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Yin F, He Y, Qiao Y, Yan Y. Tumor-derived vesicles in immune modulation: focus on signaling pathways. Front Immunol 2025; 16:1581964. [PMID: 40443670 PMCID: PMC12119490 DOI: 10.3389/fimmu.2025.1581964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Accepted: 04/28/2025] [Indexed: 06/02/2025] Open
Abstract
Tumor-derived extracellular vesicles (TDEVs) represent a heterogeneous population of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, which are essential for tumor growth. EVs function as natural carriers of bioactive molecules, including lipids, proteins, and nucleic acids, enabling them to influence and regulate complex cellular interactions within the tumor microenvironment (TME). The TDEVs mainly have immunosuppressive functions as a result of the inhibitory signals disrupting the immune cell anti-tumor activity. They enhance tumor progression and immune evasion by inhibiting the effector function of immune cells and by altering critical processes of immune cell recruitment, polarization, and functional suppression by different signaling pathways. In this sense, TDEVs modulate the NF-κB pathway, promoting inflammation and inducing immune evasion. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is required for TDEV-mediated immune suppression and the manifestation of tumor-supporting features. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, necessary for metabolic reprogramming, is orchestrated by TDEV to abrogate immune response and drive cancer cell proliferation. Finally, exosomal cargo can modulate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, activating pro-inflammatory responses that influence tumor development and immunomodulation. In this review, we take a deep dive into how TDEVs affect the immune cells by altering key signaling pathways. We also examine emerging therapeutic approaches aimed at disrupting EV-mediated pathways, offering promising avenues for the development of novel EV-based cancer immunotherapy.
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Affiliation(s)
- Fei Yin
- Department of Neurology, The Second Hospital of Jilin University, Changchun, China
| | - Yangfang He
- Department of Endocrinology and Metabolism, The Second Hospital of Jilin University, Changchun, China
| | - Yue Qiao
- Department of Physical Examination Center, The Second Hospital of Jilin University, Changchun, China
| | - Yan Yan
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, China
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2
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Gu W, Zhang W, Wu Z, Cai Y. Cabergoline-induced NDFIP1 upregulation in pituitary neuroendocrine tumor cells activates mTOR signaling and contributes to cabergoline resistance. J Neurooncol 2025; 172:587-597. [PMID: 39891847 PMCID: PMC11968467 DOI: 10.1007/s11060-025-04949-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 01/21/2025] [Indexed: 02/03/2025]
Abstract
PURPOSE To investigate the molecular mechanisms underlying resistance to dopamine agonists (DA). METHODS LC-MS/MS analysis was performed on rat pituitary neuroendocrine tumors (PitNET) cell line GH3 to identify differentially expressed proteins induced by cabergoline (CAB) treatment. A total of 180 human PITNET samples were subjected to transcriptome analysis. Immunohistochemistry (IHC) was conducted on 29 tumor samples to validate NDFIP1 alteration. A xenograft mouse model was established by subcutaneously injecting GH3 cells, with or without NDFIP1 overexpression, into nude mice to investigate tumor growth. PitNET cell lines were treated with CAB. Cell proliferation was assessed using the CCK-8, and protein expression levels were examined through Western blot analysis. RESULTS CAB treatment upregulated FDFT1 and NDFIP1 protein expression in GH3 cells, with NDFIP1 showing a significant positive correlation with tumor size, as confirmed by IHC results. MMQ and GH3 cells overexpressing NDFIP1 exhibited enhanced viability and reduced sensitivity to CAB. In vivo experiments demonstrated that subcutaneous injection of NDFIP1-overexpressing GH3 cells led to enhanced tumor growth compared to parental GH3 cells. Although the total levels of PTEN remained unaltered, NDFIP1 overexpression induced PTEN nuclear translocation, potentially activating the mTOR pathway. This was supported by increased phosphorylation of key mTOR pathway components, including p-AKT and p-4EBP1, in cells overexpressing NDFIP1. CONCLUSION CAB treatment induces the upregulation of NDFIP1 in PitNET cells, which correlates with tumor size and contributes to reduced CAB sensitivity, potentially through activation of the mTOR pathway. NDFIP1 as a potential therapeutic target for overcoming DA resistance in PitNET patients.
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Affiliation(s)
- Weiting Gu
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Weifeng Zhang
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhebao Wu
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yu Cai
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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3
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Ramezani A, Rahnama M, Mahmoudian F, Shirazi F, Ganji M, Bakhshi S, Khalesi B, Hashemi ZS, Khalili S. Current Understanding of the Exosomes and Their Associated Biomolecules in the Glioblastoma Biology, Clinical Treatment, and Diagnosis. J Neuroimmune Pharmacol 2025; 20:48. [PMID: 40299204 DOI: 10.1007/s11481-025-10204-7] [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: 07/23/2024] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
Glioblastoma is the most common and aggressive brain tumor with a low survival rate. Due to its heterogeneous composition, high invasiveness, and frequent recurrence after surgery, treatment success has been limited. In addition, due to the brain's unique immune status and the suppressor tumor microenvironment (TME), glioblastoma treatment has faced more challenges. Exosomes play a critical role in cancer metastasis by regulating cell-cell interactions that promote tumor growth, angiogenesis, metastasis, treatment resistance, and immunological regulation in the tumor microenvironment. This review explores the pivotal role of exosomes in the development of glioblastoma, with a focus on their potential as non-invasive biomarkers for prognosis, early detection and real-time monitoring of disease progression. Notably, exosome-based drug delivery methods hold promise for overcoming the blood-brain barrier (BBB) and developing targeted therapies for glioblastoma. Despite challenges in clinical translation, the potential for personalized exosome = -054321`therapies and the capacity to enhance therapeutic responses in glioblastoma, present intriguing opportunities for improving patient outcomes. It seems that getting a good and current grasp of the role of exosomes in the fight against glioblastoma would properly serve the scientific community to further their understanding of the related potentials of these biological moieties.
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Affiliation(s)
- Aghdas Ramezani
- Department of Molecular Imaging, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Maryam Rahnama
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Mahmoudian
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Shirazi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Mahmoud Ganji
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Shohreh Bakhshi
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Education and Extension Organization, Razi Vaccine and Serum Research Institute, Agricultural Research, Karaj, 3197619751, Iran
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran.
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4
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Yang X, Liu T, Cheng H. PTEN: a new dawn in Parkinson's disease treatment. Front Cell Neurosci 2025; 19:1497555. [PMID: 40129459 PMCID: PMC11931041 DOI: 10.3389/fncel.2025.1497555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 02/26/2025] [Indexed: 03/26/2025] Open
Abstract
In recent years, the study of phosphatase and tension homolog (PTEN) has gradually become a research hotspot. As an important oncogene, the role of PTEN in cancer has long been widely recognized and intensively studied, but it has been relatively less studied in other diseases. Parkinson's disease (PD) is a neurodegenerative refractory disease commonly observed in middle-aged and elderly individuals. The etiology and pathogenesis of PD are numerous, complex, and incompletely understood. With the continuous deepening of research, numerous studies have proven that PTEN is related to the occurrence of PD. In this review, we discuss the relationship between PTEN and PD through the phosphorylation and ubiquitination of PTEN and other possible regulatory mechanisms, including the role of RNA molecules, exosomes, transcriptional regulation, chemical modification, and subtype variation, with the aim of clarifying the regulatory role of PTEN in PD and better elucidating its pathogenesis. Finally, we summarize the shortcomings of PTEN in PD research and highlight the great potential of its future application in PD clinical treatment. These findings provide research ideas and new perspectives for the possible use of PTEN as a PD therapeutic target for targeted drug development and clinical application in the future.
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Affiliation(s)
| | - Tianqi Liu
- Medical College, Yangzhou University, Yangzhou, China
| | - Hong Cheng
- Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University Medical College, Institute of Translational Medicine, Yangzhou University, Yangzhou, China
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5
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Liu Y, Zhang H, Li X, He T, Zhang W, Ji C, Wang J. Molecular mechanisms and pathological implications of unconventional protein secretion in human disease: from cellular stress to therapeutic targeting. Mol Biol Rep 2025; 52:236. [PMID: 39955475 DOI: 10.1007/s11033-025-10316-6] [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: 12/04/2024] [Accepted: 01/28/2025] [Indexed: 02/17/2025]
Abstract
Unconventional protein secretion (UcPS) encompasses diverse non-canonical cellular export mechanisms that operate independently of the classical secretory pathway, representing a crucial cellular response to various physiological and pathological conditions. This comprehensive review synthesizes current understanding of UcPS mechanisms, particularly focusing on their roles in disease pathogenesis and progression. Recent advances in proteomics and cellular biology have revealed that UcPS facilitates the secretion of various biomedically significant proteins, including inflammatory mediators, growth factors, and disease-associated proteins, through multiple pathways such as membrane translocation, secretory lysosomes, and membrane-bound organelles. Notably, dysregulation of UcPS mechanisms has been implicated in various pathological conditions, including chronic inflammation, neurodegenerative disorders, and malignant transformation. We critically evaluate the molecular machinery governing UcPS, its regulation under cellular stress, and its contribution to disease mechanisms. Furthermore, we examine emerging therapeutic strategies targeting UcPS pathways, highlighting both opportunities and challenges in developing novel interventional approaches.
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Affiliation(s)
- Yukun Liu
- College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China
| | - Haolin Zhang
- College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China
| | - Xianghua Li
- College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China
| | - Tianlong He
- College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China
| | - Wenting Zhang
- College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China
| | - Cuicui Ji
- College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China.
| | - Juan Wang
- College of Chemistry and Life Science, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100124, China.
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6
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Rana R, Devi SN, Bhardwaj AK, Yashavarddhan MH, Bohra D, Ganguly NK. Exosomes as nature's nano carriers: Promising drug delivery tools and targeted therapy for glioma. Biomed Pharmacother 2025; 182:117754. [PMID: 39731936 DOI: 10.1016/j.biopha.2024.117754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
Exosomes, minute vesicles originating from diverse cell types, exhibit considerable potential as carriers for drug delivery in glioma therapy. These naturally occurring nanocarriers facilitate the transfer of proteins, RNAs, and lipids between cells, offering advantages such as biocompatibility, efficient cellular absorption, and the capability to traverse the blood-brain barrier (BBB). In the realm of cancer, particularly gliomas, exosomes play pivotal roles in modulating tumor growth, regulating immunity, and combating drug resistance. Moreover, exosomes serve as valuable biomarkers for diagnosing diseases and assessing prognosis. This review aims to elucidate the therapeutic and diagnostic promise of exosomes in glioma treatment, highlighting the innovative advances in exosome engineering that enable precise drug loading and targeting. By circumventing challenges associated with current glioma treatments, exosome-mediated drug delivery strategies can enhance the efficacy of chemotherapy drugs like temozolomide and overcome drug resistance mechanisms. This review underscores the multifaceted roles of exosomes in glioma pathogenesis and therapy, underscoring their potential as natural nanocarriers for targeted therapy and heralding a new era of hope for glioma treatment.
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Affiliation(s)
- Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
| | | | - Amit Kumar Bhardwaj
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - M H Yashavarddhan
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Deepika Bohra
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
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7
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Sekar S, Srikanth S, Mukherjee AG, Gopalakrishnan AV, Wanjari UR, Vellingiri B, Renu K, Madhyastha H. Biogenesis and functional implications of extracellular vesicles in cancer metastasis. Clin Transl Oncol 2024:10.1007/s12094-024-03815-8. [PMID: 39704958 DOI: 10.1007/s12094-024-03815-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/23/2024] [Indexed: 12/21/2024]
Abstract
Extracellular vesicles (EVs) play a crucial role in the complex process of cancer metastasis by facilitating cellular communication and influencing the microenvironment to promote the spread and establishment of cancer cells in distant locations. This paper explores the process of EV biogenesis, explaining their various sources that range from endosomal compartments to plasma membrane shedding. It also discusses the complex mechanisms that control the sorting of cargo within EVs, determining their chemical makeup. We investigate the several functions of EVs in promoting the spread of cancer to other parts of the body. These functions include influencing the immune system, creating environments that support the formation of metastases before they occur, and aiding in the transformation of cells from an epithelial to a mesenchymal state. Moreover, we explore the practical consequences of EV cargo, such as nucleic acids, proteins, and lipids, in influencing the spread of cancer cells, from the beginning of invasion to the creation of secondary tumor sites. Examining recent progress in the field of EV-based diagnostics and treatments, we explore the potential of EVs as highly promising biomarkers for predicting the course of cancer and as targets for therapeutic intervention. This review aims to provide a complete understanding of the biology of EVs in the context of cancer metastasis. By unravelling the nuances of EV biology, it seeks to pave the way for new tactics in cancer detection, treatment, and management.
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Affiliation(s)
- Sneha Sekar
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Sandhya Srikanth
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda, Punjab, 151401, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, 600077, India
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan
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8
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Zhang C, Ma HM, Wu S, Shen JM, Zhang N, Xu YL, Li CX, He P, Ge MK, Chu XL, Zhang YX, Zheng JK, Chen GQ, Shen SM. Secreted PTEN binds PLXDC2 on macrophages to drive antitumor immunity and tumor suppression. Dev Cell 2024; 59:3072-3088.e8. [PMID: 39197453 DOI: 10.1016/j.devcel.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 06/24/2024] [Accepted: 08/05/2024] [Indexed: 09/01/2024]
Abstract
Loss of phosphatase and tensin homolog (PTEN) has been linked to an immunosuppressive tumor microenvironment, but its underlying mechanisms remain largely enigmatic. Here, we report that PTEN can be secreted by the transmembrane emp24 domain-containing protein 10 (TMED10)-channeled protein secretion pathway. Inhibiting PTEN secretion from tumor cells contributes to immunosuppression and impairs the tumor-suppressive role of PTEN, while intratumoral injection of PTEN protein promotes antitumor immunity and suppresses tumor growth in mice. Mechanistically, extracellular PTEN binds to the plexin domain-containing protein 2 (PLXDC2) on macrophages, triggering subsequent activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages (TAMs) from the immunosuppressive to inflammatory phenotype, leading to enhanced activation of CD8+ T and natural killer cells. Importantly, PTEN treatment also enhances the therapeutic efficacy of anti-PD-1 treatment in mice and reverses the immune-suppressive phenotype of patient-derived primary TAMs. These data identify a cytokine-like role of PTEN in immune activation and tumor suppression and demonstrate the therapeutic potential for extracellular administration of PTEN in cancer immunotherapy.
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Affiliation(s)
- Cheng Zhang
- Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No.2019RU043), State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; School of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan 571199, China
| | - Hong-Ming Ma
- Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No.2019RU043), State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Shuai Wu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Jia-Ming Shen
- Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No.2019RU043), State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Na Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Yi-Lu Xu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Cheng-Xiao Li
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Ping He
- Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No.2019RU043), State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China
| | - Meng-Kai Ge
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Xi-Li Chu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Yu-Xue Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Jun-Ke Zheng
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China
| | - Guo-Qiang Chen
- Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No.2019RU043), State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; School of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan 571199, China.
| | - Shao-Ming Shen
- Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No.2019RU043), State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China.
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Zhang L, Wang Y, Cai X, Mao X, Sun H. Deciphering the CNS-glioma dialogue: Advanced insights into CNS-glioma communication pathways and their therapeutic potential. J Cent Nerv Syst Dis 2024; 16:11795735241292188. [PMID: 39493257 PMCID: PMC11528668 DOI: 10.1177/11795735241292188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 09/23/2024] [Indexed: 11/05/2024] Open
Abstract
The field of cancer neuroscience has rapidly evolved, shedding light on the complex interplay between the nervous system and cancer, with a particular focus on the relationship between the central nervous system (CNS) and gliomas. Recent advancements have underscored the critical influence of CNS activity on glioma progression, emphasizing the roles of neurons and neuroglial cells in both the onset and evolution of gliomas. This review meticulously explores the primary communication pathways between the CNS and gliomas, encompassing neuro-glioma synapses, paracrine mechanisms, extracellular vesicles, tunneling nanotubes, and the integrative CNS-immune-glioma axis. It also evaluates current and emerging therapeutic interventions aimed at these pathways and proposes forward-looking perspectives for research in this domain.
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Affiliation(s)
- Lu Zhang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yajing Wang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoxi Cai
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xinyuan Mao
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong–Hong Kong–Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China
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10
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Han Y, Ye M, Ye S, Liu B. Comparison of Lung Tissue-Derived Extracellular Vesicles Using Multiple Dissociation Methods for Profiling Protein Biomarkers. Biotechnol J 2024; 19:e202400329. [PMID: 39295555 DOI: 10.1002/biot.202400329] [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: 05/17/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 09/21/2024]
Abstract
Extracellular vesicles (EVs) operate as chemical messengers that facilitate intercellular communication. Emerging evidence has demonstrated that lung tissue-derived EVs play pivotal roles in pulmonary physiological processes and have potential as biomarkers and therapeutics for lung diseases. Multiple methods have been proposed for the isolation of lung tissue-derived EVs. However, the effects of different tissue pre-treatments on lung EV isolation and subsequent disease biomarker discovery have not yet been comprehensively investigated. In this study, we compared the physical characteristics, recovery yields, and protein compositions of EVs isolated from lung tissues using three methods based on different tissue dissociation principles. Methodologically, the beneficial roles of blood perfusion and gentle meshing were emphasized based on their impact on EV yield and purity. These results demonstrate that different methods enrich distinct subpopulations of EVs that exhibit significant differences in their protein cargo and surface properties. These disparities directly affect the diagnostic detection of marker proteins related to lung diseases, including lung tumors, asthma, and pulmonary fibrosis. Collectively, these findings highlight the variations in EV characteristics resulting from the applied approaches and offer compelling suggestions for guiding researchers in selecting a suitable isolation method based on downstream functional studies and clinical applications.
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Affiliation(s)
- Yue Han
- School of Engineering Medicine, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology, Beijing, China
| | - Meng Ye
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Sheng Ye
- School of Engineering Medicine, Beihang University, Beijing, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology, Beijing, China
| | - Bowen Liu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
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11
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Li X, Yang P, Hou X, Ji S. Post-Translational Modification of PTEN Protein: Quantity and Activity. Oncol Rev 2024; 18:1430237. [PMID: 39144161 PMCID: PMC11321960 DOI: 10.3389/or.2024.1430237] [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: 05/09/2024] [Accepted: 07/04/2024] [Indexed: 08/16/2024] Open
Abstract
Post-translational modifications play crucial roles in regulating protein functions and stabilities. PTEN is a critical tumor suppressor involved in regulating cellular proliferation, survival, and migration processes. However, dysregulation of PTEN is common in various human cancers. PTEN stability and activation/suppression have been extensively studied in the context of tumorigenesis through inhibition of the PI3K/AKT signaling pathway. PTEN undergoes various post-translational modifications, primarily including phosphorylation, acetylation, ubiquitination, SUMOylation, neddylation, and oxidation, which finely tune its activity and stability. Generally, phosphorylation modulates PTEN activity through its lipid phosphatase function, leading to altered power of the signaling pathways. Acetylation influences PTEN protein stability and degradation rate. SUMOylation has been implicated in PTEN localization and interactions with other proteins, affecting its overall function. Neddylation, as a novel modification of PTEN, is a key regulatory mechanism in the loss of tumor suppressor function of PTEN. Although current therapeutic approaches focus primarily on inhibiting PI3 kinase, understanding the post-translational modifications of PTEN could help provide new therapeutic strategies that can restore PTEN's role in PIP3-dependent tumors. The present review summarizes the major recent developments in the regulation of PTEN protein level and activity. We expect that these insights will contribute to better understanding of this critical tumor suppressor and its potential implications for cancer therapy in the future.
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Affiliation(s)
- Xiao Li
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Pu Yang
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Xiaoli Hou
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Shaoping Ji
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
- Department of Biochemistry and Molecular Biology, Medical School, Henan University, Kaifeng, Henan, China
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12
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Bhavsar SP, Morini M. The emerging role of the exosomal proteins in neuroblastoma. Front Oncol 2024; 14:1414063. [PMID: 38962276 PMCID: PMC11219817 DOI: 10.3389/fonc.2024.1414063] [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: 04/08/2024] [Accepted: 06/05/2024] [Indexed: 07/05/2024] Open
Abstract
Exosomes are a subclass of extracellular vesicles shown to promote the cancer growth and support metastatic progression. The proteomic analysis of neuroblastoma-derived exosomes has revealed proteins involved in cell migration, proliferation, metastasis, and in the modulation of tumor microenvironment - thus contributing to the tumor development and an aggressive metastatic phenotype. This review gives an overview of the current understanding of the exosomal proteins in neuroblastoma and of their potential as diagnostic/prognostic biomarker of disease and therapeutics.
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Affiliation(s)
- Swapnil Parashram Bhavsar
- Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Martina Morini
- Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy
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13
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Wu Y, Cao Y, Chen L, Lai X, Zhang S, Wang S. Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy. Biol Proced Online 2024; 26:15. [PMID: 38802766 PMCID: PMC11129508 DOI: 10.1186/s12575-024-00245-2] [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: 04/14/2024] [Accepted: 05/16/2024] [Indexed: 05/29/2024] Open
Abstract
Exosomes are increasingly recognized as important mediators of intercellular communication in cancer biology. Exosomes can be derived from cancer cells as well as cellular components in tumor microenvironment. After secretion, the exosomes carrying a wide range of bioactive cargos can be ingested by local or distant recipient cells. The released cargos act through a variety of mechanisms to elicit multiple biological effects and impact most if not all hallmarks of cancer. Moreover, owing to their excellent biocompatibility and capability of being easily engineered or modified, exosomes are currently exploited as a promising platform for cancer targeted therapy. In this review, we first summarize the current knowledge of roles of exosomes in risk and etiology, initiation and progression of cancer, as well as their underlying molecular mechanisms. The aptamer-modified exosome as a promising platform for cancer targeted therapy is then briefly introduced. We also discuss the future directions for emerging roles of exosome in tumor biology and perspective of aptamer-modified exosomes in cancer therapy.
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Affiliation(s)
- Yating Wu
- Fujian Key Laboratory of Aptamers Technology, Affiliated Dongfang Hospital of School of Medicine, Xiamen University, Fuzhou, Fujian Province, P. R. China
- Department of Medical Oncology, Fuzhou General Clinical Medical School (the 900th Hospital), Fujian Medical University, Fujian Province, Fuzhou, P. R. China
| | - Yue Cao
- Department of Clinical Laboratory Medicine, Fuzhou General Clinical Medical School (the 900 th Hospital), Fujian Medical University, Fujian Province, Fuzhou, P. R. China
| | - Li Chen
- Fujian Key Laboratory of Aptamers Technology, Affiliated Dongfang Hospital of School of Medicine, Xiamen University, Fuzhou, Fujian Province, P. R. China
- Department of Clinical Laboratory Medicine, Fuzhou General Clinical Medical School (the 900 th Hospital), Fujian Medical University, Fujian Province, Fuzhou, P. R. China
| | - Xiaofeng Lai
- Fujian Key Laboratory of Aptamers Technology, Affiliated Dongfang Hospital of School of Medicine, Xiamen University, Fuzhou, Fujian Province, P. R. China
- Department of Clinical Laboratory Medicine, Fuzhou General Clinical Medical School (the 900 th Hospital), Fujian Medical University, Fujian Province, Fuzhou, P. R. China
| | - Shenghang Zhang
- Fujian Key Laboratory of Aptamers Technology, Affiliated Dongfang Hospital of School of Medicine, Xiamen University, Fuzhou, Fujian Province, P. R. China.
- Department of Clinical Laboratory Medicine, Fuzhou General Clinical Medical School (the 900 th Hospital), Fujian Medical University, Fujian Province, Fuzhou, P. R. China.
| | - Shuiliang Wang
- Fujian Key Laboratory of Aptamers Technology, Affiliated Dongfang Hospital of School of Medicine, Xiamen University, Fuzhou, Fujian Province, P. R. China.
- Department of Clinical Laboratory Medicine, Fuzhou General Clinical Medical School (the 900 th Hospital), Fujian Medical University, Fujian Province, Fuzhou, P. R. China.
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14
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Chen X, Song X, Li J, Wang J, Yan Y, Yang F. Integrated proteomic, phosphoproteomic, and N-glycoproteomic analyses of small extracellular vesicles from C2C12 myoblasts identify specific PTM patterns in ligand-receptor interactions. Cell Commun Signal 2024; 22:273. [PMID: 38755675 PMCID: PMC11097525 DOI: 10.1186/s12964-024-01640-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/28/2024] [Indexed: 05/18/2024] Open
Abstract
Small extracellular vesicles (sEVs) are important mediators of intercellular communication by transferring of functional components (proteins, RNAs, and lipids) to recipient cells. Some PTMs, including phosphorylation and N-glycosylation, have been reported to play important role in EV biology, such as biogenesis, protein sorting and uptake of sEVs. MS-based proteomic technology has been applied to identify proteins and PTM modifications in sEVs. Previous proteomic studies of sEVs from C2C12 myoblasts, an important skeletal muscle cell line, focused on identification of proteins, but no PTM information on sEVs proteins is available.In this study, we systematically analyzed the proteome, phosphoproteome, and N-glycoproteome of sEVs from C2C12 myoblasts with LC-MS/MS. In-depth analyses of the three proteomic datasets revealed that the three proteomes identified different catalogues of proteins, and PTMomic analysis could expand the identification of cargos in sEVs. At the proteomic level, a high percentage of membrane proteins, especially tetraspanins, was identified. The sEVs-derived phosphoproteome had a remarkably high level of tyrosine-phosphorylated sites. The tyrosine-phosphorylated proteins might be involved with EPH-Ephrin signaling pathway. At the level of N-glycoproteomics, several glycoforms, such as complex N-linked glycans and sialic acids on glycans, were enriched in sEVs. Retrieving of the ligand-receptor interaction in sEVs revealed that extracellular matrix (ECM) and cell adhesion molecule (CAM) represented the most abundant ligand-receptor pairs in sEVs. Mapping the PTM information on the ligands and receptors revealed that N-glycosylation mainly occurred on ECM and CAM proteins, while phosphorylation occurred on different categories of receptors and ligands. A comprehensive PTM map of ECM-receptor interaction and their components is also provided.In summary, we conducted a comprehensive proteomic and PTMomic analysis of sEVs of C2C12 myoblasts. Integrated proteomic, phosphoproteomic, and N-glycoproteomic analysis of sEVs might provide some insights about their specific uptake mechanism.
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Affiliation(s)
- Xiulan Chen
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Xi Song
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jiaran Li
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jifeng Wang
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yumeng Yan
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Fuquan Yang
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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15
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Cheng X, Henick BS, Cheng K. Anticancer Therapy Targeting Cancer-Derived Extracellular Vesicles. ACS NANO 2024; 18:6748-6765. [PMID: 38393984 DOI: 10.1021/acsnano.3c06462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Abstract
Extracellular vesicles (EVs) are natural lipid nanoparticles secreted by most types of cells. In malignant cancer, EVs derived from cancer cells contribute to its progression and metastasis by facilitating tumor growth and invasion, interfering with anticancer immunity, and establishing premetastasis niches in distant organs. In recent years, multiple strategies targeting cancer-derived EVs have been proposed to improve cancer patient outcomes, including inhibiting EV generation, disrupting EVs during trafficking, and blocking EV uptake by recipient cells. Developments in EV engineering also show promising results in harnessing cancer-derived EVs as anticancer agents. Here, we summarize the current understanding of the origin and functions of cancer-derived EVs and review the recent progress in anticancer therapy targeting these EVs.
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Affiliation(s)
- Xiao Cheng
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Joint Department of Biomedical EngineeringNorth Carolina State University, Raleigh, North Carolina 27606, United States
| | - Brian S Henick
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York 10032, United States
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York, New York 10027, United States
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16
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Adnani L, Rak J. Intercellular Molecular Transfer Mediated by Extracellular Vesicles in Cancer. Results Probl Cell Differ 2024; 73:327-352. [PMID: 39242385 DOI: 10.1007/978-3-031-62036-2_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2024]
Abstract
Among multiple pathways of intercellular communication operative in multicellular organisms, the trafficking of extracellular vesicles (EVs) and particles (EP) represents a unique mode of cellular information exchange with emerging roles in health and disease, including cancer. A distinctive feature of EV/EP-mediated cell-cell communication is that it involves simultaneous short- or long-range transfer of numerous molecular constituents (cargo) from donor to recipient cells. EV/EP uptake by donor cells elicits signalling or metabolic responses, or else leads to EV-re-emission or degradation. EVs are heterogeneous membranous structures released from cells via increasingly defined mechanisms involving either formation of multivesicular endosomes (exosomes) or budding from the plasma membrane (ectosomes). EPs (exomeres, supermeres) are membraneless complex particles, smaller than EVs and of less defined biogenesis and function. EVs/EPs carry complex assemblies of proteins, lipids and nucleic acids (RNA, DNA), which they shuttle into intercellular milieu, body fluids and recipient cells, via surface contact, fusion and different forms of internalization (endocytosis, micropinocytosis). While the physiological functions of EVs/EPs communication pathways continue to be investigated, their roles in cancer are increasingly well-defined. For example, EVs are involved in the transmission of cancer-specific molecular cargo, including mutant, oncogenic, transforming, or regulatory macromolecules to indolent, or normal cells, sometimes triggering their quasi-transformation-like states, or phenotypic alterations. Conversely, a reciprocal and avid uptake of stromal EVs by cancer cells may be responsible for modulating their oncogenic repertoire, as exemplified by the angiocrine effects of endothelial EVs influencing cancer cell stemness. EV exchanges during cancer progression have also been implicated in the formation of tumour stroma, angiogenesis and non-angiogenic neovascularization processes, immunosuppression, colonization of metastatic organ sites (premetastatic niche), paraneoplastic and systemic pathologies (thrombosis, diabetes, hepatotoxicity). Thus, an EV/EP-mediated horizontal transfer of cellular content emerges as a new dimension in cancer pathogenesis with functional, diagnostic, and therapeutic implications.
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Affiliation(s)
- Lata Adnani
- The Research Institute of the McGill University Health Centre, McGill University, QC, Canada
| | - Janusz Rak
- The Research Institute of the McGill University Health Centre, McGill University, QC, Canada.
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17
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Spiliopoulou P, Holanda Lopes CD, Spreafico A. Promising and Minimally Invasive Biomarkers: Targeting Melanoma. Cells 2023; 13:19. [PMID: 38201222 PMCID: PMC10777980 DOI: 10.3390/cells13010019] [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: 11/06/2023] [Revised: 11/29/2023] [Accepted: 12/17/2023] [Indexed: 01/12/2024] Open
Abstract
The therapeutic landscape of malignant melanoma has been radically reformed in recent years, with novel treatments emerging in both the field of cancer immunotherapy and signalling pathway inhibition. Large-scale tumour genomic characterization has accurately classified malignant melanoma into four different genomic subtypes so far. Despite this, only somatic mutations in BRAF oncogene, as assessed in tumour biopsies, has so far become a validated predictive biomarker of treatment with small molecule inhibitors. The biology of tumour evolution and heterogeneity has uncovered the current limitations associated with decoding genomic drivers based only on a single-site tumour biopsy. There is an urgent need to develop minimally invasive biomarkers that accurately reflect the real-time evolution of melanoma and that allow for streamlined collection, analysis, and interpretation. These will enable us to face challenges with tumour tissue attainment and process and will fulfil the vision of utilizing "liquid biopsy" to guide clinical decisions, in a manner akin to how it is used in the management of haematological malignancies. In this review, we will summarize the most recent published evidence on the role of minimally invasive biomarkers in melanoma, commenting on their future potential to lead to practice-changing discoveries.
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Affiliation(s)
- Pavlina Spiliopoulou
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- School of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK
| | | | - Anna Spreafico
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
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18
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Skouras P, Markouli M, Kalamatianos T, Stranjalis G, Korkolopoulou P, Piperi C. Advances on Liquid Biopsy Analysis for Glioma Diagnosis. Biomedicines 2023; 11:2371. [PMID: 37760812 PMCID: PMC10525418 DOI: 10.3390/biomedicines11092371] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/16/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Gliomas comprise the most frequent primary central nervous system (CNS) tumors, characterized by remarkable genetic and epigenetic heterogeneity, difficulty in monitoring, and increased relapse and mortality rates. Tissue biopsy is an established method of tumor cell collection and analysis that enables diagnosis, classification of different tumor types, and prediction of prognosis upon confirmation of tumor's location for surgical removal. However, it is an invasive and often challenging procedure that cannot be used for frequent patient screening, detection of mutations, disease monitoring, or resistance to therapy. To this end, the minimally invasive procedure of liquid biopsy has emerged, allowing effortless tumor sampling and enabling continuous monitoring. It is considered a novel preferable way to obtain faster data on potential tumor risk, personalized diagnosis, prognosis, and recurrence evaluation. The purpose of this review is to describe the advances on liquid biopsy for glioma diagnosis and management, indicating several biomarkers that can be utilized to analyze tumor characteristics, such as cell-free DNA (cfDNA), cell-free RNA (cfRNA), circulating proteins, circulating tumor cells (CTCs), and exosomes. It further addresses the benefit of combining liquid biopsy with radiogenomics to facilitate early and accurate diagnoses, enable precise prognostic assessments, and facilitate real-time disease monitoring, aiming towards more optimal treatment decisions.
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Affiliation(s)
- Panagiotis Skouras
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- 1st Department of Neurosurgery, Evangelismos Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (T.K.); (G.S.)
| | - Mariam Markouli
- Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA;
| | - Theodosis Kalamatianos
- 1st Department of Neurosurgery, Evangelismos Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (T.K.); (G.S.)
| | - George Stranjalis
- 1st Department of Neurosurgery, Evangelismos Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (T.K.); (G.S.)
| | - Penelope Korkolopoulou
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, 11527 Athens, Greece;
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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19
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Liu J, Pan Y, Liu Y, Wei W, Hu X, Xin W, Chen N. The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets. J Cell Physiol 2023; 238:1693-1715. [PMID: 37334436 DOI: 10.1002/jcp.31053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023]
Abstract
This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3-kinases (PI3K)-protein kinase B-mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)-3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein-protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted.
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Affiliation(s)
- Jie Liu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yongli Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Yuheng Liu
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Xiaoping Hu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Nan Chen
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
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20
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Qin W, Cheah JS, Xu C, Messing J, Freibaum BD, Boeynaems S, Taylor JP, Udeshi ND, Carr SA, Ting AY. Dynamic mapping of proteome trafficking within and between living cells by TransitID. Cell 2023; 186:3307-3324.e30. [PMID: 37385249 PMCID: PMC10527209 DOI: 10.1016/j.cell.2023.05.044] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 03/17/2023] [Accepted: 05/26/2023] [Indexed: 07/01/2023]
Abstract
The ability to map trafficking for thousands of endogenous proteins at once in living cells would reveal biology currently invisible to both microscopy and mass spectrometry. Here, we report TransitID, a method for unbiased mapping of endogenous proteome trafficking with nanometer spatial resolution in living cells. Two proximity labeling (PL) enzymes, TurboID and APEX, are targeted to source and destination compartments, and PL with each enzyme is performed in tandem via sequential addition of their small-molecule substrates. Mass spectrometry identifies the proteins tagged by both enzymes. Using TransitID, we mapped proteome trafficking between cytosol and mitochondria, cytosol and nucleus, and nucleolus and stress granules (SGs), uncovering a role for SGs in protecting the transcription factor JUN from oxidative stress. TransitID also identifies proteins that signal intercellularly between macrophages and cancer cells. TransitID offers a powerful approach for distinguishing protein populations based on compartment or cell type of origin.
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Affiliation(s)
- Wei Qin
- Departments of Biology, Genetics, and Chemistry, Stanford University, Stanford, CA 94305, USA
| | - Joleen S Cheah
- Departments of Biology, Genetics, and Chemistry, Stanford University, Stanford, CA 94305, USA
| | - Charles Xu
- The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - James Messing
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Brian D Freibaum
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Steven Boeynaems
- Department of Molecular and Human Genetics, Therapeutic Innovation Center, Center for Alzheimer's and Neurodegenerative Diseases, and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA
| | - J Paul Taylor
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Namrata D Udeshi
- The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Steven A Carr
- The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Alice Y Ting
- Departments of Biology, Genetics, and Chemistry, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub-San Francisco, San Francisco, CA 94158, USA.
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21
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Mahmoodpour M, Kiasari BA, Karimi M, Abroshan A, Shamshirian D, Hosseinalizadeh H, Delavari A, Mirzei H. Paper-based biosensors as point-of-care diagnostic devices for the detection of cancers: a review of innovative techniques and clinical applications. Front Oncol 2023; 13:1131435. [PMID: 37456253 PMCID: PMC10348714 DOI: 10.3389/fonc.2023.1131435] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
The development and rapid progression of cancer are major social problems. Medical diagnostic techniques and smooth clinical care of cancer are new necessities that must be supported by innovative diagnostic methods and technologies. Current molecular diagnostic tools based on the detection of blood protein markers are the most common tools for cancer diagnosis. Biosensors have already proven to be a cost-effective and accessible diagnostic tool that can be used where conventional laboratory methods are not readily available. Paper-based biosensors offer a new look at the world of analytical techniques by overcoming limitations through the creation of a simple device with significant advantages such as adaptability, biocompatibility, biodegradability, ease of use, large surface-to-volume ratio, and cost-effectiveness. In this review, we covered the characteristics of exosomes and their role in tumor growth and clinical diagnosis, followed by a discussion of various paper-based biosensors for exosome detection, such as dipsticks, lateral flow assays (LFA), and microfluidic paper-based devices (µPADs). We also discussed the various clinical studies on paper-based biosensors for exosome detection.
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Affiliation(s)
- Mehrdad Mahmoodpour
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary, The University of Tehran, Tehran, Iran
| | - Merat Karimi
- Institute of Nanoscience and Nanotechnology, University of Kashan, Kashan, Iran
| | - Arezou Abroshan
- Student Research Committee, Faculty of Veterinary Medicine, Shahid Bahonar University, Kerman, Iran
| | - Danial Shamshirian
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Hosseinalizadeh
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Alireza Delavari
- Student's Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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22
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Skouras P, Gargalionis AN, Piperi C. Exosomes as Novel Diagnostic Biomarkers and Therapeutic Tools in Gliomas. Int J Mol Sci 2023; 24:10162. [PMID: 37373314 DOI: 10.3390/ijms241210162] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor-microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment.
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Affiliation(s)
- Panagiotis Skouras
- Department of Neurosurgery, 'Evangelismos' Hospital, Medical School, National and Kapodistrian University of Athens, 10676 Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Biopathology, 'Eginition' Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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23
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Orozco-García E, van Meurs DJ, Calderón JC, Narvaez-Sanchez R, Harmsen MC. Endothelial plasticity across PTEN and Hippo pathways: A complex hormetic rheostat modulated by extracellular vesicles. Transl Oncol 2023; 31:101633. [PMID: 36905871 PMCID: PMC10020115 DOI: 10.1016/j.tranon.2023.101633] [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: 10/24/2022] [Revised: 12/20/2022] [Accepted: 01/25/2023] [Indexed: 03/11/2023] Open
Abstract
Vascularization is a multifactorial and spatiotemporally regulated process, essential for cell and tissue survival. Vascular alterations have repercussions on the development and progression of diseases such as cancer, cardiovascular diseases, and diabetes, which are the leading causes of death worldwide. Additionally, vascularization continues to be a challenge for tissue engineering and regenerative medicine. Hence, vascularization is the center of interest for physiology, pathophysiology, and therapeutic processes. Within vascularization, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Hippo signaling have pivotal roles in the development and homeostasis of the vascular system. Their suppression is related to several pathologies, including developmental defects and cancer. Non-coding RNAs (ncRNAs) are among the regulators of PTEN and/or Hippo pathways during development and disease. The purpose of this paper is to review and discuss the mechanisms by which exosome-derived ncRNAs modulate endothelial cell plasticity during physiological and pathological angiogenesis, through the regulation of PTEN and Hippo pathways, aiming to establish new perspectives on cellular communication during tumoral and regenerative vascularization.
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Affiliation(s)
- Elizabeth Orozco-García
- Physiology and biochemistry research group - PHYSIS, Faculty of Medicine, University of Antioquia, Colombia; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands
| | - D J van Meurs
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands
| | - J C Calderón
- Physiology and biochemistry research group - PHYSIS, Faculty of Medicine, University of Antioquia, Colombia
| | - Raul Narvaez-Sanchez
- Physiology and biochemistry research group - PHYSIS, Faculty of Medicine, University of Antioquia, Colombia
| | - M C Harmsen
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands.
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24
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Kalluri R, McAndrews KM. The role of extracellular vesicles in cancer. Cell 2023; 186:1610-1626. [PMID: 37059067 PMCID: PMC10484374 DOI: 10.1016/j.cell.2023.03.010] [Citation(s) in RCA: 262] [Impact Index Per Article: 131.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/17/2023] [Accepted: 03/07/2023] [Indexed: 04/16/2023]
Abstract
Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics.
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Affiliation(s)
- Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Kathleen M McAndrews
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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25
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Xu WQ, Cheah JS, Xu C, Messing J, Freibaum BD, Boeynaems S, Taylor JP, Udeshi ND, Carr SA, Ting AY. Dynamic mapping of proteome trafficking within and between living cells by TransitID. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.07.527548. [PMID: 36798302 PMCID: PMC9934598 DOI: 10.1101/2023.02.07.527548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
The ability to map trafficking for thousands of endogenous proteins at once in living cells would reveal biology currently invisible to both microscopy and mass spectrometry. Here we report TransitID, a method for unbiased mapping of endogenous proteome trafficking with nanometer spatial resolution in living cells. Two proximity labeling (PL) enzymes, TurboID and APEX, are targeted to source and destination compartments, and PL with each enzyme is performed in tandem via sequential addition of their small-molecule substrates. Mass spectrometry identifies the proteins tagged by both enzymes. Using TransitID, we mapped proteome trafficking between cytosol and mitochondria, cytosol and nucleus, and nucleolus and stress granules, uncovering a role for stress granules in protecting the transcription factor JUN from oxidative stress. TransitID also identifies proteins that signal intercellularly between macrophages and cancer cells. TransitID introduces a powerful approach for distinguishing protein populations based on compartment or cell type of origin.
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26
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Extracellular Vesicles: New Classification and Tumor Immunosuppression. BIOLOGY 2023; 12:biology12010110. [PMID: 36671802 PMCID: PMC9856004 DOI: 10.3390/biology12010110] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/05/2023] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
Extracellular vesicles (EVs) are cell-derived membrane-surrounded vesicles carrying various types of molecules. These EV cargoes are often used as pathophysiological biomarkers and delivered to recipient cells whose fates are often altered in local and distant tissues. Classical EVs are exosomes, microvesicles, and apoptotic bodies, while recent studies discovered autophagic EVs, stressed EVs, and matrix vesicles. Here, we classify classical and new EVs and non-EV nanoparticles. We also review EVs-mediated intercellular communication between cancer cells and various types of tumor-associated cells, such as cancer-associated fibroblasts, adipocytes, blood vessels, lymphatic vessels, and immune cells. Of note, cancer EVs play crucial roles in immunosuppression, immune evasion, and immunotherapy resistance. Thus, cancer EVs change hot tumors into cold ones. Moreover, cancer EVs affect nonimmune cells to promote cellular transformation, including epithelial-to-mesenchymal transition (EMT), chemoresistance, tumor matrix production, destruction of biological barriers, angiogenesis, lymphangiogenesis, and metastatic niche formation.
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27
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Khayamzadeh M, Niazi V, Hussen BM, Taheri M, Ghafouri-Fard S, Samadian M. Emerging role of extracellular vesicles in the pathogenesis of glioblastoma. Metab Brain Dis 2023; 38:177-184. [PMID: 36083425 DOI: 10.1007/s11011-022-01074-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/22/2022] [Indexed: 02/03/2023]
Abstract
While brain tumors are not extremely frequent, they cause high mortality due to lack of appropriate treatment and late detection. Glioblastoma is the most frequent type of primary brain tumor. This malignant tumor has a highly aggressive behavior. Expression profile of different types of transcripts, methylation status of a number of genomic loci and chromosomal aberrations have been found to affect course of glioblastoma and propensity for recurrence and metastasis. Recent studies have shown that glioblastoma cells produce extracellular vesicles whose cargo can affect behavior of neighboring cells. Several miRNAs such as miR-301a, miR-221, miR-21, miR-16, miR-19b, miR-20, miR-26a, miR-92, miR-93, miR-29a, miR-222, miR-221 and miR-30a have been shown to be transferred by glioblastoma-derived extracellular vesicles and enhance the malignant behavior of these cells. Other components of glioblastoma-derived extracellular vesicles are EGFRvIII mRNA/protein, Ndfip1, PTEN, MYC ssDNA and IDH1 mRNA. In the current review, we discuss the available data about the molecular composition of glioblastoma-derived extracellular vesicles and their impact on the progression of this malignant tumor and its resistance to therapeutic modalities.
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Affiliation(s)
- Maryam Khayamzadeh
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Academy of Medical Sciences, Tehran, Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Samadian
- Skull Base Research Center, Loghman Hakin Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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28
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Chen Y, Huang Y, Deng Y, Liu X, Ye J, Li Q, Luo Y, Lin Y, Liang R, Wei J, Zhang J, Li Y. Cancer Therapy Empowered by Extracellular Vesicle-Mediated Targeted Delivery. Biol Pharm Bull 2023; 46:1353-1364. [PMID: 37779037 DOI: 10.1248/bpb.b23-00378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Extracellular vesicles (EVs) are a class of nanoparticles that mediate signaling molecules delivery between donor and recipient cells. Heterogeneity in the content of EVs and their membrane surface proteins determines their unique targetability. Their low immunogenicity, capability to cross various biological barriers, and superior biocompatibility enable engineering-modified EVs to be ideal drug delivery carriers. In addition, the engineered EVs that emerge in recent years have become a powerful tool for cancer treatment through the selective delivery of bioactive molecules to therapeutic targets, such as tumor cells and stroma. Our review focuses on the various types of EV modifications and their promoting therapeutic capabilities, which provide an innovative means for cancer precision therapy.
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Affiliation(s)
- Yong Chen
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Yujuan Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Yayan Deng
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Xue Liu
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Jiaxiang Ye
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Qiuyun Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Yue Luo
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Jiazhang Wei
- Department of Otolaryngology & Head and Neck, The People's Hospital of Guangxi Zhuang Autonomous Region
- Institute of Oncology, Guangxi Academy of Medical Sciences
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education/Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor
| | - Jinyan Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital
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29
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Adnani L, Spinelli C, Tawil N, Rak J. Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature. Semin Cancer Biol 2022; 87:196-213. [PMID: 36371024 DOI: 10.1016/j.semcancer.2022.11.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/25/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the underlying circuitry, as crucial constituents of angiogenesis, angiocrine stimulation, non-angiogenic vascular growth, interactions with the coagulation system and other responses. Tumour-vascular interactions involve soluble factors, extracellular matrix molecules, cell-cell contacts, as well as extracellular vesicles (EVs) carrying assemblies of molecular effectors. Oncogenic mutations and transforming changes in the cancer cell genome, epigenome and signalling circuitry exert important and often cancer-specific influences upon pathways of tumour-vascular interactions, including the biogenesis, content, and biological activity of EVs and responses of cancer cells to them. Notably, EVs may carry and transfer bioactive, oncogenic macromolecules (oncoproteins, RNA, DNA) between tumour and vascular cells and thereby elicit unique functional changes and forms of vascular growth and remodeling. Cancer EVs influence the state of the vasculature both locally and systemically, as exemplified by cancer-associated thrombosis. EV-mediated communication pathways represent attractive targets for therapies aiming at modulation of the tumour-vascular interface (beyond angiogenesis) and could also be exploited for diagnostic purposes in cancer.
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Affiliation(s)
- Lata Adnani
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Cristiana Spinelli
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Nadim Tawil
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Janusz Rak
- McGill University and Research Institute of the McGill University Health Centre, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
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30
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The equilibrium of tumor suppression: DUBs as active regulators of PTEN. Exp Mol Med 2022; 54:1814-1821. [PMID: 36385557 PMCID: PMC9723170 DOI: 10.1038/s12276-022-00887-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have shown that several deubiquitinating enzymes, including HAUSP/USP7, USP10, USP11, USP13, OTUD3 and Ataxin-3, can remove ubiquitin from ubiquitinated PTEN in cancer-specific contexts and thus reverse ubiquitination-mediated PTEN regulation. Researchers continue to reveal the precise molecular mechanisms by which cancer-specific deubiquitinases of PTEN regulate its roles in the pathobiology of cancer, and new methods of pharmacologically for modulating PTEN deubiquitinases are critical areas of investigation for cancer treatment and prevention. Here, we assess the mechanisms and functions of deubiquitination as a recently appreciated mode of PTEN regulation and review the link between deubiquitinases and PTEN reactivation and its implications for therapeutic strategies.
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31
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Targeting PTEN Regulation by Post Translational Modifications. Cancers (Basel) 2022; 14:cancers14225613. [PMID: 36428706 PMCID: PMC9688753 DOI: 10.3390/cancers14225613] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 11/07/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Phosphatidylinositol-3,4,5-triphosphate (PIP3) is a lipidic second messenger present at very low concentrations in resting normal cells. PIP3 levels, though, increase quickly and transiently after growth factor addition, upon activation of phosphatidylinositol 3-kinase (PI3-kinase). PIP3 is required for the activation of intracellular signaling pathways that induce cell proliferation, cell migration, and survival. Given the critical role of this second messenger for cellular responses, PIP3 levels must be tightly regulated. The lipid phosphatase PTEN (phosphatase and tensin-homolog in chromosome 10) is the phosphatase responsible for PIP3 dephosphorylation to PIP2. PTEN tumor suppressor is frequently inactivated in endometrium and prostate carcinomas, and also in glioblastoma, illustrating the contribution of elevated PIP3 levels for cancer development. PTEN biological activity can be modulated by heterozygous gene loss, gene mutation, and epigenetic or transcriptional alterations. In addition, PTEN can also be regulated by post-translational modifications. Acetylation, oxidation, phosphorylation, sumoylation, and ubiquitination can alter PTEN stability, cellular localization, or activity, highlighting the complexity of PTEN regulation. While current strategies to treat tumors exhibiting a deregulated PI3-kinase/PTEN axis have focused on PI3-kinase inhibition, a better understanding of PTEN post-translational modifications could provide new therapeutic strategies to restore PTEN action in PIP3-dependent tumors.
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32
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Hallal S, Tűzesi Á, Grau GE, Buckland ME, Alexander KL. Understanding the extracellular vesicle surface for clinical molecular biology. J Extracell Vesicles 2022; 11:e12260. [PMID: 36239734 PMCID: PMC9563386 DOI: 10.1002/jev2.12260] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 12/17/2022] Open
Abstract
Extracellular vesicles (EVs) are lipid-membrane enclosed nanoparticles that play significant roles in health and disease. EVs are abundant in body fluids and carry an array of molecules (proteins, lipids, nucleic acids and glycans) that reflect the identity and activity of their cell-of-origin. While the advent of high throughput omics technologies has allowed in-depth characterisation of EV compositions, how these molecular species are spatially distributed within EV structures is not well appreciated. This is particularly true of the EV surface where a plethora of molecules are reported to be both integral and peripherally associated to the EV membrane. This coronal layer or 'atmosphere' that surrounds the EV membrane contributes to a large, highly interactive and dynamic surface area that is responsible for facilitating EV interactions with the extracellular environment. The EV coronal layer harbours surface molecules that reflect the identity of parent cells, which is likely a highly valuable property in the context of diagnostic liquid biopsies. In this review, we describe the current understanding of the mechanical, electrostatic and molecular properties of the EV surface that offer significant biomarker potential and contribute to a highly dynamic interactome.
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Affiliation(s)
- Susannah Hallal
- Neurosurgery DepartmentChris O'Brien LifehouseCamperdownNSWAustralia,Brainstorm Brain Cancer Research, Brain and Mind CentreThe University of SydneyNSWAustralia,Neuropathology DepartmentRoyal Prince Alfred HospitalCamperdownNSWAustralia
| | - Ágota Tűzesi
- Brainstorm Brain Cancer Research, Brain and Mind CentreThe University of SydneyNSWAustralia,Neuropathology DepartmentRoyal Prince Alfred HospitalCamperdownNSWAustralia,School of Medical SciencesFaculty of Medicine & HealthThe University of SydneyCamperdownNSWAustralia
| | - Georges E. Grau
- School of Medical SciencesFaculty of Medicine & HealthThe University of SydneyCamperdownNSWAustralia
| | - Michael E. Buckland
- Brainstorm Brain Cancer Research, Brain and Mind CentreThe University of SydneyNSWAustralia,Neuropathology DepartmentRoyal Prince Alfred HospitalCamperdownNSWAustralia,School of Medical SciencesFaculty of Medicine & HealthThe University of SydneyCamperdownNSWAustralia
| | - Kimberley L. Alexander
- Neurosurgery DepartmentChris O'Brien LifehouseCamperdownNSWAustralia,Brainstorm Brain Cancer Research, Brain and Mind CentreThe University of SydneyNSWAustralia,Neuropathology DepartmentRoyal Prince Alfred HospitalCamperdownNSWAustralia,School of Medical SciencesFaculty of Medicine & HealthThe University of SydneyCamperdownNSWAustralia
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33
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Song MS, Pandolfi PP. The HECT family of E3 ubiquitin ligases and PTEN. Semin Cancer Biol 2022; 85:43-51. [PMID: 34129913 PMCID: PMC8665946 DOI: 10.1016/j.semcancer.2021.06.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/22/2022]
Abstract
Members of the HECT family of E3 ubiquitin ligases have emerged as prominent regulators of PTEN function, subcellular localization and levels. In turn this unfolding regulatory network is allowing for the identification of genes directly involved in both tumorigenesis at large and cancer susceptibility syndromes. While the complexity of this regulatory network is still being unraveled, these new findings are paving the way for novel therapeutic modalities for cancer prevention and therapy as well as for other diseases. Here we will review the signal transduction and therapeutic implications of the cross-talk between HECT family members and PTEN.
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Affiliation(s)
- Min Sup Song
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX77030, USA.
| | - Pier Paolo Pandolfi
- Renown Institute for Cancer, Nevada System of Higher Education, Reno, NV89502, USA.
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Mansourabadi AH, Aghamajidi A, Faraji F, Taghizadeh S, Mohamed Khosroshahi L, Bahramkiya M, Azimi M. Mesenchymal stem cells- derived exosomes inhibit the expression of Aquaporin-5 and EGFR in HCT-116 human colorectal carcinoma cell line. BMC Mol Cell Biol 2022; 23:40. [PMID: 36114463 PMCID: PMC9479423 DOI: 10.1186/s12860-022-00439-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 08/16/2022] [Indexed: 11/23/2022] Open
Abstract
Background Aquaporins are channel proteins, form pores in the membrane of biological cells to facilitate the transcellular and transepithelial water movement. The role of Aquaporins in carcinogenesis has become an area of interest. In this study, we aimed to investigate the effects of adipose-derived mesenchymal stem cells secreted exosomes on the expression of aquaporin 5 and EGFR genes in the HCT-116 tumor cell line. Methods and results Surface antigenic profile of Ad-MSCs was evaluated using specific markers. Exosomes were purified from the Ad-MSc supernatant while the quality and the shape of isolated exosomes were assessed by western blot and transmission electron microscopy (TEM) respectively. HCT-116 cells were co-cultured with MSC-conditioned medium (MSC-CM) and/or with 100 μg/ml of MSC-derived exosomes for 48 h and. Real-time PCR was carried out to determine the expression of aquaporin5 and EGFR in HCT-116. Relative expression levels were calculated using the 2-ΔΔct method. Our result showed that AQP5 and EGFR mRNA levels were significantly reduced in CM and/or exosomes treated HCT116 compare to the control group (P-value < 0.05). Conclusion The current study showed that MSC derived exosomes could inhibit expression of two important molecules involved in tumor progression. Hence it seems MSCs-derived exosomes may hold a hopeful future as drug delivery vehicles which need the furtherer investigation.
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35
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Karami Fath M, Azami J, Masoudi A, Mosaddeghi Heris R, Rahmani E, Alavi F, Alagheband Bahrami A, Payandeh Z, Khalesi B, Dadkhah M, Pourzardosht N, Tarhriz V. Exosome-based strategies for diagnosis and therapy of glioma cancer. Cancer Cell Int 2022; 22:262. [PMID: 35989351 PMCID: PMC9394011 DOI: 10.1186/s12935-022-02642-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/26/2022] [Indexed: 11/10/2022] Open
Abstract
Glioblastoma belongs to the most aggressive type of cancer with a low survival rate that is characterized by the ability in forming a highly immunosuppressive tumor microenvironment. Intercellular communication are created via exosomes in the tumor microenvironment through the transport of various biomolecules. They are primarily involved in tumor growth, differentiation, metastasis, and chemotherapy or radiation resistance. Recently several studies have highlighted the critical role of tumor-derived exosomes against immune cells. According to the structural and functional properties, exosomes could be essential instruments to gain a better molecular mechanism for tumor understanding. Additionally, they are qualified as diagnostic/prognostic markers and therapeutic tools for specific targeting of invasive tumor cells such as glioblastomas. Due to the strong dependency of exosome features on the original cells and their developmental status, it is essential to review their critical modulating molecules, clinical relevance to glioma, and associated signaling pathways. This review is a non-clinical study, as the possible role of exosomes and exosomal microRNAs in glioma cancer are reported. In addition, their content to overcome cancer resistance and their potential as diagnostic biomarkers are analyzed.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Jalil Azami
- Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Alireza Masoudi
- Department of Laboratory Sciences, Faculty of Alied Medical Sciences, Qom University of Medical Sciences, Qom, Iran
| | | | - Elnaz Rahmani
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Alavi
- Department of Pathobiology, Faculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Armina Alagheband Bahrami
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research, Tabriz, Iran
| | - Masoomeh Dadkhah
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Navid Pourzardosht
- Biochemistry Department, Guilan University of Medical Sciences, Rasht, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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36
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PTEN Dual Lipid- and Protein-Phosphatase Function in Tumor Progression. Cancers (Basel) 2022; 14:cancers14153666. [PMID: 35954330 PMCID: PMC9367293 DOI: 10.3390/cancers14153666] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/17/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a multifunctional tumor suppressor with protein- and lipid-phosphatase activities. The inactivation of PTEN is commonly found in all human cancers and is correlated with tumor progression. PTEN-lipid-phosphatase activity has been well documented to dephosphorylate phosphatidylinositol-3, 4, 5-phosphate (PIP3), which hinders cell growth and survival by dampening the PI3K and AKT signaling activity. PTEN-protein-phosphatase activity is less well studied and understood. Recent studies have reported that PTEN-protein-phosphatase activity dephosphorylates the different proteins and acts in various cell functions. We here review the PTEN mutations and protein-phosphatase substrates in tumor progression. We aim to address the gap in our understanding as to how PTEN protein phosphatase contributes to its tumor-suppression functions. Abstract PTEN is the second most highly mutated tumor suppressor in cancer, following only p53. The PTEN protein functions as a phosphatase with lipid- and protein-phosphatase activity. PTEN-lipid-phosphatase activity dephosphorylates PIP3 to form PIP2, and it then antagonizes PI3K and blocks the activation of AKT, while its protein-phosphatase activity dephosphorylates different protein substrates and plays various roles in tumorigenesis. Here, we review the PTEN mutations and protein-phosphatase substrates in tumorigenesis and metastasis. Our purpose is to clarify how PTEN protein phosphatase contributes to its tumor-suppressive functions through PI3K-independent activities.
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Zhang J, Qin Y, Jiang Q, Li F, Jing X, Cao L, Cai S, Wu F, Li Q, Lian J, Song Y, Huang C. Glycopattern Alteration of Glycoproteins in Gastrointestinal Cancer Cell Lines and Their Cell-Derived Exosomes. J Proteome Res 2022; 21:1876-1893. [PMID: 35786973 DOI: 10.1021/acs.jproteome.2c00159] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Gastrointestinal (GI) cancers constitute the largest portion of all human cancers, and the most prevalent GI cancers in China are colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC). Exosomes are nanosized vesicles containing proteins, lipids, glycans, and nucleic acid, which play important roles in the tumor microenvironment and progression. Aberrant glycosylation is closely associated with GI cancers; however, little is known about the glycopattern of the exosomes from GI cancer cells. In this study, glycopatterns of HCC, CRC, and GC cell lines and their exosomes were detected using lectin microarrays. For all exosomes, (GlcNAcβ1-4)n and Galβ1-4GlcNAc (DSA) were the most abundant glycans, but αGalNAc and αGal (GSL-II and SBA) were the least. Different cancers had various characteristic glycans in either cells or exosomes. Glycans altered in cell-derived exosomes were not always consistent with the host cells in the same cancer. However, Fucα1-6GlcNAc (core fucose) and Fucα1-3(Galβ1-4)GlcNAc (AAL) were altered consistently in cells and exosomes although they were decreased in HCC and CRC but increased in GC. The study drew the full-scale glycan fingerprint of cells and exosomes related to GI cancer, which may provide useful information for finding specific biomarkers and exploring the underlying mechanism of glycosylation in exosomes.
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Affiliation(s)
- Jinyuan Zhang
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
| | - Yannan Qin
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
| | - Qiuyu Jiang
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
| | - Fang Li
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
| | - Xintao Jing
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
| | - Li Cao
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
| | - Shuang Cai
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
| | - Fei Wu
- Department of Oncology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Qian Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Medical University, Xi'an 710000, China
| | - Jiangfang Lian
- Department of Cardiovascular, Lihuili Hospital Facilitated to Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yongfei Song
- Ningbo Institute for Medicine & Biomedical Engineering Combined Innovation, Ningbo, Zhejiang 315000, China
| | - Chen Huang
- Institute of Genetics and Development Biology, Translational Medcine Institute, Xi'an Jiaotong University, Xi'an 710301, China
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Marei HE, Althani A, Afifi N, Hasan A, Caceci T, Cifola I, Caratelli S, Sconocchia G, D'Agnano I, Cenciarelli C. Glioma extracellular vesicles for precision medicine: prognostic and theragnostic application. Discov Oncol 2022; 13:49. [PMID: 35716231 PMCID: PMC9206693 DOI: 10.1007/s12672-022-00514-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/30/2022] [Indexed: 12/24/2022] Open
Abstract
EV produced by tumour cells carry a diverse population of proteins, lipids, DNA, and RNA molecules throughout the body and appear to play an important role in the overall development of the disease state, according to growing data. Gliomas account for a sizable fraction of all primary brain tumours and the vast majority of brain malignancies. Glioblastoma multiforme (GBM) is a kind of grade IV glioma that has a very dismal prognosis despite advancements in diagnostic methods and therapeutic options. The authors discuss advances in understanding the function of extracellular vesicles (EVs), in overall glioma growth, as well as how recent research is uncovering the utility of EVs in glioma diagnostics, prognostic and therapeutics approaches.
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Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35116, Egypt.
| | - Asmaa Althani
- Biomedical Research Center, Qatar University, Doha, Qatar
| | | | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| | - Thomas Caceci
- Biomedical Sciences, Virginia Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Ingrid Cifola
- Institute for Biomedical Technologies (ITB)-CNR, Segrate, Italy
| | - Sara Caratelli
- Institute of Translational Pharmacology (IFT)-CNR, Rome, Italy
| | | | - Igea D'Agnano
- Institute for Biomedical Technologies (ITB)-CNR, Segrate, Italy
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Mousavi SM, Amin Mahdian SM, Ebrahimi MS, Taghizadieh M, Vosough M, Sadri Nahand J, Hosseindoost S, Vousooghi N, Javar HA, Larijani B, Hadjighassem MR, Rahimian N, Hamblin MR, Mirzaei H. Microfluidics for detection of exosomes and microRNAs in cancer: State of the art. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 28:758-791. [PMID: 35664698 PMCID: PMC9130092 DOI: 10.1016/j.omtn.2022.04.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Exosomes are small extracellular vesicles with sizes ranging from 30-150 nanometers that contain proteins, lipids, mRNAs, microRNAs, and double-stranded DNA derived from the cells of origin. Exosomes can be taken up by target cells, acting as a means of cell-to-cell communication. The discovery of these vesicles in body fluids and their participation in cell communication has led to major breakthroughs in diagnosis, prognosis, and treatment of several conditions (e.g., cancer). However, conventional isolation and evaluation of exosomes and their microRNA content suffers from high cost, lengthy processes, difficult standardization, low purity, and poor yield. The emergence of microfluidics devices with increased efficiency in sieving, trapping, and immunological separation of small volumes could provide improved detection and monitoring of exosomes involved in cancer. Microfluidics techniques hold promise for advances in development of diagnostic and prognostic devices. This review covers ongoing research on microfluidics devices for detection of microRNAs and exosomes as biomarkers and their translation to point-of-care and clinical applications.
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Affiliation(s)
- Seyed Mojtaba Mousavi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Mahdian
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Saeid Ebrahimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saereh Hosseindoost
- Pain Research Center, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran
| | - Nasim Vousooghi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Akbari Javar
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Reza Hadjighassem
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Brain and Spinal Cord Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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An emerging role of KRAS in biogenesis, cargo sorting and uptake of cancer-derived extracellular vesicles. Future Med Chem 2022; 14:827-845. [PMID: 35502655 DOI: 10.4155/fmc-2021-0332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Extracellular vesicles (EVs) are nanovesicles secreted for intercellular communication with endosomal network regulating secretion of small EVs (or exosomes) that play roles in cancer progression. As an essential oncoprotein, Kirsten rat sarcoma virus (KRAS) is tightly regulated by its endosomal trafficking for membrane attachment. However, the crosstalk between KRAS and EVs has been scarcely discussed despite its endocytic association. An overview of the oncogenic role of KRAS focusing on its correlation with cancer-associated EVs should provide important clues for disease prognosis and inspire novel therapeutic approaches for treating KRAS mutant cancers. Therefore, this review summarizes the relevant studies that provide substantial evidence linking KRAS mutation to EVs and discusses the oncogenic implication from the aspects of biogenesis, cargo sorting, and release and uptake of the EVs.
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Wang K, Liu J, Li YL, Li JP, Zhang R. Ubiquitination/de-ubiquitination: A promising therapeutic target for PTEN reactivation in cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188723. [DOI: 10.1016/j.bbcan.2022.188723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 02/07/2023]
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Robinson I, Bertsch A, Leithner K, Stiegler P, Olschewski H, Hrzenjak A. Circulating microRNAs as molecular biomarkers for lung adenocarcinoma. Cancer Biomark 2022; 34:591-606. [DOI: 10.3233/cbm-210205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND: The potential of microRNAs (miRNAs) as molecular tumor biomarkers for early diagnosis and prognosis in lung cancer is still unclear. OBJECTIVE: To analyze expression of miRNAs in A549 lung adenocarcinoma (LUAD) cells and in primary, non-malignant bronchial epithelial (BE) cells from healthy donors. To analyze the most prominently deregulated miRNAs in plasma samples of LUAD patients and healthy donors. MATERIALS AND METHODS: The expression of 752 miRNAs in LUAD and BE cells was assessed by RT-qPCR with mean-centering restricted normalization. The relative plasma levels of 18 miRNAs in LUAD patients and healthy donors were analyzed using RT-qPCR and normalized to miR-191-5p and miR-16-3p. Putative interactions between miRNAs and their target genes were investigated in silico. RESULTS: Out of 752 miRNAs, 37 miRNAs were significantly deregulated in A549 cells compared to BE cells. MiR-15b-3p, miR-148a-3p, miR-193b-3p, and miR-195-5p were significantly deregulated in plasma samples of LUAD patients compared to donors. The target genes of those four miRNAs are involved in essential mechanisms in cancer development and progression. CONCLUSIONS: There are substantial differences between cancer and control miRNA expression in vitro and in plasma samples of LUAD patients compared to healthy donors. Four deregulated miRNAs are promising as a diagnostic biomarker for adenocarcinoma of the lung.
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Affiliation(s)
- Irina Robinson
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria
| | - Alexandra Bertsch
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria
| | - Katharina Leithner
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria
- BioTechMed-Graz, Graz, Austria
| | - Philipp Stiegler
- Division of Transplantation Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Horst Olschewski
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria
| | - Andelko Hrzenjak
- Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria
- Ludwig Boltzmann Institute for Lung Vascular Research, Medical University of Graz, Graz, Austria
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43
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Extracellular Vesicles Secreted by Glioma Stem Cells Are Involved in Radiation Resistance and Glioma Progression. Int J Mol Sci 2022; 23:ijms23052770. [PMID: 35269915 PMCID: PMC8911495 DOI: 10.3390/ijms23052770] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma is the most aggressive brain tumour with short survival, partly due to resistance to conventional therapy. Glioma stem cells (GSC) are likely to be involved in treatment resistance, by releasing extracellular vesicles (EVs) containing specific molecular cargoes. Here, we studied the EVs secreted by glioma stem cells (GSC-EVs) and their effects on radiation resistance and glioma progression. EVs were isolated from 3 GSCs by serial centrifugation. NanoSight measurement, cryo-electron microscopy and live imaging were used to study the EVs size, morphology and uptake, respectively. The non-GSC glioma cell lines LN229 and U118 were utilised as a recipient cell model. Wound healing assays were performed to detect cell migration. Colony formation, cell viability and invadopodium assays were conducted to detect cell survival of irradiated recipient cells and cell invasion post GSC-EV treatment. NanoString miRNA global profiling was used to select for the GSC-EVs’ specific miRNAs. All three GSC cell lines secreted different amounts of EVs, and all expressed consistent levels of CD9 but different level of Alix, TSG101 and CD81. EVs were taken up by both LN229 and U118 recipient cells. In the presence of GSC-EVs, these recipient cells survived radiation exposure and initiated colony formation. After GSC-EVs exposure, LN229 and U118 cells exhibited an invasive phenotype, as indicated by an increase in cell migration. We also identified 25 highly expressed miRNAs in the GSC-EVs examined, and 8 of these miRNAs can target PTEN. It is likely that GSC-EVs and their specific miRNAs induced the phenotypic changes in the recipient cells due to the activation of the PTEN/Akt pathway. This study demonstrated that GSC-EVs have the potential to induce radiation resistance and modulate the tumour microenvironment to promote glioma progression. Future therapeutic studies should be designed to interfere with these GSC-EVs and their specific miRNAs.
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Hassing B, Candy A, Eaton CJ, Fernandes TR, Mesarich CH, Di Pietro A, Scott B. Localisation of phosphoinositides in the grass endophyte Epichloë festucae and genetic and functional analysis of key components of their biosynthetic pathway in E. festucae symbiosis and Fusarium oxysporum pathogenesis. Fungal Genet Biol 2022; 159:103669. [PMID: 35114379 DOI: 10.1016/j.fgb.2022.103669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/15/2022] [Accepted: 01/27/2022] [Indexed: 11/24/2022]
Abstract
Phosphoinositides (PI) are essential components of eukaryotic membranes and function in a large number of signaling processes. While lipid second messengers are well studied in mammals and yeast, their role in filamentous fungi is poorly understood. We used fluorescent PI-binding molecular probes to localize the phosphorylated phosphatidylinositol species PI[3]P, PI[3,5]P2, PI[4]P and PI[4,5]P2 in hyphae of the endophyte Epichloë festucae in axenic culture and during interaction with its grass host Lolium perenne. We also analysed the roles of the phosphatidylinositol-4-phosphate 5-kinase MssD and the predicted phosphatidylinositol-3,4,5-triphosphate 3-phosphatase TepA, a homolog of the mammalian tumour suppressor protein PTEN. Deletion of tepA in E. festucae and in the root-infecting tomato pathogen Fusarium oxysporum had no impact on growth in culture or the host interaction phenotype. However, this mutation did enable the detection of PI[3,4,5]P3 in septa and mycelium of E. festucae and showed that TepA is required for chemotropism in F. oxysporum. The identification of PI[3,4,5]P3 in ΔtepA strains suggests that filamentous fungi are able to generate PI[3,4,5]P3 and that fungal PTEN homologs are functional lipid phosphatases. The F. oxysporum chemotropism defect suggests a conserved role of PTEN homologs in chemotaxis across protists, fungi and mammals.
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Affiliation(s)
- Berit Hassing
- School of Fundamental Sciences, Massey University, Palmerston North, New Zealand; Bio-Protection Research Centre, New Zealand
| | - Alyesha Candy
- School of Fundamental Sciences, Massey University, Palmerston North, New Zealand; Bio-Protection Research Centre, New Zealand
| | - Carla J Eaton
- School of Fundamental Sciences, Massey University, Palmerston North, New Zealand; Bio-Protection Research Centre, New Zealand
| | - Tania R Fernandes
- Departamento de Genética, Campus de Excelencia Internacional Agroalimentario ceiA3, Universidad de Córdoba, Córdoba, Spain
| | - Carl H Mesarich
- Bio-Protection Research Centre, New Zealand; School of Agriculture and Environment, Massey University, Palmerston North, New Zealand
| | - Antonio Di Pietro
- Departamento de Genética, Campus de Excelencia Internacional Agroalimentario ceiA3, Universidad de Córdoba, Córdoba, Spain
| | - Barry Scott
- School of Fundamental Sciences, Massey University, Palmerston North, New Zealand; Bio-Protection Research Centre, New Zealand.
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45
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Li C, Teixeira AF, Zhu HJ, Ten Dijke P. Cancer associated-fibroblast-derived exosomes in cancer progression. Mol Cancer 2021; 20:154. [PMID: 34852849 PMCID: PMC8638446 DOI: 10.1186/s12943-021-01463-y] [Citation(s) in RCA: 193] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/11/2021] [Indexed: 02/08/2023] Open
Abstract
To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.
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Affiliation(s)
- Chao Li
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Adilson Fonseca Teixeira
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
| | - Hong-Jian Zhu
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.
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De Morais JA, Zelanis A. Bioinformatic reanalysis of public proteomics data reveals that nuclear proteins are recurrent in cancer secretomes. Traffic 2021; 23:98-108. [PMID: 34806804 DOI: 10.1111/tra.12827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/05/2021] [Accepted: 11/18/2021] [Indexed: 11/27/2022]
Abstract
Proteins secreted by tumoral cells (cancer secretomes) have been continuously associated with cancer development and progression processes. In this context, secreted proteins contribute to the signaling mechanisms related to tumor growth and spreading and studies on tumor secretomes provide valuable clues on putative tumor biomarkers. Although the in vitro identification of intracellular proteins in cancer secretome studies has usually been associated with contamination derived from cell lysis or fetal bovine serum, accumulated evidence reports on intracellular proteins with moonlighting functions in the extracellular environment. In this study, we performed a systematic reanalysis of public proteomics data regarding different cancer secretomes, aiming to identify intracellular proteins potentially secreted by tumor cells via unconventional secretion pathways. We found a similar repertoire of unconventionally secreted proteins, including the recurrent identification of nuclear proteins secreted by different cancer cells. In addition, in some cancer types, immunohistochemical data were in line with proteomics identifications and suggested that nuclear proteins might relocate from the nucleus to the cytoplasm. Both the presence of nuclear proteins and the likely unconventional secretion of such proteins may comprise biological signatures of malignant transformation in distinct cancer types and may be targeted for further analysis aiming at the prognostic/therapeutic value of such features.
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Affiliation(s)
- Juliana A De Morais
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, UNIFESP, São José dos Campos, São Paulo, Brazil
| | - André Zelanis
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, UNIFESP, São José dos Campos, São Paulo, Brazil
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47
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Somiya M, Kuroda S. Reporter gene assay for membrane fusion of extracellular vesicles. J Extracell Vesicles 2021; 10:e12171. [PMID: 34807503 PMCID: PMC8607979 DOI: 10.1002/jev2.12171] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 11/01/2021] [Accepted: 11/08/2021] [Indexed: 01/05/2023] Open
Abstract
Extracellular vesicles (EVs) secreted by living cells are expected to deliver biological cargo molecules, including RNA and proteins, to the cytoplasm of recipient cells. There is an increasing need to understand the mechanism of intercellular cargo delivery by EVs. However, the lack of a feasible bioassay has hampered our understanding of the biological processes of EV uptake, membrane fusion, and cargo delivery to recipient cells. Here, we describe a reporter gene assay that can measure the membrane fusion efficiency of EVs during cargo delivery to recipient cells. When EVs containing tetracycline transactivator (tTA)-fused tetraspanins are internalized by recipient cells and fuse with cell membranes, the tTA domain is exposed to the cytoplasm and cleaved by tobacco etch virus protease to induce tetracycline responsive element (TRE)-mediated reporter gene expression in recipient cells. This assay (designated as EV-mediated tetraspanin-tTA delivery assay, ETTD assay), enabled us to assess the cytoplasmic cargo delivery efficiency of EVs in recipient cells. With the help of a vesicular stomatitis virus-derived membrane fusion protein, the ETTD assay could detect significant enhancement of cargo delivery efficiency of EVs. Furthermore, the ETTD assay could evaluate the effect of potential cargo delivery enhancers/inhibitors. Thus, the ETTD assay may contribute to a better understanding of the underlying mechanism of the cytoplasmic cargo delivery by EVs.
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Affiliation(s)
- Masaharu Somiya
- SANKEN (The Institute of Scientific and Industrial Research)Osaka UniversityOsakaJapan
| | - Shun'ichi Kuroda
- SANKEN (The Institute of Scientific and Industrial Research)Osaka UniversityOsakaJapan
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Aagab acts as a novel regulator of NEDD4-1-mediated Pten nuclear translocation to promote neurological recovery following hypoxic-ischemic brain damage. Cell Death Differ 2021; 28:2367-2384. [PMID: 33712741 PMCID: PMC8328997 DOI: 10.1038/s41418-021-00757-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 01/31/2023] Open
Abstract
Hypoxic-ischemic encephalopathy (HIE) is a main cause of mortality and severe neurologic impairment in the perinatal and neonatal period. However, few satisfactory therapeutic strategies are available. Here, we reported that a rapid nuclear translocation of phosphatase and tensin homolog deleted on chromosome TEN (PTEN) is an essential step in hypoxic-ischemic brain damage (HIBD)- and oxygen-glucose deprivation (OGD)-induced neuronal injures both in vivo and in vitro. In addition, we found that OGD-induced nuclear translocation of PTEN is dependent on PTEN mono-ubiquitination at the lysine 13 residue (K13) that is mediated by neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1). Importantly, we for the first time identified α- and γ-adaptin binding protein (Aagab) as a novel NEDD4-1 regulator to regulate the level of NEDD4-1, subsequently mediating Pten nuclear translocation. Finally, we demonstrated that genetic upregulation of Aagab or application of Tat-K13 peptide (a short interference peptide that flanks K13 residue of PTEN) not only reduced Pten nuclear translocation, but also significantly alleviated the deficits of myodynamia, motor and spatial learning and memory in HIBD model rats. These results suggest that Aagab may serve as a regulator of NEDD4-1-mediated Pten nuclear translocation to promote functional recovery following HIBD in neonatal rats, and provide a new potential therapeutic target to guide the clinical treatment for HIE.
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49
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Zhang Y, Xiao Y, Sun G, Jin X, Guo L, Li T, Yin H. Harnessing the therapeutic potential of extracellular vesicles for cancer treatment. Semin Cancer Biol 2021; 74:92-104. [PMID: 33962020 DOI: 10.1016/j.semcancer.2021.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 04/30/2021] [Accepted: 05/01/2021] [Indexed: 12/22/2022]
Abstract
Cancer therapeutic strategies include surgeries, radiotherapy, chemotherapy, targeted therapy and immunotherapies. However, current cancer treatment still faces challenges such as postoperative residuals, postoperative recurrence, chemoradiotherapy resistance and lack of drugs with high specificity, due to the complexity of the cancer environment. Extracellular vesicles (EVs) are lipid-capsuled membrane vesicles secreted from cells, communicating vital messages between cells and regarding function in tumorigenesis and metastasis. Investigation of compositions and functions of EVs may open unprecedented, promising avenues for cancer therapeutics. This review brings new perspectives from both researchers and clinicians in the EV field, emphasizing the ties between basic research and ongoing clinical trials. In sum, our review summarizes the roles EVs play in cancer therapy, ranging from mechanisms to applications in cancer treatment. In particular, it focuses on their therapeutic potential with an eye toward clinical relevance.
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Affiliation(s)
- Ying Zhang
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100082, China; Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China; Beijing Advanced Innovation, Center for Structural Biology, Tsinghua University, Beijing, China
| | - Yu Xiao
- Zhujiang Hospital, Laboratory of Medicine Center, Southern Medical University, Guangzhou, Guangdong, China
| | - Gaoge Sun
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100082, China; Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China; Beijing Advanced Innovation, Center for Structural Biology, Tsinghua University, Beijing, China
| | - Xue Jin
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100082, China; Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China; Beijing Advanced Innovation, Center for Structural Biology, Tsinghua University, Beijing, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Lerui Guo
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100082, China; Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China; Beijing Advanced Innovation, Center for Structural Biology, Tsinghua University, Beijing, China
| | - Tian Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Hang Yin
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100082, China; Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China; Beijing Advanced Innovation, Center for Structural Biology, Tsinghua University, Beijing, China.
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Zhang Q, Liang H, Zhao X, Zheng L, Li Y, Gong J, Zhu Y, Jin Y, Yin Y. PTENε suppresses tumor metastasis through regulation of filopodia formation. EMBO J 2021; 40:e105806. [PMID: 33755220 PMCID: PMC8126949 DOI: 10.15252/embj.2020105806] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 01/03/2021] [Accepted: 02/01/2021] [Indexed: 01/16/2023] Open
Abstract
PTEN is one of the most frequently mutated genes in malignancies and acts as a powerful tumor suppressor. Tumorigenesis is involved in multiple and complex processes including initiation, invasion, and metastasis. The complexity of PTEN function is partially attributed to PTEN family members such as PTENα and PTENβ. Here, we report the identification of PTENε (also named as PTEN5), a novel N‐terminal‐extended PTEN isoform that suppresses tumor invasion and metastasis. We show that the translation of PTENε/PTEN5 is initiated from the CUG816 codon within the 5′UTR region of PTEN mRNA. PTENε/PTEN5 mainly localizes in the cell membrane and physically associates with and dephosphorylates VASP and ACTR2, which govern filopodia formation and cell motility. We found that endogenous depletion of PTENε/PTEN5 promotes filopodia formation and enhances the metastasis capacity of tumor cells. Overall, we identify a new isoform of PTEN with distinct subcellular localization and molecular function compared to the known members of the PTEN family. These findings advance our current understanding of the importance and diversity of PTEN functions.
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Affiliation(s)
- Qiaoling Zhang
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Hui Liang
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Xuyang Zhao
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Zheng
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yunqiao Li
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Jingjing Gong
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yizhang Zhu
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yan Jin
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yuxin Yin
- Department of Pathology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China.,Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, China
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