSCs were further characterized by multiple approaches. Transcriptome sequencing data analysis was conducted to identify highly expressed genes in LCSCs and classify different subtypes of liver cancers. RESULTS Total sixteen cell strains were directly isolated from 24 tissues of three types of HPLC without sorting, seven of which could be maintained long-term culture as colony growth on MEFs, which is unique characteristics of stem cells. Even 10 of cloned cells formed the tumors in immunodeficient mice, indicating that those cloned cells were tumorgenic. The histologies and gene expression pattern of human xenografts were very similar to those of HPLC where these cloned cells were isolated. Moreover, putative markers of LCSCs were further verified to all express in cloned cells, confirming that these cells were LCSCs. These cloned LCSCs could be cryopreserved, and still maintained the feature of colony growth on MEFs after the recovery. Compared to suspension culture as conventional approach to culture LCSCs, our approach much better maintained stemness of LCSCs for a long time. To date, these cloned cells could be cultured on MEFs over 12 passages. Moreover, bioinformatics analysis of sequencing data revealed the gene expression profiles in LCSCs, and liver cancers were classified into two subtypes C1 and C2 based on genes associated with the prognosis of LCSCs. Patients of the C2 subtype, which is closely related to the extracellular matrix, were found to be sensitive to treatments such as Cisplatin, Axitinib, JAK1 inhibitors, WNT-c59, Sorafenib, and RO-3306. CONCLUSION In summary, this effective approach offers new insights into the molecular landscape of human liver cancers, and the identification of the C2 subtype and its unique response to the treatment pave the way for the creation of more effective, personalized therapeutic strategies.
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Affiliation(s)
- Tingting Guo
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Shuai Zhang
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, 510180, P.R. China
| | - Weiping Zeng
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yan Liang
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Jinghe Xie
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, P.R. China
| | - ShouPei Liu
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yaqi Qiu
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yingjie Fu
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yimeng Ou
- Department of General Surgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510699, P.R. China
| | - Keqiang Ma
- Department of Hepatobiliary Pancreatic Surgery, Huadu District People's Hospital of Guangzhou, Guangzhou, 510800, P.R. China
| | - Bailin Wang
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, P.R. China
| | - Weili Gu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, 510180, P.R. China.
- Department of Gastroenterology and Hepatology Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, No.1 Panfu Road, Guangzhou, 510180, P.R. China.
| | - Yuyou Duan
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China.
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China.
- The Innovation Centre of Ministry of Education for Development and Diseases, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Laboratory of Stem Cells and Translational Medicine, Institute for Clinical Medicine, The Second Affiliation Hospital, School of Medicine, South China University of Technology, No.10 Huanyu Erlu, 9th Floor, Guangzhou, 510180, P.R. China.
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Niharika, Garg M. Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance. Expert Rev Mol Med 2024; 26:e23. [PMID: 39375840 PMCID: PMC11488345 DOI: 10.1017/erm.2024.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/25/2023] [Accepted: 06/25/2024] [Indexed: 10/09/2024]
Abstract
Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.
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Affiliation(s)
- Niharika
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
| | - Minal Garg
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
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7
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Friess D, Brauer S, Pöysti A, Choudhury C, Harris L. Tools to study neural and glioma stem cell quiescence. Trends Neurosci 2024; 47:736-748. [PMID: 39191628 DOI: 10.1016/j.tins.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/12/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024]
Abstract
Quiescence is a prolonged but reversible state of cell-cycle arrest that is an adaptive feature of most adult stem cell populations. In the brain, quiescence helps to protect adult neural stem cells from stress and supports lifelong neurogenesis. Unfortunately however, entry into a quiescent or a slow-cycling state is also a malignant feature of brain cancer stem cells. In glioblastoma, where the process has been best characterised, quiescent glioma stem cells preferentially survive chemoradiation, and after therapy, reactivate to regrow the tumour and drive recurrence. In this Review, we discuss the in vitro and in vivo models that have been developed for studying neural stem cell quiescence and how these tools may be used to deepen biological understanding and to develop novel therapies targeting quiescent glioma stem cells.
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Affiliation(s)
- Dana Friess
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia; The University of Queensland, Brisbane, School of Biomedical Sciences, QLD, 4067, Australia
| | - Stephanie Brauer
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia; Queensland University of Technology, School of Biomedical Sciences, QLD, 4059, Australia
| | - Anni Pöysti
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, WC1E 6DD London, UK
| | - Chandra Choudhury
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia; The University of Queensland, Brisbane, School of Biomedical Sciences, QLD, 4067, Australia
| | - Lachlan Harris
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia; The University of Queensland, Brisbane, School of Biomedical Sciences, QLD, 4067, Australia; Queensland University of Technology, School of Biomedical Sciences, QLD, 4059, Australia.
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [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: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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9
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Li J, Zhang Y, Liang C, Yan X, Hui X, Liu Q. Advancing precision medicine in gliomas through single-cell sequencing: unveiling the complex tumor microenvironment. Front Cell Dev Biol 2024; 12:1396836. [PMID: 39156969 PMCID: PMC11327033 DOI: 10.3389/fcell.2024.1396836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 07/22/2024] [Indexed: 08/20/2024] Open
Abstract
Glioblastoma (GBM) displays an infiltrative growth characteristic that recruits neighboring normal cells to facilitate tumor growth, maintenance, and invasion into the brain. While the blood-brain barrier serves as a critical natural defense mechanism for the central nervous system, GBM disrupts this barrier, resulting in the infiltration of macrophages from the peripheral bone marrow and the activation of resident microglia. Recent advancements in single-cell transcriptomics and spatial transcriptomics have refined the categorization of cells within the tumor microenvironment for precise identification. The intricate interactions and influences on cell growth within the tumor microenvironment under multi-omics conditions are succinctly outlined. The factors and mechanisms involving microglia, macrophages, endothelial cells, and T cells that impact the growth of GBM are individually examined. The collaborative mechanisms of tumor cell-immune cell interactions within the tumor microenvironment synergistically promote the growth, infiltration, and metastasis of gliomas, while also influencing the immune status and therapeutic response of the tumor microenvironment. As immunotherapy continues to progress, targeting the cells within the inter-tumor microenvironment emerges as a promising novel therapeutic approach for GBM. By comprehensively understanding and intervening in the intricate cellular interactions within the tumor microenvironment, novel therapeutic modalities may be developed to enhance treatment outcomes for patients with GBM.
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Affiliation(s)
- Jinwei Li
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Neurosurgery, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Yang Zhang
- Graduate School of Medicine, Kunming Medical University, Kunming, Yunnan, China
| | - Cong Liang
- Department of Pharmacy, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Xianlei Yan
- Department of Neurosurgery, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Xuhui Hui
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Quan Liu
- Department of Neurosurgery, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
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10
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Qin Z, Zhong Y, Li P, Ma Z, Kang H, Huang Y, Zhong Y, Wang L. Vasorin promotes endothelial differentiation of glioma stem cells via stimulating the transcription of VEGFR2. FASEB J 2024; 38:e23682. [PMID: 38780524 DOI: 10.1096/fj.202400159r] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/27/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024]
Abstract
Gliomas are highly vascularized malignancies, but current anti-angiogenic treatments have not demonstrated practical improvements in patient survival. Studies have suggested that glioma-derived endothelial cell (GdEC) formed by glioma stem cell (GSC) differentiation may contribute to the failure of this treatment. However, the molecular mechanisms involved in GSC endothelial differentiation remain poorly understood. We previously reported that vasorin (VASN) is highly expressed in glioma and promotes angiogenesis. Here, we show that VASN expression positively correlates with GdEC signatures in glioma patients. VASN promotes the endothelial differentiation capacity of GSC in vitro and participates in the formation of GSC-derived vessels in vivo. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) is a critical factor that mediates the regulation of VASN on GSC endothelial differentiation. Separation of cell chromatin fractionation and chromatin immunoprecipitation-sequencing analysis show that VASN interacts with Notch1 and co-translocates into the cell nuclei, where VASN binds to the VEGFR2 gene promoter to stimulate its transcription during the progression of GSC differentiation into GdEC. Together, these findings elucidate the role and mechanisms of VASN in promoting the endothelial differentiation of GSC and suggest VASN as a potential target for anti-angiogenic therapy based on intervention in GdEC formation in gliomas.
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Affiliation(s)
- Zixi Qin
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Ying Zhong
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Peiwen Li
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Ziqing Ma
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Hui Kang
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Youwei Huang
- Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Guangzhou, China
| | - Ying Zhong
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Lihui Wang
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
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Agosti E, Zeppieri M, Ghidoni M, Ius T, Tel A, Fontanella MM, Panciani PP. Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments. World J Stem Cells 2024; 16:604-614. [PMID: 38817336 PMCID: PMC11135247 DOI: 10.4252/wjsc.v16.i5.604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 03/06/2024] [Accepted: 04/19/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs' role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs' high plasticity. AIM To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms. METHODS A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including "glioma stem cells", "radiotherapy", "chemotherapy", "resistance", and "targeted therapies". Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR). RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (e.g., LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (e.g., cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies. CONCLUSION GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.
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Affiliation(s)
- Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy.
| | - Mattia Ghidoni
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Tamara Ius
- Neurosurgery Unit, Department of Head-Neck and NeuroScience, University Hospital of Udine, Udine 33100, Italy
| | - Alessandro Tel
- Clinic of Maxillofacial Surgery, Department of Head-Neck and NeuroScience, University Hospital of Udine, Udine 33100, Italy
| | - Marco Maria Fontanella
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Pier Paolo Panciani
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
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12
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Guo Q, Zhou Y, Xie T, Yuan Y, Li H, Shi W, Zheng L, Li X, Zhang W. Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting. Genes Dis 2024; 11:101043. [PMID: 38292177 PMCID: PMC10825311 DOI: 10.1016/j.gendis.2023.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/25/2023] [Indexed: 02/01/2024] Open
Abstract
There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numerous signal pathways play an important role in signaling transduction. These factors promote or maintain cancer cell stemness, and participate in cancer recurrence, metastasis, and resistance. This review aims to summarize the recent molecular data concerning the multilayered relationship between CSCs and CSC-favorable microenvironments. We also discuss the therapeutic implications of targeting this synergistic interplay, hoping to give an insight into targeting cancer cell stemness for tumor therapy and prognosis.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Yi Zhou
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Tianyuan Xie
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yin Yuan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Huilong Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Wanjin Shi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
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13
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Lamichhane A, Tavana H. Three-Dimensional Tumor Models to Study Cancer Stemness-Mediated Drug Resistance. Cell Mol Bioeng 2024; 17:107-119. [PMID: 38737455 PMCID: PMC11082110 DOI: 10.1007/s12195-024-00798-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/01/2024] [Indexed: 05/14/2024] Open
Abstract
Solid tumors often contain genetically different populations of cancer cells, stromal cells, various structural and soluble proteins, and other soluble signaling molecules. The American Cancer society estimated 1,958,310 new cancer cases and 609,820 cancer deaths in the United States in 2023. A major barrier against successful treatment of cancer patients is drug resistance. Gain of stem cell-like states by cancer cells under drug pressure or due to interactions with the tumor microenvironment is a major mechanism that renders therapies ineffective. Identifying approaches to target cancer stem cells is expected to improve treatment outcomes for patients. Most of our understanding of drug resistance and the role of cancer stemness is from monolayer cell cultures. Recent advances in cell culture technologies have enabled developing sophisticated three-dimensional tumor models that facilitate mechanistic studies of cancer drug resistance. This review summarizes the role of cancer stemness in drug resistance and highlights the various tumor models that are used to discover the underlying mechanisms and test potentially novel therapeutics.
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Affiliation(s)
- Astha Lamichhane
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
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14
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He T, Wang Y, Lv W, Wang Y, Li X, Zhang Q, Shen HM, Hu J. FBP1 inhibits NSCLC stemness by promoting ubiquitination of Notch1 intracellular domain and accelerating degradation. Cell Mol Life Sci 2024; 81:87. [PMID: 38349431 PMCID: PMC10864425 DOI: 10.1007/s00018-024-05138-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/06/2024] [Accepted: 01/22/2024] [Indexed: 02/15/2024]
Abstract
The existence of cancer stem cells is widely acknowledged as the underlying cause for the challenging curability and high relapse rates observed in various tumor types, including non-small cell lung cancer (NSCLC). Despite extensive research on numerous therapeutic targets for NSCLC treatment, the strategies to effectively combat NSCLC stemness and achieve a definitive cure are still not well defined. The primary objective of this study was to examine the underlying mechanism through which Fructose-1,6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme, functions as a tumor suppressor to regulate the stemness of NSCLC. Herein, we showed that overexpression of FBP1 led to a decrease in the proportion of CD133-positive cells, weakened tumorigenicity, and decreased expression of stemness factors. FBP1 inhibited the activation of Notch signaling, while it had no impact on the transcription level of Notch 1 intracellular domain (NICD1). Instead, FBP1 interacted with NICD1 and the E3 ubiquitin ligase FBXW7 to facilitate the degradation of NICD1 through the ubiquitin-proteasome pathway, which is independent of the metabolic enzymatic activity of FBP1. The aforementioned studies suggest that targeting the FBP1-FBXW7-NICD1 axis holds promise as a therapeutic approach for addressing the challenges of NSCLC recurrence and drug resistance.
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Affiliation(s)
- Tianyu He
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanye Wang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wang Lv
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiqing Wang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinye Li
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingyi Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Han-Ming Shen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Faculty of Health Sciences, University of Macau, Macau, China.
| | - Jian Hu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Key Laboratory of Clinical Evaluation Technology for Medical Device of Zhejiang Province, Hangzhou, China.
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15
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Borlongan MC, Saha D, Wang H. Tumor Microenvironment: A Niche for Cancer Stem Cell Immunotherapy. Stem Cell Rev Rep 2024; 20:3-24. [PMID: 37861969 DOI: 10.1007/s12015-023-10639-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Tumorigenic Cancer Stem Cells (CSCs), often called tumor-initiating cells (TICs), represent a unique subset of cells within the tumor milieu. They stand apart from the bulk of tumor cells due to their exceptional self-renewal, metastatic, and differentiation capabilities. Despite significant progress in classifying CSCs, these cells remain notably resilient to conventional radiotherapy and chemotherapy, contributing to cancer recurrence. In this review, our objective is to explore novel avenues of research that delve into the distinctive characteristics of CSCs within their surrounding tumor microenvironment (TME). We will start with an overview of the defining features of CSCs and then delve into their intricate interactions with cells from the lymphoid lineage, namely T cells, B cells, and natural killer (NK) cells. Furthermore, we will discuss their dynamic interplay with myeloid lineage cells, including macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). Moreover, we will illuminate the crosstalk between CSCs and cells of mesenchymal origin, specifically fibroblasts, adipocytes, and endothelial cells. Subsequently, we will underscore the pivotal role of CSCs within the context of the tumor-associated extracellular matrix (ECM). Finally, we will highlight pre-clinical and clinical studies that target CSCs within the intricate landscape of the TME, including CAR-T therapy, oncolytic viruses, and CSC-vaccines, with the ultimate goal of uncovering novel avenues for CSC-based cancer immunotherapy.
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Affiliation(s)
- Mia C Borlongan
- College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA
| | - Dipongkor Saha
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
| | - Hongbin Wang
- College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
- Master Program of Pharmaceutical Sciences College of Graduate Studies, Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, Department of Basic Science College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
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16
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Sahoo L, Tripathy NS, Dilnawaz F. Naringenin Nanoformulations for Neurodegenerative Diseases. Curr Pharm Biotechnol 2024; 25:2108-2124. [PMID: 38347794 DOI: 10.2174/0113892010281459240118091137] [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: 10/12/2023] [Revised: 12/20/2023] [Accepted: 12/28/2023] [Indexed: 09/10/2024]
Abstract
Glioblastoma (GBM) is a grade-IV astrocytoma, which is the most common and aggressive type of brain tumor, spreads rapidly and has a life-threatening catastrophic effect. GBM mostly occurs in adults with an average survival time of 15 to 18 months, and the overall mortality rate is 5%. Significant invasion and drug resistance activity cause the poor diagnosis of GBM. Naringenin (NRG) is a plant secondary metabolite byproduct of the flavanone subgroup. NRG can cross the blood-brain barrier and deliver drugs into the central nervous system when conjugated with appropriate nanocarriers to overcome the challenges associated with gliomas through naringenin-loaded nanoformulations. Here, we discuss several nanocarriers employed that are as delivery systems, such as polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles (SLNs), nanosuspensions, and nanoemulsions. These naringenin-loaded nanoformulations have been tested in various in vitro and in vivo models as a potential treatment for brain disorders. This review nanoformulations of NRG can a possible therapeutic alternative for the treatment of neurological diseases are discussed.
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Affiliation(s)
- Liza Sahoo
- Department of Biotechnology, School of Engineering and Technology, Centurion University of Technology and Management, Jatni, 752050, Bhubaneswar, Odisha, India
| | - Nigam Sekhar Tripathy
- Department of Biotechnology, School of Engineering and Technology, Centurion University of Technology and Management, Jatni, 752050, Bhubaneswar, Odisha, India
| | - Fahima Dilnawaz
- Department of Biotechnology, School of Engineering and Technology, Centurion University of Technology and Management, Jatni, 752050, Bhubaneswar, Odisha, India
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17
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Liu Q, Guo Z, Li G, Zhang Y, Liu X, Li B, Wang J, Li X. Cancer stem cells and their niche in cancer progression and therapy. Cancer Cell Int 2023; 23:305. [PMID: 38041196 PMCID: PMC10693166 DOI: 10.1186/s12935-023-03130-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/09/2023] [Indexed: 12/03/2023] Open
Abstract
High recurrence and metastasis rates and poor prognoses are the major challenges of current cancer therapy. Mounting evidence suggests that cancer stem cells (CSCs) play an important role in cancer development, chemoradiotherapy resistance, recurrence, and metastasis. Therefore, targeted CSC therapy has become a new strategy for solving the problems of cancer metastasis and recurrence. Since the properties of CSCs are regulated by the specific tumour microenvironment, the so-called CSC niche, which targets crosstalk between CSCs and their niches, is vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. In this review, we aim to highlight the factors within the CSC niche that have important roles in regulating CSC properties, including the extracellular matrix (ECM), stromal cells (e.g., associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and mesenchymal stem cells (MSCs)), and physiological changes (e.g., inflammation, hypoxia, and angiogenesis). We also discuss recent progress regarding therapies targeting CSCs and their niche to elucidate developments of more effective therapeutic strategies to eliminate cancer.
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Affiliation(s)
- Qiuping Liu
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Zongliang Guo
- Department of General Surgery, Shanxi Province Cancer Hospital, Affiliated of Shanxi Medical University, Taiyuan, 030013, Shanxi, China
| | - Guoyin Li
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Yunxia Zhang
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Xiaomeng Liu
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Bing Li
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Jinping Wang
- Department of Ultrasound, Shanxi Province People's Hospital, Taiyuan, 030012, Shanxi, China.
| | - Xiaoyan Li
- Department of blood transfusion, Shanxi Provincial People's Hospital, Taiyuan, 030032, Shanxi, China.
- Department of central laboratory, Shanxi Provincial People's Hospital, Taiyuan, 030032, Shanxi, China.
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18
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Nowosad A, Marine JC, Karras P. Perivascular niches: critical hubs in cancer evolution. Trends Cancer 2023; 9:897-910. [PMID: 37453870 DOI: 10.1016/j.trecan.2023.06.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/15/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Tumors are heterogeneous ecosystems in which cancer cells coexist within a complex tumor immune microenvironment (TIME). The malignant, stromal, and immune cell compartments establish a plethora of bidirectional cell-cell communication crosstalks that influence tumor growth and metastatic dissemination, which we are only beginning to understand. Cancer cells either co-opt or promote the formation of new blood and lymphatic vessels to cope with their need for nutrients and oxygen. Recent studies have highlighted additional key roles for the tumor vasculature and have identified the perivascular niche as a cellular hub, where intricate and dynamic cellular interactions promote cancer stemness, immune evasion, dormancy, and metastatic spreading. Here, we review these findings, and discuss how they may be exploited therapeutically.
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Affiliation(s)
- Ada Nowosad
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jean-Christophe Marine
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
| | - Panagiotis Karras
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
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19
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Farouk SM, Khafaga AF, Abdellatif AM. Bladder cancer: therapeutic challenges and role of 3D cell culture systems in the screening of novel cancer therapeutics. Cancer Cell Int 2023; 23:251. [PMID: 37880676 PMCID: PMC10601189 DOI: 10.1186/s12935-023-03069-4] [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: 03/30/2023] [Accepted: 09/17/2023] [Indexed: 10/27/2023] Open
Abstract
Bladder cancer (BC) is the sixth most common worldwide urologic malignancy associated with elevated morbidity and mortality rates if not well treated. The muscle-invasive form of BC develops in about 25% of patients. Moreover, according to estimates, 50% of patients with invasive BC experience fatal metastatic relapses. Currently, resistance to drug-based therapy is the major tumble to BC treatment. The three-dimensional (3D) cell cultures are clearly more relevant not only as a novel evolving gadget in drug screening but also as a bearable therapeutic for different diseases. In this review, various subtypes of BC and mechanisms of drug resistance to the commonly used anticancer therapies are discussed. We also summarize the key lineaments of the latest cell-based assays utilizing 3D cell culture systems and their impact on understanding the pathophysiology of BC. Such knowledge could ultimately help to address the most efficient BC treatment.
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Affiliation(s)
- Sameh M Farouk
- Department of Cytology & Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt.
| | - Asmaa F Khafaga
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt
| | - Ahmed M Abdellatif
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.
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20
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Liu G, Zhang P, Chen S, Chen Z, Qiu Y, Peng P, Huang W, Cheng F, Zhang Y, Li H, Xiao Q, Mao F, Wang B, Jiang X, Wan F, Guo D, Yu X. FAM129A promotes self-renewal and maintains invasive status via stabilizing the Notch intracellular domain in glioma stem cells. Neuro Oncol 2023; 25:1788-1801. [PMID: 37083136 PMCID: PMC10547521 DOI: 10.1093/neuonc/noad079] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Glioma stem cells (GSCs) are a subpopulation of tumor cells with self-renewal and tumorigenic capabilities in glioblastomas (GBMs). Diffuse infiltration of GSCs facilitates tumor progression and frustrates efforts at effective treatment. Further compounding this situation is the currently limited understanding of what drives GSC invasion. Here we comprehensively evaluated the significance of a novel invasion-related protein, Family with Sequence Similarity 129 Member A (FAM129A), in infiltrative GSCs. METHODS Western blotting, immunohistochemistry, and gene expression analysis were used to quantify FAM129A in glioma specimens and cancer datasets. Overexpression and knockdown of FAM129A in GSCs were used to investigate its effects on tumor growth and invasion. RNA-seq, qRT-PCR, western blotting, and co-precipitation assays were used to investigate FAM129A signaling mechanisms. RESULTS FAM129A is preferentially expressed in invasive frontiers. Targeting FAM129A impairs GSC invasion and self-renewal. Mechanistically, FAM129A acted as a positive regulator of Notch signaling by binding with the Notch1 intracellular domain (NICD1) and preventing its degradation. CONCLUSIONS FAM129A and NICD1 provide a precise indicator for identifying tumor margins and aiding prognosis. Targeting them may provide a significantly therapeutic strategy for GSCs.
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Affiliation(s)
- Guohao Liu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Po Zhang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sui Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zirong Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanmei Qiu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Peng
- Department of Neurosurgery, Xiangyang Central Hospital, Affiliated Hospital to Hubei University of Arts and Science, Xiangyang, China
| | - Wenda Huang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fangling Cheng
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Zhang
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Li
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qungen Xiao
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Mao
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baofeng Wang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaobing Jiang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Wan
- Department of Neurosurgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Dongsheng Guo
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingjiang Yu
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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21
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Yuwen Y, Wang X, Liu J, Liu Z, Zhu H. Delta- like ligand 4- expressing macrophages and human diseases: Insights into pathophysiology and therapeutic opportunities. Heliyon 2023; 9:e20777. [PMID: 37842562 PMCID: PMC10569996 DOI: 10.1016/j.heliyon.2023.e20777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/20/2023] [Accepted: 10/06/2023] [Indexed: 10/17/2023] Open
Abstract
Macrophages are key players in the immune response and have been implicated in various human diseases, including atherosclerosis, cancer, and chronic inflammatory disorders. While numerous studies have delved into the nuances of macrophage behavior in these conditions, there remains a gap in understanding the specific role of Delta-like ligand 4 (Dll4)-expressing macrophages and their overarching implications across these diseases. Among the plethora of factors expressed by macrophages, Dll4 has emerged as a molecule of particular interest. Recent studies have highlighted its unique role in modulating macrophage functions and its potential implications in various diseases. This review seeks to consolidate existing knowledge, address this gap, and present a comprehensive overview of Dll4-expressing macrophages in the context of these disorders and highlight their potential as therapeutic targets. We examined the involvement of Dll4-expressing macrophages in multiple human diseases such as atherosclerosis, cancer and chronic inflammatory diseases, emphasizing their influence on disease progression. We also discussed the challenges, limitations, and emerging research areas in targeting Dll4-expressing macrophages and provide an outlook on potential therapeutic strategies for the treatment of these diseases. By addressing the previously existing research gap, we've provided a roadmap that brings together fragmented insights, paving the way for more holistic research and potentially more effective therapeutic strategies centered on Dll4-expressing macrophages.
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Affiliation(s)
- Ya Yuwen
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Medical School, Xizang Minzu University, Xianyang, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Jing Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Integrative Chinese and Western Medicine Key Laboratory of Atherosclerosis, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, China
| | - Haitao Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an, China
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22
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Lv S, Liu Y, Xie C, Xue C, Du S, Yao J. Emerging role of interactions between tumor angiogenesis and cancer stem cells. J Control Release 2023; 360:468-481. [PMID: 37391031 DOI: 10.1016/j.jconrel.2023.06.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/16/2023] [Accepted: 06/27/2023] [Indexed: 07/02/2023]
Abstract
Tumor angiogenesis and cancer stem cells (CSCs) are two major hallmarks of solid tumors. They have long received attention for their critical roles in tumor progression, metastasis and recurrence. Meanwhile, plenty of evidence indicates the close association between CSCs and tumor vasculature. CSCs are proven to promote tumor angiogenesis, and the highly vascularized tumor microenvironment further maintains CSCs growth in return, thereby forming a hard-breaking vicious circle to promote tumor development. Hence, though monotherapy targeting tumor vasculature or CSCs has been extensively studied over the past decades, the poor prognosis has been limiting the clinical application. This review summarizes the crosstalk between tumor vasculature and CSCs with emphasis on small-molecule compounds and the associated biological signaling pathways. We also highlight the importance of linking tumor vessels to CSCs to disrupt the CSCs-angiogenesis vicious circle. More precise treatment regimens targeting tumor vasculature and CSCs are expected to benefit future tumor treatment development.
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Affiliation(s)
- Shuai Lv
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Yufei Liu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Changheng Xie
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Chenyang Xue
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Shi Du
- Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
| | - Jing Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
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23
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Lin S, Li K, Qi L. Cancer stem cells in brain tumors: From origin to clinical implications. MedComm (Beijing) 2023; 4:e341. [PMID: 37576862 PMCID: PMC10412776 DOI: 10.1002/mco2.341] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/24/2023] [Accepted: 07/04/2023] [Indexed: 08/15/2023] Open
Abstract
Malignant brain tumors are highly heterogeneous tumors with a poor prognosis and a high morbidity and mortality rate in both children and adults. The cancer stem cell (CSC, also named tumor-initiating cell) model states that tumor growth is driven by a subset of CSCs. This model explains some of the clinical observations of brain tumors, including the almost unavoidable tumor recurrence after initial successful chemotherapy and/or radiotherapy and treatment resistance. Over the past two decades, strategies for the identification and characterization of brain CSCs have improved significantly, supporting the design of new diagnostic and therapeutic strategies for brain tumors. Relevant studies have unveiled novel characteristics of CSCs in the brain, including their heterogeneity and distinctive immunobiology, which have provided opportunities for new research directions and potential therapeutic approaches. In this review, we summarize the current knowledge of CSCs markers and stemness regulators in brain tumors. We also comprehensively describe the influence of the CSCs niche and tumor microenvironment on brain tumor stemness, including interactions between CSCs and the immune system, and discuss the potential application of CSCs in brain-based therapies for the treatment of brain tumors.
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Affiliation(s)
- Shuyun Lin
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
| | - Kaishu Li
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
| | - Ling Qi
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
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24
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Russo MN, Whaley LA, Norton ES, Zarco N, Guerrero-Cázares H. Extracellular vesicles in the glioblastoma microenvironment: A diagnostic and therapeutic perspective. Mol Aspects Med 2023; 91:101167. [PMID: 36577547 PMCID: PMC10073317 DOI: 10.1016/j.mam.2022.101167] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 11/29/2022] [Accepted: 12/12/2022] [Indexed: 12/28/2022]
Abstract
Glioblastoma (GBM), is the most malignant form of gliomas and the most common and lethal primary brain tumor in adults. Conventional cancer treatments have limited to no efficacy on GBM. GBM cells respond and adapt to the surrounding brain parenchyma known as tumor microenvironment (TME) to promote tumor preservation. Among specific TME, there are 3 of particular interest for GBM biology: the perivascular niche, the subventricular zone neurogenic niche, and the immune microenvironment. GBM cells and TME cells present a reciprocal feedback which results in tumor maintenance. One way that these cells can communicate is through extracellular vesicles. These vesicles include exosomes and microvesicles that have the ability to carry both cancerous and non-cancerous cargo, such as miRNA, RNA, proteins, lipids, and DNA. In this review we will discuss the booming topic that is extracellular vesicles, and how they have the novelty to be a diagnostic and targetable vehicle for GBM.
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Affiliation(s)
- Marissa N Russo
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA
| | - Lauren A Whaley
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Biology Graduate Program, University of North Florida, Jacksonville, FL, USA
| | - Emily S Norton
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA; Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Natanael Zarco
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA
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25
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Higginbottom SL, Tomaskovic-Crook E, Crook JM. Considerations for modelling diffuse high-grade gliomas and developing clinically relevant therapies. Cancer Metastasis Rev 2023; 42:507-541. [PMID: 37004686 PMCID: PMC10348989 DOI: 10.1007/s10555-023-10100-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/16/2023] [Indexed: 04/04/2023]
Abstract
Diffuse high-grade gliomas contain some of the most dangerous human cancers that lack curative treatment options. The recent molecular stratification of gliomas by the World Health Organisation in 2021 is expected to improve outcomes for patients in neuro-oncology through the development of treatments targeted to specific tumour types. Despite this promise, research is hindered by the lack of preclinical modelling platforms capable of recapitulating the heterogeneity and cellular phenotypes of tumours residing in their native human brain microenvironment. The microenvironment provides cues to subsets of glioma cells that influence proliferation, survival, and gene expression, thus altering susceptibility to therapeutic intervention. As such, conventional in vitro cellular models poorly reflect the varied responses to chemotherapy and radiotherapy seen in these diverse cellular states that differ in transcriptional profile and differentiation status. In an effort to improve the relevance of traditional modelling platforms, recent attention has focused on human pluripotent stem cell-based and tissue engineering techniques, such as three-dimensional (3D) bioprinting and microfluidic devices. The proper application of these exciting new technologies with consideration of tumour heterogeneity and microenvironmental interactions holds potential to develop more applicable models and clinically relevant therapies. In doing so, we will have a better chance of translating preclinical research findings to patient populations, thereby addressing the current derisory oncology clinical trial success rate.
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Affiliation(s)
- Sarah L Higginbottom
- Intelligent Polymer Research Institute, AIIM Facility, Innovation Campus, University of Wollongong, Fairy Meadow, NSW, 2519, Australia
- Arto Hardy Family Biomedical Innovation Hub, Chris O'Brien Lifehouse, Camperdown, NSW, 2050, Australia
| | - Eva Tomaskovic-Crook
- Intelligent Polymer Research Institute, AIIM Facility, Innovation Campus, University of Wollongong, Fairy Meadow, NSW, 2519, Australia.
- Arto Hardy Family Biomedical Innovation Hub, Chris O'Brien Lifehouse, Camperdown, NSW, 2050, Australia.
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.
| | - Jeremy M Crook
- Intelligent Polymer Research Institute, AIIM Facility, Innovation Campus, University of Wollongong, Fairy Meadow, NSW, 2519, Australia.
- Arto Hardy Family Biomedical Innovation Hub, Chris O'Brien Lifehouse, Camperdown, NSW, 2050, Australia.
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.
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26
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Shi T, Zhu J, Zhang X, Mao X. The Role of Hypoxia and Cancer Stem Cells in Development of Glioblastoma. Cancers (Basel) 2023; 15:cancers15092613. [PMID: 37174078 PMCID: PMC10177528 DOI: 10.3390/cancers15092613] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/22/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Glioblastoma multiform (GBM) is recognized as the most malignant brain tumor with a high level of hypoxia, containing a small population of glioblastoma stem like cells (GSCs). These GSCs have the capacity of self-renewal, proliferation, invasion and recapitulating the parent tumor, and are major causes of radio-and chemoresistance of GBM. Upregulated expression of hypoxia inducible factors (HIFs) in hypoxia fundamentally contributes to maintenance and progression of GSCs. Therefore, we thoroughly reviewed the currently acknowledged roles of hypoxia-associated GSCs in development of GBM. In detail, we recapitulated general features of GBM, especially GSC-related features, and delineated essential responses resulted from interactions between GSC and hypoxia, including hypoxia-induced signatures, genes and pathways, and hypoxia-regulated metabolic alterations. Five hypothesized GSC niches are discussed and integrated into one comprehensive concept: hypoxic peri-arteriolar niche of GSCs. Autophagy, another protective mechanism against chemotherapy, is also closely related to hypoxia and is a potential therapeutic target for GBM. In addition, potential causes of therapeutic resistance (chemo-, radio-, surgical-, immuno-), and chemotherapeutic agents which can improve the therapeutic effects of chemo-, radio-, or immunotherapy are introduced and discussed. At last, as a potential approach to reverse the hypoxic microenvironment in GBM, hyperbaric oxygen therapy (HBOT) might be an adjuvant therapy to chemo-and radiotherapy after surgery. In conclusion, we focus on demonstrating the important role of hypoxia on development of GBM, especially by affecting the function of GSCs. Important advantages have been made to understand the complicated responses induced by hypoxia in GBM. Further exploration of targeting hypoxia and GSCs can help to develop novel therapeutic strategies to improve the survival of GBM patients.
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Affiliation(s)
- Tingyu Shi
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
- Tangdu Hospital, Fourth Military Medical University, Xi'an 710024, China
| | - Jun Zhu
- State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Xiang Zhang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Xinggang Mao
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
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27
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Hasan SS, Fischer A. Notch Signaling in the Vasculature: Angiogenesis and Angiocrine Functions. Cold Spring Harb Perspect Med 2023; 13:a041166. [PMID: 35667708 PMCID: PMC9899647 DOI: 10.1101/cshperspect.a041166] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Formation of a functional blood vessel network is a complex process tightly controlled by pro- and antiangiogenic signals released within the local microenvironment or delivered through the bloodstream. Endothelial cells precisely integrate such temporal and spatial changes in extracellular signals and generate an orchestrated response by modulating signaling transduction, gene expression, and metabolism. A key regulator in vessel formation is Notch signaling, which controls endothelial cell specification, proliferation, migration, adhesion, and arteriovenous differentiation. This review summarizes the molecular biology of endothelial Notch signaling and how it controls angiogenesis and maintenance of the established, quiescent vasculature. In addition, recent progress in the understanding of Notch signaling in endothelial cells for controlling organ homeostasis by transcriptional regulation of angiocrine factors and its relevance to disease will be discussed.
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Affiliation(s)
- Sana S Hasan
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Andreas Fischer
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Institute for Clinical Chemistry, University Medical Center Göttingen, 37075 Göttingen, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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28
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Extracellular vesicles throughout development: A potential roadmap for emerging glioblastoma therapies. Semin Cell Dev Biol 2023; 133:32-41. [PMID: 35697594 DOI: 10.1016/j.semcdb.2022.05.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) are membrane-delimited vesicular bodies carrying different molecules, classified according to their size, density, cargo, and origin. Research on this topic has been actively growing through the years, as EVs are associated with critical pathological processes such as neurodegenerative diseases and cancer. Despite that, studies exploring the physiological functions of EVs are sparse, with particular emphasis on their role in organismal development, initial cell differentiation, and morphogenesis. In this review, we explore the topic of EVs from a developmental perspective, discussing their role in the earliest cell-fate decisions and neural tissue morphogenesis. We focus on the function of EVs through development to highlight possible conserved or novel processes that can impact disease progression. Specifically, we take advantage of what was learned about their role in development so far to discuss EVs impact on glioblastoma, a particular brain tumor of stem-cell origin and poor prognosis, and how their function can be hijacked to improve current therapies.
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29
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Chiu HW, Hung SW, Chiu CF, Hong JR. A Mitochondrion-Targeting Protein (B2) Primes ROS/Nrf2-Mediated Stress Signals, Triggering Apoptosis and Necroptosis in Lung Cancer. Biomedicines 2023; 11:biomedicines11010186. [PMID: 36672696 PMCID: PMC9855812 DOI: 10.3390/biomedicines11010186] [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: 10/04/2022] [Revised: 01/03/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
The betanodavirus B2 protein targets mitochondria and triggers mitochondrion-mediated cell death signaling in lung cancer cells; however, its molecular mechanism remains unknown. In this study, we observed that B2 triggers hydrogen peroxide/Nrf2-involved stress signals in the dynamic regulation of non-small lung cancer cell (NSCLC)-programmed cell death. Here, the B2 protein works as a necrotic inducer that triggers lung cancer death via p53 upregulation and RIP3 expression, suggesting a new perspective on lung cancer therapy. We employed the B2 protein to target A549 lung cancer cells and solid tumors in NOD/SCID mice. Tumors were collected and processed for the hematoxylin and eosin staining of tissue and cell sections, and their sera were used for blood biochemistry analysis. We observed that B2 killed an A549 cell-induced solid tumor in NOD/SCID mice; however, the mutant ΔB2 did not. In NOD/SCID mice, B2 (but not ΔB2) induced both p53/Bax-mediated apoptosis and RIPK3-mediated necroptosis. Finally, immunochemistry analysis showed hydrogen peroxide /p38/Nrf2 stress strongly inhibited the production of tumor markers CD133, Thy1, and napsin, which correlate with migration and invasion in cancer cells. This B2-triggered, ROS/Nrf2-mediated stress signal triggered multiple signals via pathways that killed A549 lung cancer tumor cells in vivo. Our results provide novel insight into lung cancer management and drug therapy.
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Affiliation(s)
- Hsuan-Wen Chiu
- Laboratory of Molecular Virology and Biotechnology, Institute of Biotechnology, National Cheng Kung University, Tainan 701, Taiwan
- Department of Biotechnology and Bioindustry, National Cheng Kung University, Tainan 701, Taiwan
| | - Shao-Wen Hung
- Division of Animal Industry, Animal Technology Research Center, Agricultural Technology Research Institute, Hsinchu 300, Taiwan
| | - Ching-Feng Chiu
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
- Graduate TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Jiann-Ruey Hong
- Laboratory of Molecular Virology and Biotechnology, Institute of Biotechnology, National Cheng Kung University, Tainan 701, Taiwan
- Department of Biotechnology and Bioindustry, National Cheng Kung University, Tainan 701, Taiwan
- Correspondence: ; Tel.: +886-6-2003082; Fax: +886-6-2766505
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30
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Zamfirescu AM, Yatsenko AS, Shcherbata HR. Notch signaling sculpts the stem cell niche. Front Cell Dev Biol 2022; 10:1027222. [PMID: 36605720 PMCID: PMC9810114 DOI: 10.3389/fcell.2022.1027222] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
Adult stem cells depend on their niches for regulatory signaling that controls their maintenance, division, and their progeny differentiation. While communication between various types of stem cells and their niches is becoming clearer, the process of stem cell niche establishment is still not very well understood. Model genetic organisms provide simplified systems to address various complex questions, for example, how is a stem cell niche formed? What signaling cascades induce the stem cell niche formation? Are the mechanisms of stem cell niche formation conserved? Notch signaling is an evolutionarily conserved pathway first identified in fruit flies, crucial in fate acquisition and spatiotemporal patterning. While the core logic behind its activity is fairly simple and requires direct cell-cell interaction, it reaches an astonishing complexity and versatility by combining its different modes of action. Subtleties such as equivalency between communicating cells, their physical distance, receptor and ligand processing, and endocytosis can have an effect on the way the events unfold, and this review explores some important general mechanisms of action, later on focusing on its involvement in stem cell niche formation. First, looking at invertebrates, we will examine how Notch signaling induces the formation of germline stem cell niche in male and female Drosophila. In the developing testis, a group of somatic gonadal precursor cells receive Delta signals from the gut, activating Notch signaling and sealing their fate as niche cells even before larval hatching. Meanwhile, the ovarian germline stem cell niche is built later during late larval stages and requires a two-step process that involves terminal filament formation and cap cell specification. Intriguingly, double security mechanisms of Notch signaling activation coordinated by the soma or the germline control both steps to ensure the robustness of niche assembly. Second, in the vast domains of mammalian cellular signaling, there is an emerging picture of Notch being an active player in a variety of tissues in health and disease. Notch involvement has been shown in stem cell niche establishment in multiple organs, including the brain, muscle, and intestine, where the stem cell niches are essential for the maintenance of adult stem cells. But adult stem cells are not the only cells looking for a home. Cancer stem cells use Notch signaling at specific stages to gain an advantage over endogenous tissue and overpower it, at the same time acquiring migratory and invasive abilities to claim new tissues (e.g., bone) as their territory. Moreover, in vitro models such as organoids reveal similar Notch employment when it comes to the developing stem cell niches. Therefore, a better understanding of the processes regulating stem cell niche assembly is key for the fields of stem cell biology and regenerative medicines.
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Affiliation(s)
| | | | - Halyna R. Shcherbata
- Mount Desert Island Biological Laboratory, Bar Harbor, ME, United States,*Correspondence: Halyna R. Shcherbata,
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31
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Alsina-Sanchis E, Mülfarth R, Moll I, Böhn S, Wiedmann L, Jordana-Urriza L, Ziegelbauer T, Zimmer E, Taylor J, De Angelis Rigotti F, Stögbauer A, Giaimo BD, Cerwenka A, Borggrefe T, Fischer A, Rodriguez-Vita J. Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages. Cancer Res 2022; 82:4414-4428. [PMID: 36200806 DOI: 10.1158/0008-5472.can-22-0076] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 08/03/2022] [Accepted: 09/30/2022] [Indexed: 01/24/2023]
Abstract
Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic cancers worldwide. EOC cells educate tumor-associated macrophages (TAM) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (EC) to facilitate metastasis. However, further work is required to establish whether the endothelium also influences the education of recruited monocytes. Here, we report that canonical Notch signaling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature; this was associated with stronger cytotoxic activity of T cells and decreased tumor burden. Mechanistically, CXCL2 was identified as a novel Notch/RBPJ target gene that regulated the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. Together, these findings indicate that EOC cells induce the tumor endothelium to secrete CXCL2 to establish an immunosuppressive microenvironment. SIGNIFICANCE Endothelial Notch signaling favors immunosuppression by increasing CXCL2 secretion to stimulate CD44 expression in macrophages, facilitating their education by tumor cells.
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Affiliation(s)
- Elisenda Alsina-Sanchis
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute for Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany
| | - Ronja Mülfarth
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Iris Moll
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sarah Böhn
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lena Wiedmann
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Lorea Jordana-Urriza
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tara Ziegelbauer
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Eleni Zimmer
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jacqueline Taylor
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Francesca De Angelis Rigotti
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Tumour-Stroma Communication Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Adrian Stögbauer
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Adelheid Cerwenka
- Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany Tissue
| | - Tilman Borggrefe
- Institute of Biochemistry, University of Giessen, Giessen, Germany
| | - Andreas Fischer
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute for Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany
| | - Juan Rodriguez-Vita
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Tumour-Stroma Communication Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
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32
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Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm (Beijing) 2022; 3:e176. [PMID: 36226253 PMCID: PMC9534377 DOI: 10.1002/mco2.176] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
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Affiliation(s)
- Wang Manni
- Department of Biotherapy, Cancer Center, West China HospitalSichuan UniversityChengduP. R. China
| | - Wu Min
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
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33
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Ishikawa T, Ogura Y, Tanaka K, Nagashima H, Sasayama T, Endo M, Minami Y. Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell-like property of glioblastoma cells. Cancer Sci 2022; 114:561-573. [PMID: 36314076 PMCID: PMC9899608 DOI: 10.1111/cas.15630] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/27/2022] [Accepted: 10/13/2022] [Indexed: 02/07/2023] Open
Abstract
Ror1 plays a crucial role in cancer progression by regulating cell proliferation and migration. Ror1 is expressed abundantly in various types of cancer cells and cancer stem-like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of Ror1 expression are correlated positively with poorer prognosis in patients with gliomas. We show that Ror1 expression can be upregulated in glioblastoma cells under spheroid culture, but not adherent culture conditions. Notch and hypoxia signaling pathways have been shown to be activated in spheroid-forming glioblastoma stem-like cells (GSCs), and Ror1 expression in glioblastoma cells is indeed suppressed by inhibiting either Notch or hypoxia signaling. Meanwhile, either forced expression of the Notch intracellular domain (NICD) in or hypoxic culture of glioblastoma cells result in enhanced expression of Ror1 in the cells. Consistently, we show that both NICD and hypoxia-inducible factor 1 alpha bind to upstream regions within the Ror1 gene more efficiently in GSCs under spheroid culture conditions. Furthermore, we provide evidence indicating that binding of Wnt5a to Ror1, upregulated by Notch and hypoxia signaling pathways in GSCs, might promote their spheroid-forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a-Ror1 axis through transcriptional activation of Ror1 in glioblastoma cells, thereby promoting their stem cell-like property.
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Affiliation(s)
- Tomohiro Ishikawa
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of MedicineKobe UniversityKobeJapan
| | - Yasuka Ogura
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of MedicineKobe UniversityKobeJapan
| | - Kazuhiro Tanaka
- Department of Neurosurgery, Graduate School of MedicineKobe UniversityKobeJapan
| | - Hiroaki Nagashima
- Department of Neurosurgery, Graduate School of MedicineKobe UniversityKobeJapan
| | - Takashi Sasayama
- Department of Neurosurgery, Graduate School of MedicineKobe UniversityKobeJapan
| | - Mitsuharu Endo
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of MedicineKobe UniversityKobeJapan
| | - Yasuhiro Minami
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of MedicineKobe UniversityKobeJapan
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Ngo MT, Sarkaria JN, Harley BA. Perivascular Stromal Cells Instruct Glioblastoma Invasion, Proliferation, and Therapeutic Response within an Engineered Brain Perivascular Niche Model. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201888. [PMID: 36109186 PMCID: PMC9631060 DOI: 10.1002/advs.202201888] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/12/2022] [Indexed: 06/15/2023]
Abstract
Glioblastoma (GBM) tumor cells are found in the perivascular niche microenvironment and are believed to associate closely with the brain microvasculature. However, it is largely unknown how the resident cells of the perivascular niche, such as endothelial cells, pericytes, and astrocytes, influence GBM tumor cell behavior and disease progression. A 3D in vitro model of the brain perivascular niche developed by encapsulating brain-derived endothelial cells, pericytes, and astrocytes in a gelatin hydrogel is described. It is shown that brain perivascular stromal cells, namely pericytes and astrocytes, contribute to vascular architecture and maturation. Cocultures of patient-derived GBM tumor cells with brain microvascular cells are used to identify a role for pericytes and astrocytes in establishing a perivascular niche environment that modulates GBM cell invasion, proliferation, and therapeutic response. Engineered models provide unique insight regarding the spatial patterning of GBM cell phenotypes in response to a multicellular model of the perivascular niche. Critically, it is shown that engineered perivascular models provide an important resource to evaluate mechanisms by which intercellular interactions modulate GBM tumor cell behavior, drug response, and provide a framework to consider patient-specific disease phenotypes.
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Affiliation(s)
- Mai T. Ngo
- Department Chemical and Biomolecular EngineeringUniversity of Illinois Urbana‐ChampaignUrbanaIL61801USA
| | | | - Brendan A.C. Harley
- Department Chemical and Biomolecular EngineeringUniversity of Illinois Urbana‐ChampaignUrbanaIL61801USA
- Carl R. Woese Institute for Genomic BiologyUniversity of Illinois Urbana‐ChampaignUrbanaIL61801USA
- Cancer Center at IllinoisUniversity of Illinois Urbana‐ChampaignUrbanaIL61801USA
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35
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Brooks LJ, Simpson Ragdale H, Hill CS, Clements M, Parrinello S. Injury programs shape glioblastoma. Trends Neurosci 2022; 45:865-876. [PMID: 36089406 DOI: 10.1016/j.tins.2022.08.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/30/2022] [Accepted: 08/09/2022] [Indexed: 11/20/2022]
Abstract
Glioblastoma is the most common and aggressive primary brain cancer in adults and is almost universally fatal due to its stark therapeutic resistance. During the past decade, although survival has not substantially improved, major advances have been made in our understanding of the underlying biology. It has become clear that these devastating tumors recapitulate features of neurodevelopmental hierarchies which are influenced by the microenvironment. Emerging evidence also highlights a prominent role for injury responses in steering cellular phenotypes and contributing to tumor heterogeneity. This review highlights how the interplay between injury and neurodevelopmental programs impacts on tumor growth, invasion, and treatment resistance, and discusses potential therapeutic considerations in view of these findings.
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Affiliation(s)
- Lucy J Brooks
- Samantha Dickson Brain Cancer Unit, Department of Cancer Biology, University College London Cancer Institute, London, UK.
| | - Holly Simpson Ragdale
- Samantha Dickson Brain Cancer Unit, Department of Cancer Biology, University College London Cancer Institute, London, UK
| | - Ciaran Scott Hill
- Samantha Dickson Brain Cancer Unit, Department of Cancer Biology, University College London Cancer Institute, London, UK; Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
| | - Melanie Clements
- Samantha Dickson Brain Cancer Unit, Department of Cancer Biology, University College London Cancer Institute, London, UK
| | - Simona Parrinello
- Samantha Dickson Brain Cancer Unit, Department of Cancer Biology, University College London Cancer Institute, London, UK.
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Chen HM, Nikolic A, Singhal D, Gallo M. Roles of Chromatin Remodelling and Molecular Heterogeneity in Therapy Resistance in Glioblastoma. Cancers (Basel) 2022; 14:4942. [PMID: 36230865 PMCID: PMC9563350 DOI: 10.3390/cancers14194942] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 09/29/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer stem cells (CSCs) represent a therapy-resistant reservoir in glioblastoma (GBM). It is now becoming clear that epigenetic and chromatin remodelling programs link the stemlike behaviour of CSCs to their treatment resistance. New evidence indicates that the epigenome of GBM cells is shaped by intrinsic and extrinsic factors, including their genetic makeup, their interactions and communication with other neoplastic and non-neoplastic cells, including immune cells, and their metabolic niche. In this review, we explore how all these factors contribute to epigenomic heterogeneity in a tumour and the selection of therapy-resistant cells. Lastly, we discuss current and emerging experimental platforms aimed at precisely understanding the epigenetic mechanisms of therapy resistance that ultimately lead to tumour relapse. Given the growing arsenal of drugs that target epigenetic enzymes, our review addresses promising preclinical and clinical applications of epidrugs to treat GBM, and possible mechanisms of resistance that need to be overcome.
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Affiliation(s)
- Huey-Miin Chen
- Arnie Charbonneau Cancer Institute, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Ana Nikolic
- Arnie Charbonneau Cancer Institute, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Divya Singhal
- Arnie Charbonneau Cancer Institute, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Marco Gallo
- Arnie Charbonneau Cancer Institute, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
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Song S, Wu H, Wang F, Jiao J, Xu L, Wang H, Tong X, Yan H. Global research trends and hotspots on glioma stem cells. Front Oncol 2022; 12:926025. [PMID: 36248966 PMCID: PMC9558893 DOI: 10.3389/fonc.2022.926025] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundGlioma stem cells (GSCs) are a sub-population of cancer stem cells with capacity of self-renewal and differentiation. Accumulated evidence has revealed that GSCs were shown to contribute to gliomagenesis, distant metastasis as well as the resistance to radiotherapy and chemotherapy. As a result, GSCs were regarded as a promising therapeutic target in human glioma. The purpose of our study is to identify current state and hotspots of GSCs research by analyzing scientific publications through bibliometric methods.MethodsAll relevant publications on GSCs during 2003-2021 were extracted from the Science Citation Index Expanded of Web of Science Core Collection (WoSCC), and related information was collected and analyzed using Microsoft Excel 2016, GraphPad Prism 8 and VOSviewer software.ResultsA total of 4990 papers were included. The United States accounted for the largest number of publications (1852), the second average citations per item (ACI) value (67.54) as well as the highest H-index (157). Cancer Research was the most influential journal in this field. The most contributive institution was League of European Research Universities. RICH JN was the author with the most publications (109) and the highest H-index (59). All studies were clustered into 3 groups: “glioma stem cell properties”, “cell biological properties” and “oncology therapy”. The keywords “identification”, “CD133” and “side population” appeared earlier with the smaller average appearing years (AAY), and the keywords”radiotherapy” and “chemotherapy” had the latest AAY. The analysis of top cited articles showed that “temozolomide”, “epithelial-mesenchymal transition”, and “immunotherapy” emerged as new focused issues.ConclusionThere has been a growing number of researches on GSCs. The United States has always been a leading player in this domain. In general, the research focus has gradually shifted from basic cellular biology to the solutions of clinical concerns. “Temozolomide resistance”, “epithelial-mesenchymal transition”, and “immunotherapy” should be given more attention in the future.
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Affiliation(s)
- Sirong Song
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Haiyang Wu
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Fanchen Wang
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Jiji Jiao
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Lixia Xu
- Tianjin Neurosurgical Institute, Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin, China
| | - Hongguang Wang
- Tianjin Neurosurgical Institute, Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin, China
- Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China
- *Correspondence: Hua Yan, ; Hongguang Wang, ; Xiaoguang Tong,
| | - Xiaoguang Tong
- Tianjin Neurosurgical Institute, Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin, China
- Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China
- *Correspondence: Hua Yan, ; Hongguang Wang, ; Xiaoguang Tong,
| | - Hua Yan
- Tianjin Neurosurgical Institute, Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin, China
- Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China
- *Correspondence: Hua Yan, ; Hongguang Wang, ; Xiaoguang Tong,
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Gimple RC, Yang K, Halbert ME, Agnihotri S, Rich JN. Brain cancer stem cells: resilience through adaptive plasticity and hierarchical heterogeneity. Nat Rev Cancer 2022; 22:497-514. [PMID: 35710946 DOI: 10.1038/s41568-022-00486-x] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/03/2022] [Indexed: 02/07/2023]
Abstract
Malignant brain tumours are complex ecosystems containing neoplastic and stromal components that generate adaptive and evolutionarily driven aberrant tissues in the central nervous system. Brain cancers are cultivated by a dynamic population of stem-like cells that enforce intratumoural heterogeneity and respond to intrinsic microenvironment or therapeutically guided insults through proliferation, plasticity and restructuring of neoplastic and stromal components. Far from a rigid hierarchy, heterogeneous neoplastic populations transition between cellular states with differential self-renewal capacities, endowing them with powerful resilience. Here we review the biological machinery used by brain tumour stem cells to commandeer tissues in the intracranial space, evade immune responses and resist chemoradiotherapy. Through recent advances in single-cell sequencing, improved models to investigate the role of the tumour microenvironment and a deeper understanding of the fundamental role of the immune system in cancer biology, we are now better equipped to explore mechanisms by which these processes can be exploited for therapeutic benefit.
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Affiliation(s)
- Ryan C Gimple
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Kailin Yang
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Matthew E Halbert
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sameer Agnihotri
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jeremy N Rich
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
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Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma. Cells 2022; 11:cells11162530. [PMID: 36010607 PMCID: PMC9406959 DOI: 10.3390/cells11162530] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies.
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40
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Park S, Avera AD, Kim Y. BIOMANUFACTURING OF GLIOBLASTOMA ORGANOIDS EXHIBITING HIERARCHICAL AND SPATIALLY ORGANIZED TUMOR MICROENVIRONMENT VIA TRANSDIFFERENTIATION. Biotechnol Bioeng 2022; 119:3252-3274. [DOI: 10.1002/bit.28191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 07/14/2022] [Accepted: 07/20/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Seungjo Park
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
| | - Alexandra D. Avera
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
| | - Yonghyun Kim
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
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41
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Sengupta S, Mondal M, Prasasvi KR, Mukherjee A, Magod P, Urbach S, Friedmann-Morvinski D, Marin P, Somasundaram K. Differentiated glioma cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth. eLife 2022; 11:78972. [PMID: 35642785 PMCID: PMC9259034 DOI: 10.7554/elife.78972] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/29/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) alone can initiate and maintain tumors, but the function of non-cancer stem cells (non-CSCs) that form the tumor bulk remains poorly understood. Proteomic analysis showed a higher abundance of the extracellular matrix small leucine-rich proteoglycan fibromodulin (FMOD) in the conditioned medium of differentiated glioma cells (DGCs), the equivalent of glioma non-CSCs, compared to that of glioma stem-like cells (GSCs). DGCs silenced for FMOD fail to cooperate with co-implanted GSCs to promote tumor growth. FMOD downregulation neither affects GSC growth and differentiation nor DGC growth and reprogramming in vitro. DGC-secreted FMOD promotes angiogenesis by activating integrin-dependent Notch signaling in endothelial cells. Furthermore, conditional silencing of FMOD in newly generated DGCs in vivo inhibits the growth of GSC-initiated tumors due to poorly developed vasculature and increases mouse survival. Collectively, these findings demonstrate that DGC-secreted FMOD promotes glioma tumor angiogenesis and growth through paracrine signaling in endothelial cells and identifies a DGC-produced protein as a potential therapeutic target in glioma.
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Affiliation(s)
- Shreoshi Sengupta
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Mainak Mondal
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Kaval Reddy Prasasvi
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Arani Mukherjee
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Prerna Magod
- School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel
| | - Serge Urbach
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | | | - Philippe Marin
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Kumaravel Somasundaram
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
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Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment. Cancer Metastasis Rev 2022; 41:737-747. [PMID: 35624227 DOI: 10.1007/s10555-022-10041-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 05/18/2022] [Indexed: 11/02/2022]
Abstract
Glioblastoma is the most malignant form of glioma, which is the most commonly occurring tumor of the central nervous system. Notch signaling in glioblastoma is considered to be a marker of an undifferentiated tumor cell state, associated with tumor stem cells. Notch is also known for facilitating tumor dormancy escape, recurrence and progression after treatment. Studies in vitro suggest that reducing, removing or blocking the expression of this gene triggers tumor cell differentiation, which shifts the phenotype away from stemness status and consequently facilitates treatment. In contrast, in the vasculature, Notch appears to also function as an important receptor that defines mature non-leaking vessels, and increasing its expression promotes tumor normalization in models of cancer in vivo. Failures in clinical trials with Notch inhibitors are potentially related to their opposing effects on the tumor versus the tumor vasculature, which points to the need for a greater understanding of this signaling pathway.
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Ribatti D, Pezzella F. Vascular Co-Option and Other Alternative Modalities of Growth of Tumor Vasculature in Glioblastoma. Front Oncol 2022; 12:874554. [PMID: 35433447 PMCID: PMC9005970 DOI: 10.3389/fonc.2022.874554] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/04/2022] [Indexed: 12/12/2022] Open
Abstract
Non-angiogenic tumors grow in the absence of angiogenesis by two main mechanisms: cancer cells infiltrating and occupying the normal tissues to exploit pre-existing vessels (vascular co-option); the cancer cells themselves forms channels able to provide blood flow (the so called vasculogenic mimicry). In the original work on vascular co-option initiated by Francesco Pezzella, the non-angiogenic cancer cells were described as “exploiting” pre-existing vessels. Vascular co-option has been described in primary and secondary (metastatic) sites. Vascular co-option is defined as a process in which tumor cells interact with and exploit the pre-existing vasculature of the normal tissue in which they grow. As part of this process, cancer cells first migrate toward vessels of the primary tumor, or extravasate at a metastatic site and rest along the ab-luminal vascular surface. The second hallmark of vascular co-option is the interaction of cancer cells with the ab-luminal vascular surface. The first evidence for this was provided in a rat C6 glioblastoma model, showing that the initial tumor growth phase was not always avascular as these initial tumors can be vascularized by pre-existing vessels. The aim of this review article is to analyze together with vascular co-option, other alternative mode of vascularization occurring in glioblastoma multiforme (GBM), including vasculogenic mimicry, angiotropism and trans-differentiation of glioblastoma stem cells.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Francesco Pezzella
- Nuffield Division of Laboratory Science, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
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Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther 2022; 7:95. [PMID: 35332121 PMCID: PMC8948217 DOI: 10.1038/s41392-022-00934-y] [Citation(s) in RCA: 536] [Impact Index Per Article: 178.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
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Fasoulakis Z, Koutras A, Ntounis T, Pergialiotis V, Chionis A, Katrachouras A, Palios VC, Symeonidis P, Valsamaki A, Syllaios A, Diakosavvas M, Angelou K, Samara AA, Pagkalos A, Theodora M, Schizas D, Kontomanolis EN. The Prognostic Role and Significance of Dll4 and Toll-like Receptors in Cancer Development. Cancers (Basel) 2022; 14:1649. [PMID: 35406423 PMCID: PMC8996945 DOI: 10.3390/cancers14071649] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/05/2022] [Accepted: 03/18/2022] [Indexed: 02/01/2023] Open
Abstract
The Notch signaling pathway regulates the development of embryonic and tissue homeostasis of various types of cells. It also controls cell proliferation, variation, fate and cell death because it emits short-range messages to nearby cells. The pathway plays an important role in the pathophysiology of various malignancies, controlling cancer creation. It also limits cancer development by adjusting preserved angiogenesis and cellular programs. One of the Notch signaling ligands (in mammals) is Delta-like ligand 4 (Dll4), which plays a significant role in the overall malignancies' advancement. Particularly, sequencing Notch gene mutations, including those of Dll4, have been detected in many types of cancers portraying information on the growth of particular gynecological types of tumors. The current research article examines the background theory that implies the ability of Dll4 in the development of endometrial and other cancer types, and the probable therapeutic results of Dll4 inhibition.
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Affiliation(s)
- Zacharias Fasoulakis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece; (Z.F.); (A.K.); (T.N.); (V.P.); (M.D.); (K.A.); (M.T.)
| | - Antonios Koutras
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece; (Z.F.); (A.K.); (T.N.); (V.P.); (M.D.); (K.A.); (M.T.)
| | - Thomas Ntounis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece; (Z.F.); (A.K.); (T.N.); (V.P.); (M.D.); (K.A.); (M.T.)
| | - Vasilios Pergialiotis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece; (Z.F.); (A.K.); (T.N.); (V.P.); (M.D.); (K.A.); (M.T.)
| | - Athanasios Chionis
- Department of Obstetrics and Gynecology, Laiko General Hospital of Athens, Agiou Thoma 17, 11527 Athens, Greece;
| | - Alexandros Katrachouras
- Department of Obstetrics and Gynecology, University of Ioannina, University General Hospital of Ioannina, Stavros Niarchos Str., 45500 Ioannina, Greece;
| | - Vasileios-Chrysovalantis Palios
- Department of Obstetrics and Gynecology, University of Larisa, University General Hospital of Larisa, Mezourlo, 41110 Larisa, Greece;
| | - Panagiotis Symeonidis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Vasilissis Sofias Str. 12, 67100 Alexandroupolis, Greece; (P.S.); (E.N.K.)
| | - Asimina Valsamaki
- Department of Internal Medicine, General Hospital of Larisa, Tsakal of 1, 41221 Larisa, Greece;
| | - Athanasios Syllaios
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Agiou Thoma Str. 17, 11527 Athens, Greece
| | - Michail Diakosavvas
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece; (Z.F.); (A.K.); (T.N.); (V.P.); (M.D.); (K.A.); (M.T.)
| | - Kyveli Angelou
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece; (Z.F.); (A.K.); (T.N.); (V.P.); (M.D.); (K.A.); (M.T.)
| | - Athina A. Samara
- Department of Surgery, University Hospital of Larissa, Mezourlo, 41110 Larissa, Greece;
| | - Athanasios Pagkalos
- Department of Obstetrics and Gynecology, General Hospital of Xanthi, Neapoli, 67100 Xanthi, Greece;
| | - Marianna Theodora
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece; (Z.F.); (A.K.); (T.N.); (V.P.); (M.D.); (K.A.); (M.T.)
| | - Dimitrios Schizas
- 1st Department of Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Emmanuel N. Kontomanolis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Vasilissis Sofias Str. 12, 67100 Alexandroupolis, Greece; (P.S.); (E.N.K.)
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Liu C, Chen Q, Shang Y, Chen L, Myers J, Awadallah A, Sun J, Yu S, Umphred-Wilson K, Che D, Dou Y, Li L, Wearsch P, Ramírez-Bergeron D, Beck R, Xin W, Jin G, Adoro S, Zhou L. Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche. Theranostics 2022; 12:2894-2907. [PMID: 35401837 PMCID: PMC8965499 DOI: 10.7150/thno.67710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 03/06/2022] [Indexed: 11/22/2022] Open
Abstract
The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL). Methods: in this study, we assessed the transcriptomic and phenotypic alterations in UPR response of the bone marrow endothelial cells (ECs) in mice engrafted with T-ALL and in bone marrow specimens from patients who have T-ALL. We used PERK inhibitor and generated endothelial specific PERK knockout mice to study the impact of PERK on leukemia progression and hematopoiesis. We performed chromatin immunoprecipitation (ChIP) to study the mechanistic regulation of JAG1 by ATF4. We characterized small extracellular vesicles (SEV) from leukemia-developing mice and studied the effect of SEVs on EC function. Results: we found that T-ALL development induced a robust activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dominant UPR in the bone marrow endothelial vascular niche. The activation of PERK-eIF2a-ATF4 axis remodels the vascular niche, upregulates angiogenic factors including VEGFα and ATF4-regulated JAG1, and suppresses the expression of SCF and CXCL12, which are important to HSC maintenance and regeneration. Further, targeting endothelial PERK significantly improved T-ALL outcome. EC-specific deletion of PERK abolished the aberrant JAG1 up-regulation, improved HSC maintenance, promoted leukemia apoptosis, and improved overall survival. Finally, we showed that small extracellular vesicles are critical mediators of endothelial PERK-eIF2a-ATF4 activation and JAG1 up-regulation in leukemia. Corroborating animal model studies, activation of PERK-ATF4-JAG1 is prominent in human T-ALL bone marrow and T-ALL xenografts. Conclusion: our studies thus revealed for the first time that the leukemia-initiated PERK-ATF4-JAG1 axis plays a critical role in the remodeling of the bone marrow vascular niche and that targeting vascular niche UPR is a potential therapeutic opportunity in T-ALL.
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Affiliation(s)
- Cui Liu
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Qiuyun Chen
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Yinghui Shang
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Lechuang Chen
- Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jay Myers
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Amad Awadallah
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Jinger Sun
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Shuiliang Yu
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | | | - Danian Che
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Yingtong Dou
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Luoyi Li
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Pamela Wearsch
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | | | - Rose Beck
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Wei Xin
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Ge Jin
- Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Stanley Adoro
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lan Zhou
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
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Beiriger J, Habib A, Jovanovich N, Kodavali CV, Edwards L, Amankulor N, Zinn PO. The Subventricular Zone in Glioblastoma: Genesis, Maintenance, and Modeling. Front Oncol 2022; 12:790976. [PMID: 35359410 PMCID: PMC8960165 DOI: 10.3389/fonc.2022.790976] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.
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Affiliation(s)
- Jamison Beiriger
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Ahmed Habib
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Nicolina Jovanovich
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Chowdari V. Kodavali
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Lincoln Edwards
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Nduka Amankulor
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Pascal O. Zinn
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
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48
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Uribe D, Niechi I, Rackov G, Erices JI, San Martín R, Quezada C. Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity. BIOLOGY 2022; 11:313. [PMID: 35205179 PMCID: PMC8869716 DOI: 10.3390/biology11020313] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is the most frequent and aggressive brain tumor, characterized by great resistance to treatments, as well as inter- and intra-tumoral heterogeneity. GBM exhibits infiltration, vascularization and hypoxia-associated necrosis, characteristics that shape a unique microenvironment in which diverse cell types are integrated. A subpopulation of cells denominated GBM stem-like cells (GSCs) exhibits multipotency and self-renewal capacity. GSCs are considered the conductors of tumor progression due to their high tumorigenic capacity, enhanced proliferation, invasion and therapeutic resistance compared to non-GSCs cells. GSCs have been classified into two molecular subtypes: proneural and mesenchymal, the latter showing a more aggressive phenotype. Tumor microenvironment and therapy can induce a proneural-to-mesenchymal transition, as a mechanism of adaptation and resistance to treatments. In addition, GSCs can transition between quiescent and proliferative substates, allowing them to persist in different niches and adapt to different stages of tumor progression. Three niches have been described for GSCs: hypoxic/necrotic, invasive and perivascular, enhancing metabolic changes and cellular interactions shaping GSCs phenotype through metabolic changes and cellular interactions that favor their stemness. The phenotypic flexibility of GSCs to adapt to each niche is modulated by dynamic epigenetic modifications. Methylases, demethylases and histone deacetylase are deregulated in GSCs, allowing them to unlock transcriptional programs that are necessary for cell survival and plasticity. In this review, we described the effects of GSCs plasticity on GBM progression, discussing the role of GSCs niches on modulating their phenotype. Finally, we described epigenetic alterations in GSCs that are important for stemness, cell fate and therapeutic resistance.
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Affiliation(s)
- Daniel Uribe
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Ignacio Niechi
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Gorjana Rackov
- Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), 28049 Madrid, Spain;
| | - José I. Erices
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Rody San Martín
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Claudia Quezada
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
- Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile
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49
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Rusu MC, Vrapciu AD, Nicolescu MI, Stoenescu MD, Jianu AM, Lighezan R, Oancea R, Mănoiu VS, Hostiuc S. Extruded Nucleoli of Human Dental Pulp Cells. Medicina (B Aires) 2022; 58:medicina58020260. [PMID: 35208583 PMCID: PMC8876639 DOI: 10.3390/medicina58020260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/04/2022] [Accepted: 02/06/2022] [Indexed: 11/22/2022] Open
Abstract
Background and Objectives: The dental pulp stem cells are highly proliferative and can differentiate into various cell types, including endothelial cells. We aimed to evaluate the ultrastructural characteristics of the human dental pulp cells of the permanent frontal teeth. Materials and Methods: Human adult bioptic dental pulp was collected from n = 10 healthy frontal teeth of five adult patients, prior to prosthetic treatments for aesthetic purposes. Tissues were examined under transmission electron microscopy. Results: We identified cells with a peculiar trait: giant nucleoli resembling intranuclear endoplasmic reticulum, which mimicked extrusion towards the cytoplasm. These were either partly embedded within the nuclei, the case in which their adnuclear side was coated by marginal heterochromatin and the abnuclear side was coated by a thin rim of ribosomes, or were apparently isolated from the nuclei, while still being covered by ribosomes. Conclusions: Similar electron microscopy features were previously reported in the human endometrium, as nucleolar channel system; or R-Rings induced by Nopp140. To our knowledge, this is the first report of extruded nucleolar structure in the dental pulp. Moreover, the aspect of giant extruded nucleoli was not previously reported in any human cell type, although similar evidence was gathered in other species as well as in plants.
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Affiliation(s)
- Mugurel Constantin Rusu
- Division of Anatomy, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.C.R.); (A.D.V.)
| | - Alexandra Diana Vrapciu
- Division of Anatomy, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.C.R.); (A.D.V.)
| | - Mihnea Ioan Nicolescu
- Division of Histology, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Laboratory of Radiobiology, “Victor Babeș” National Institute of Pathology, 050096 Bucharest, Romania
- Correspondence: (M.I.N.); (A.M.J.)
| | - Mihai Dragomir Stoenescu
- Research Department, “Dr. Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania;
| | - Adelina Maria Jianu
- Department of Anatomy, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timişoara, Romania
- Correspondence: (M.I.N.); (A.M.J.)
| | - Rodica Lighezan
- Department of Histology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timişoara, Romania;
| | - Roxana Oancea
- Department of Preventive and Community Dentistry, Faculty of Dental Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timişoara, Romania;
| | - Vasile Sorin Mănoiu
- Department of Cellular and Molecular Biology, National Institute of Research and Development for Biological Sciences, 060031 Bucharest, Romania;
| | - Sorin Hostiuc
- Division of Legal Medicine, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
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50
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Beeghly GF, Amofa KY, Fischbach C, Kumar S. Regulation of Tumor Invasion by the Physical Microenvironment: Lessons from Breast and Brain Cancer. Annu Rev Biomed Eng 2022; 24:29-59. [PMID: 35119915 DOI: 10.1146/annurev-bioeng-110220-115419] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The success of anticancer therapies is often limited by heterogeneity within and between tumors. While much attention has been devoted to understanding the intrinsic molecular diversity of tumor cells, the surrounding tissue microenvironment is also highly complex and coevolves with tumor cells to drive clinical outcomes. Here, we propose that diverse types of solid tumors share common physical motifs that change in time and space, serving as universal regulators of malignancy. We use breast cancer and glioblastoma as instructive examples and highlight how invasion in both diseases is driven by the appropriation of structural guidance cues, contact-dependent heterotypic interactions with stromal cells, and elevated interstitial fluid pressure and flow. We discuss how engineering strategies show increasing value for measuring and modeling these physical properties for mechanistic studies. Moreover, engineered systems offer great promise for developing and testing novel therapies that improve patient prognosis by normalizing the physical tumor microenvironment. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 24 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Garrett F Beeghly
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA;
| | - Kwasi Y Amofa
- University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, Berkeley, California, USA; .,Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA
| | - Claudia Fischbach
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA; .,Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York, USA
| | - Sanjay Kumar
- University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, Berkeley, California, USA; .,Department of Bioengineering, University of California, Berkeley, Berkeley, California, USA.,Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, California, USA.,Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA
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