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Zhao B, Wu J, Zhang T, Han M, Zhang C, Rong X, Zhang R, Chen X, Peng F, Jin J, Liu S, Dong X, Zhao S. A spatial transcriptomics study of MES-like and mono/macro cells in gliomas. Sci Rep 2025; 15:12730. [PMID: 40222970 PMCID: PMC11994772 DOI: 10.1038/s41598-025-95277-3] [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: 11/15/2024] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
Gliomas, including both glioblastoma multiforme (GBM) and lower-grade glioma (LGG), present a substantial challenge in neuro-oncology because of genetic heterogeneity and unsatisfactory prognosis. This study aimed to conduct a comprehensive multi-omics analysis of gliomas using various bioinformatics approaches to identify potential therapeutic targets and prognostic markers. A comprehensive analysis was conducted on 1327 sequencing data samples alongside their relevant clinical information sourced from The Cancer Genome Atlas (TCGA) pertaining to glioblastoma (GBM), low-grade glioma (LGG), the Chinese Glioma Genome Atlas (CCGA) and University of California Santa Cruz Xena (UCSC Xena) datasets. These tools were employed for gene expression profiling, survival analysis, and cell communication mapping. Spatial transcriptomics revealed the localization of mesenchymal (MES)-like malignant tumors, and drug sensitivity analysis was performed to evaluate responses to quinpirole and meropenem. Additionally, the Tumor Immune Dysfunction and Exclusion (TIDE) framework was utilized to gauge the responsiveness to immunotherapy. The MES-like malignant and monocyte/macrophage (mono/macro) cell subsets showed high hallmark scores, playing key roles in the tumor microenvironment. MES-like malignant marker gene scores correlated with overall survival across datasets, whereas mono/macro marker gene scores were significant in the TCGA-LGG and CCGA datasets. Key interactions between these cell types were found, especially with CD14-ITGB2, LGALS1-CD69, and APOE-TREM2. The mono/macro cell subset demonstrated better immune therapy responsiveness, as indicated by lower TIDE scores. Spatial transcriptomics revealed that MES-like malignant tumors are predominantly localized in four distinct regions, with the marker genes CHI3L1 and ADM confirming these locations. Drug sensitivity analysis revealed differential responses of the MES-like malignant cell subset to quinpirole and meropenem. Our results offer fresh perspectives on the differential roles of MES-like malignant and monocyte/macrophage cell subsets in tumor progression and immune modulation, providing novel insights into glioma biology.
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Affiliation(s)
- Boyan Zhao
- Department of Neurosurgery, Shenzhen University General Hospital, Shenzhen, 518000, Guangdong, China
- Shenzhen University School of Medicine, Shenzhen, 518000, Guangdong, China
| | - Jianing Wu
- Department of Neurosurgery, Shenzhen University General Hospital, Shenzhen, 518000, Guangdong, China
| | - Tiehui Zhang
- Shenzhen Clinical College of Integrated Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 518104, Guangdong, China
| | - Mingyang Han
- Department of Neurosurgery, Shenzhen University General Hospital, Shenzhen, 518000, Guangdong, China
| | - Cheng Zhang
- University of Toronto Scarborough 1265 Military Trail, Scarborough, ON, M1C 1A4, Canada
| | - Xuan Rong
- Department of Neurosurgery, Shenzhen University General Hospital, Shenzhen, 518000, Guangdong, China
| | - Ruotian Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xin Chen
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- Key Laboratory of Neurosurgery of Colleges and Universities in Heilongjiang Province, Harbin, 150001, Heilongjiang, China
| | - Fei Peng
- Department of Neurosurgery and Neurosurgical Disease Research Centre, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jin Jin
- Shenzhen University School of Medicine, Shenzhen, 518000, Guangdong, China
| | - Shiya Liu
- Shenzhen University School of Medicine, Shenzhen, 518000, Guangdong, China
| | - Xingli Dong
- Central Laboratory, Shenzhen University General Hospital, Shenzhen, 518000, Guangdong, China.
| | - Shiguang Zhao
- Department of Neurosurgery, Shenzhen University General Hospital, Shenzhen, 518000, Guangdong, China.
- Shenzhen University School of Medicine, Shenzhen, 518000, Guangdong, China.
- Department of Neurosurgery, Shenzhen University General Hospital, 1088 Xueyuan Avenue, Nanshan District, Shenzhen, 518036, Guangdong, China.
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2
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Novák J, Takács T, Tilajka Á, László L, Oravecz O, Farkas E, Than NG, Buday L, Balogh A, Vas V. The sweet and the bitter sides of galectin-1 in immunity: its role in immune cell functions, apoptosis, and immunotherapies for cancer with a focus on T cells. Semin Immunopathol 2025; 47:24. [PMID: 40178639 PMCID: PMC11968517 DOI: 10.1007/s00281-025-01047-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/07/2025] [Indexed: 04/05/2025]
Abstract
Galectin-1 (Gal-1), a member of the β-galactoside-binding soluble lectin family, is a double-edged sword in immunity. On one hand, it plays a crucial role in regulating diverse immune cell functions, including the apoptosis of activated T cells. These processes are key in resolving inflammation and preventing autoimmune diseases. On the other hand, Gal-1 has significant implications in cancer, where tumor cells and the tumor microenvironment (TME) (e.g., tumor-associated fibroblasts, myeloid-derived suppressor cells) secrete Gal-1 to evade immune surveillance and promote cancer cell growth. Within the TME, Gal-1 enhances the differentiation of tolerogenic dendritic cells, induces the apoptosis of effector T cells, and enhances the proliferation of regulatory T cells, collectively facilitating tumor immune escape. Therefore, targeting Gal-1 holds the potential to boost anti-tumor immunity and improve the efficacy of cancer immunotherapy. This review provides insights into the intricate role of Gal-1 in immune cell regulation, with an emphasis on T cells, and elucidates how tumors exploit Gal-1 for immune evasion and growth. Furthermore, we discuss the potential of Gal-1 as a therapeutic target to augment current immunotherapies across various cancer types.
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Affiliation(s)
- Julianna Novák
- Signal Transduction and Functional Genomics Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
| | - Tamás Takács
- Signal Transduction and Functional Genomics Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
- Doctoral School of Biology, Institute of Biology, Eötvös Loránd University, Budapest, 1117, Hungary
| | - Álmos Tilajka
- Signal Transduction and Functional Genomics Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
- Doctoral School of Biology, Institute of Biology, Eötvös Loránd University, Budapest, 1117, Hungary
| | - Loretta László
- Signal Transduction and Functional Genomics Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
- Doctoral School of Biology, Institute of Biology, Eötvös Loránd University, Budapest, 1117, Hungary
| | - Orsolya Oravecz
- Doctoral School of Biology, Institute of Biology, Eötvös Loránd University, Budapest, 1117, Hungary
- Systems Biology of Reproduction Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
| | - Emese Farkas
- Systems Biology of Reproduction Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
- Károly Rácz Conservative Medicine Division, Doctoral College, Semmelweis University, Budapest, 1091, Hungary
| | - Nándor Gábor Than
- Systems Biology of Reproduction Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
- Department of Obstetrics and Gynecology, Semmelweis University, Budapest, 1088, Hungary
| | - László Buday
- Signal Transduction and Functional Genomics Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary
- Department of Molecular Biology, Semmelweis University, Budapest, 1094, Hungary
| | - Andrea Balogh
- Systems Biology of Reproduction Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary.
| | - Virág Vas
- Signal Transduction and Functional Genomics Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary.
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3
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Bhayana S, Dougherty JA, Kamigaki Y, Agrawal S, Wijeratne S, Fitch J, Waller AP, Wolfgang KJ, White P, Kerlin BA, Smoyer WE. Glucocorticoid- and pioglitazone-induced proteinuria reduction in experimental NS both correlate with glomerular ECM modulation. iScience 2024; 27:108631. [PMID: 38188512 PMCID: PMC10770536 DOI: 10.1016/j.isci.2023.108631] [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: 04/10/2023] [Revised: 10/31/2023] [Accepted: 11/30/2023] [Indexed: 01/09/2024] Open
Abstract
Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution in silico revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS.
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Affiliation(s)
- Sagar Bhayana
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Julie A. Dougherty
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Yu Kamigaki
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Shipra Agrawal
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Saranga Wijeratne
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - James Fitch
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Amanda P. Waller
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Katelyn J. Wolfgang
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Peter White
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Bryce A. Kerlin
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - William E. Smoyer
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
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Luo Y, Cheng J, Fu Y, Zhang M, Gou M, Li J, Li X, Bai J, Zhou Y, Zhang L, Gao D. D-allose Inhibits TLR4/PI3K/AKT Signaling to Attenuate Neuroinflammation and Neuronal Apoptosis by Inhibiting Gal-3 Following Ischemic Stroke. Biol Proced Online 2023; 25:30. [PMID: 38017376 PMCID: PMC10683335 DOI: 10.1186/s12575-023-00224-z] [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: 08/22/2023] [Accepted: 11/01/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Ischemic stroke (IS) occurs when a blood vessel supplying the brain becomes obstructed, resulting in cerebral ischemia. This type of stroke accounts for approximately 87% of all strokes. Globally, IS leads to high mortality and poor prognosis and is associated with neuroinflammation and neuronal apoptosis. D-allose is a bio-substrate of glucose that is widely expressed in many plants. Our previous study showed that D-allose exerted neuroprotective effects against acute cerebral ischemic/reperfusion (I/R) injury by reducing neuroinflammation. Here, we aimed to clarify the beneficial effects D-allose in suppressing IS-induced neuroinflammation damage, cytotoxicity, neuronal apoptosis and neurological deficits and the underlying mechanism in vitro and in vivo. METHODS In vivo, an I/R model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R) in C57BL/6 N mice, and D-allose was given by intraperitoneal injection within 5 min after reperfusion. In vitro, mouse hippocampal neuronal cells (HT-22) with oxygen-glucose deprivation and reperfusion (OGD/R) were established as a cell model of IS. Neurological scores, some cytokines, cytotoxicity and apoptosis in the brain and cell lines were measured. Moreover, Gal-3 short hairpin RNAs, lentiviruses and adeno-associated viruses were used to modulate Gal-3 expression in neurons in vitro and in vivo to reveal the molecular mechanism. RESULTS D-allose alleviated cytotoxicity, including cell viability, LDH release and apoptosis, in HT-22 cells after OGD/R, which also alleviated brain injury, as indicated by lesion volume, brain edema, neuronal apoptosis, and neurological functional deficits, in a mouse model of I/R. Moreover, D-allose decreased the release of inflammatory factors, such as IL-1β, IL-6 and TNF-α. Furthermore, the expression of Gal-3 was increased by I/R in wild-type mice and HT-22 cells, and this factor further bound to TLR4, as confirmed by three-dimensional structure prediction and Co-IP. Silencing the Gal-3 gene with shRNAs decreased the activation of TLR4 signaling and alleviated IS-induced neuroinflammation, apoptosis and brain injury. Importantly, the loss of Gal-3 enhanced the D-allose-mediated protection against I/R-induced HT-22 cell injury, inflammatory insults and apoptosis, whereas activation of TLR4 by the selective agonist LPS increased the degree of neuronal injury and abolished the protective effects of D-allose. CONCLUSIONS In summary, D-allose plays a crucial role in inhibiting inflammation after IS by suppressing Gal-3/TLR4/PI3K/AKT signaling pathway in vitro and in vivo.
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Affiliation(s)
- Yaowen Luo
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China
| | - Junkai Cheng
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China
| | - Yihao Fu
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China
| | - Min Zhang
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China
| | - Maorong Gou
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China
| | - Juan Li
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China
| | - Xiaobing Li
- Department of Neurology, Xijing Hospital, Air Force Medical University, Changle West Road 127, Xi'an, China
| | - Jing Bai
- Department of Neurology, Xijing Hospital, Air Force Medical University, Changle West Road 127, Xi'an, China
| | - Yuefei Zhou
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China
| | - Lei Zhang
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China.
| | - Dakuan Gao
- Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Changle West Road NO.127, Xi'an, China.
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5
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Martínez-Bosch N, Vilariño N, Alameda F, Mojal S, Arumí-Uria M, Carrato C, Aldecoa I, Ribalta T, Vidal N, Bellosillo B, Menéndez S, Del Barco S, Gallego O, Pineda E, López-Martos R, Hernández A, Mesia C, Esteve-Codina A, de la Iglesia N, Balañá C, Martínez-García M, Navarro P. Gal-1 Expression Analysis in the GLIOCAT Multicenter Study: Role as a Prognostic Factor and an Immune-Suppressive Biomarker. Cells 2023; 12:cells12060843. [PMID: 36980184 PMCID: PMC10047329 DOI: 10.3390/cells12060843] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/02/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Glioblastoma (GBM) is the most frequent primary malignant brain tumor and has a dismal prognosis. Unfortunately, despite the recent revolution of immune checkpoint inhibitors in many solid tumors, these have not shown a benefit in overall survival in GBM patients. Therefore, new potential treatment targets as well as diagnostic, prognostic, and/or predictive biomarkers are needed to improve outcomes in this population. The β-galactoside binding protein Galectin-1 (Gal-1) is a protein with a wide range of pro-tumor functions such as proliferation, invasion, angiogenesis, and immune suppression. Here, we evaluated Gal-1 expression by immunohistochemistry in a homogenously treated cohort of GBM (the GLIOCAT project) and correlated its expression with clinical and molecular data. We observed that Gal-1 is a negative prognostic factor in GBM. Interestingly, we observed higher levels of Gal-1 expression in the mesenchymal/classical subtypes compared to the less aggressive proneural subtype. We also observed a Gal-1 expression correlation with immune suppressive signatures of CD4 T-cells and macrophages, as well as with several GBM established biomarkers, including SHC1, PD-L1, PAX2, MEOX2, YKL-40, TCIRG1, YWHAG, OLIG2, SOX2, Ki-67, and SOX11. Moreover, Gal-1 levels were significantly lower in grade 4 IDH-1 mutant astrocytomas, which have a better prognosis. Our results confirm the role of Gal-1 as a prognostic factor and also suggest its value as an immune-suppressive biomarker in GBM.
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Affiliation(s)
- Neus Martínez-Bosch
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain
| | - Noelia Vilariño
- Medical Oncology Department, Hospital Duran i Reynals, Catalan Institute of Oncology, L’Hospitalet, 08908 Barcelona, Spain
| | - Francesc Alameda
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain
- Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain
| | - Sergi Mojal
- Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Institut d’Investigacions Biomèdiques IIB-Sant Pau, 08025 Barcelona, Spain
| | - Montserrat Arumí-Uria
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain
- Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain
| | - Cristina Carrato
- Department of Pathology, Hospital Germans Trias i Pujol, 08916 Badalona, Spain
| | - Iban Aldecoa
- Department of Pathology, Center for Biomedical Diagnosis, Hospital Clinic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
- Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS (Instituto de Investigaciones Biomédicas August Pi i Sunyer), 08036 Barcelona, Spain
| | - Teresa Ribalta
- Department of Pathology, Center for Biomedical Diagnosis, Hospital Clinic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - Noemí Vidal
- Department of Pathology, Hospital Universitari de Bellvitge, L’Hospitalet, 08907 Barcelona, Spain
| | - Beatriz Bellosillo
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain
- Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain
| | - Silvia Menéndez
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain
| | - Sonia Del Barco
- Medical Oncology, Institut Catala d’Oncologia (ICO) Girona, Hospital Josep Trueta, 17007 Girona, Spain
| | - Oscar Gallego
- Department of Medical Oncology, Hospital de Sant Pau, 08036 Barcelona, Spain
| | - Estela Pineda
- Department of Medical Oncology, Hospital Clínic Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
| | - Raquel López-Martos
- Department of Pathology, Hospital Germans Trias i Pujol, 08916 Badalona, Spain
| | - Ainhoa Hernández
- Badalona Applied Research Group in Oncology (B-ARGO Group), Institut Investigació Germans Trias i Pujol (IGTP), Institut Catalá d’Oncologia (ICO), 08916 Badalona, Spain
| | - Carlos Mesia
- Neuro-Oncology Unit and Medical Oncology Department, Institut Catala d’Oncologia (ICO), Institut de Investigació Bellvitge (IDIBELL), L’Hospitalet, 08908 Barcelona, Spain
| | - Anna Esteve-Codina
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Nuria de la Iglesia
- IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
| | - Carme Balañá
- Badalona Applied Research Group in Oncology (B-ARGO Group), Institut Investigació Germans Trias i Pujol (IGTP), Institut Catalá d’Oncologia (ICO), 08916 Badalona, Spain
| | - María Martínez-García
- Department of Medical Oncology, Hospital del Mar, 08003 Barcelona, Spain
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain
- Correspondence: (M.M.-G.); (P.N.)
| | - Pilar Navarro
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, 08003 Barcelona, Spain
- Departamento de Muerte y Proliferación Celular, Instituto de Investigaciones Biomédicas de Barcelona–Centro Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Correspondence: (M.M.-G.); (P.N.)
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Kruk L, Braun A, Cosset E, Gudermann T, Mammadova-Bach E. Galectin functions in cancer-associated inflammation and thrombosis. Front Cardiovasc Med 2023; 10:1052959. [PMID: 36873388 PMCID: PMC9981828 DOI: 10.3389/fcvm.2023.1052959] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 01/12/2023] [Indexed: 02/19/2023] Open
Abstract
Galectins are carbohydrate-binding proteins that regulate many cellular functions including proliferation, adhesion, migration, and phagocytosis. Increasing experimental and clinical evidence indicates that galectins influence many steps of cancer development by inducing the recruitment of immune cells to the inflammatory sites and modulating the effector function of neutrophils, monocytes, and lymphocytes. Recent studies described that different isoforms of galectins can induce platelet adhesion, aggregation, and granule release through the interaction with platelet-specific glycoproteins and integrins. Patients with cancer and/or deep-venous thrombosis have increased levels of galectins in the vasculature, suggesting that these proteins could be important contributors to cancer-associated inflammation and thrombosis. In this review, we summarize the pathological role of galectins in inflammatory and thrombotic events, influencing tumor progression and metastasis. We also discuss the potential of anti-cancer therapies targeting galectins in the pathological context of cancer-associated inflammation and thrombosis.
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Affiliation(s)
- Linus Kruk
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
| | - Attila Braun
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany
| | - Erika Cosset
- CRCL, UMR INSERM 1052, CNRS 5286, Centre Léon Bérard, Lyon, France
| | - Thomas Gudermann
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,German Center for Lung Research (DZL), Munich, Germany
| | - Elmina Mammadova-Bach
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
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7
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Bieberich E. Synthesis, Processing, and Function of N-Glycans in N-Glycoproteins. ADVANCES IN NEUROBIOLOGY 2023; 29:65-93. [PMID: 36255672 DOI: 10.1007/978-3-031-12390-0_3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
Many membrane-resident and secreted proteins, including growth factors and their receptors are N-glycosylated. The initial N-glycan structure is synthesized in the endoplasmic reticulum (ER) as a branched structure on a lipid anchor (dolicholpyrophosphate) and then co-translationally, "en bloc" transferred and linked via N-acetylglucosamine to asparagine within a specific N-glycosylation acceptor sequence of the nascent recipient protein. In the ER and then the Golgi apparatus, the N-linked glycan structure is modified by hydrolytic removal of sugar residues ("trimming") followed by re-glycosylation with additional sugar residues ("processing") such as galactose, fucose or sialic acid to form complex N-glycoproteins. While the sequence of the reactions leading to biosynthesis, "en bloc" transfer and processing of N-glycans is well investigated, it is still not completely understood how N-glycans affect the biological fate and function of N-glycoproteins. This review will discuss the biology of N-glycoprotein synthesis, processing and function with specific reference to the physiology and pathophysiology of the immune and nervous system, as well as infectious diseases such as Covid-19.
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Affiliation(s)
- Erhard Bieberich
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.
- Veteran Affairs Medical Center, Lexington, KY, USA.
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8
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Zafari R, Razi S, Rezaei N. The role of dendritic cells in neuroblastoma: Implications for immunotherapy. Immunobiology 2022; 227:152293. [DOI: 10.1016/j.imbio.2022.152293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 09/09/2022] [Accepted: 10/19/2022] [Indexed: 11/26/2022]
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9
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Faisal SM, Comba A, Varela ML, Argento AE, Brumley E, Abel C, Castro MG, Lowenstein PR. The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications. Front Oncol 2022; 12:1005069. [PMID: 36276147 PMCID: PMC9583158 DOI: 10.3389/fonc.2022.1005069] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/20/2022] [Indexed: 11/26/2022] Open
Abstract
Glioblastoma (GBM), an aggressive high-grade glial tumor, is resistant to therapy and has a poor prognosis due to its universal recurrence rate. GBM cells interact with the non-cellular components in the tumor microenvironment (TME), facilitating their rapid growth, evolution, and invasion into the normal brain. Herein we discuss the complexity of the interactions between the cellular and non-cellular components of the TME and advances in the field as a whole. While the stroma of non-central nervous system (CNS) tissues is abundant in fibrillary collagens, laminins, and fibronectin, the normal brain extracellular matrix (ECM) predominantly includes proteoglycans, glycoproteins, and glycosaminoglycans, with fibrillary components typically found only in association with the vasculature. However, recent studies have found that in GBMs, the microenvironment evolves into a more complex array of components, with upregulated collagen gene expression and aligned fibrillary ECM networks. The interactions of glioma cells with the ECM and the degradation of matrix barriers are crucial for both single-cell and collective invasion into neighboring brain tissue. ECM-regulated mechanisms also contribute to immune exclusion, resulting in a major challenge to immunotherapy delivery and efficacy. Glioma cells chemically and physically control the function of their environment, co-opting complex signaling networks for their own benefit, resulting in radio- and chemo-resistance, tumor recurrence, and cancer progression. Targeting these interactions is an attractive strategy for overcoming therapy resistance, and we will discuss recent advances in preclinical studies, current clinical trials, and potential future clinical applications. In this review, we also provide a comprehensive discussion of the complexities of the interconnected cellular and non-cellular components of the microenvironmental landscape of brain tumors to guide the development of safe and effective therapeutic strategies against brain cancer.
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Affiliation(s)
- Syed M. Faisal
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrea Comba
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Maria L. Varela
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Anna E. Argento
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Emily Brumley
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Clifford Abel
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Maria G. Castro
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Pedro R. Lowenstein
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Pedro R. Lowenstein,
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10
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Galectins—Potential Therapeutic Targets for Neurodegenerative Disorders. Int J Mol Sci 2022; 23:ijms231911012. [PMID: 36232314 PMCID: PMC9569834 DOI: 10.3390/ijms231911012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Advancements in medicine have increased the longevity of humans, resulting in a higher incidence of chronic diseases. Due to the rise in the elderly population, age-dependent neurodegenerative disorders are becoming increasingly prevalent. The available treatment options only provide symptomatic relief and do not cure the underlying cause of the disease. Therefore, it has become imperative to discover new markers and therapies to modulate the course of disease progression and develop better treatment options for the affected individuals. Growing evidence indicates that neuroinflammation is a common factor and one of the main inducers of neuronal damage and degeneration. Galectins (Gals) are a class of β-galactoside-binding proteins (lectins) ubiquitously expressed in almost all vital organs. Gals modulate various cellular responses and regulate significant biological functions, including immune response, proliferation, differentiation, migration, and cell growth, through their interaction with glycoproteins and glycolipids. In recent years, extensive research has been conducted on the Gal superfamily, with Gal-1, Gal-3, and Gal-9 in prime focus. Their roles have been described in modulating neuroinflammation and neurodegenerative processes. In this review, we discuss the role of Gals in the causation and progression of neurodegenerative disorders. We describe the role of Gals in microglia and astrocyte modulation, along with their pro- and anti-inflammatory functions. In addition, we discuss the potential use of Gals as a novel therapeutic target for neuroinflammation and restoring tissue damage in neurodegenerative diseases.
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11
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Minic Janicijevic S, Jovanovic IP, Gajovic NM, Jurisevic MM, Debnath M, Arsenijevic NN, Borovcanin MM. Galectin-3 mediated risk of inflammation in stable schizophrenia, with only possible secondary consequences for cognition. World J Psychiatry 2022; 12:1183-1193. [PMID: 36186503 PMCID: PMC9521526 DOI: 10.5498/wjp.v12.i9.1183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/14/2022] [Accepted: 08/11/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Evidence suggests that cytokines cause immune disturbances, shape immunological sequelae later in life, and modulate the risk of schizophrenia (SC). Galectin-3 (Gal-3), a multifaceted molecule of the glycan family, is involved in the formation of the immunological synapse and modulates the signalling pathway and effector functions of T lymphocytes, which are major producers of cytokines. We have previously reported elevated serum Gal-3 levels in stable SC patients. However, Gal-3 as a link between cognitive functioning and inflammation has not yet been investigated in SC.
AIM To investigate the relationship between serum Gal-3 levels and cognitive performance, serum cytokines, and white blood cell count in three-month stably treated SC patients.
METHODS Twenty-seven patients with SC in remission and 18 healthy volunteers participated in this case-control and correlational study. Clinical assessment was performed using the Positive and Negative Syndrome Scale and the Montreal-Cognitive Assessment. The results of previously measured serum levels of Gal-3, interleukin (IL)-33, soluble suppression of tumorigenicity 2 (sST2), tumor necrosis factor-alpha (TNF-α), IL-6 and IL-17 were used for further statistical analyses, and IL-4, IL-23, IL-1β and transforming growth factor-beta (TGF-β) were now additionally measured with a sensitive enzyme-linked immunosorbent assay. The number of leukocytes in the blood and the percentage of neutrophils, lymphocytes, and monocytes were determined with a standardized routine measurement procedure (Sysmex Technology). Statistical analyses were performed using SPSS 20.0 software.
RESULTS We found no correlation between serum Gal-3 levels and cognitive functioning in SC patients. A positive correlation was found between the levels of Gal-3 and TNF-α (r = 0.476; P = 0.012), Gal-3 and IL-23 (r = 0.417; P = 0.031), and Gal-3 and sST2 (r = 0.402; P = 0.038). The binary logistic model, which included all nine cytokines measured in this patient sample, indicated the particular role of Gal-3 and TGF-β in the duration of SC. In the stabilization phase of SC, we observed a moderate and negative correlation between serum Gal-3 levels and leukocytes (r = -0.449; P < 0.019). Additional linear regression analysis showed a positive correlation between Gal-3 expression and risperidone dose (F: 4.467; P < 0.045; r2 = 0.396).
CONCLUSION The combined activity of Gal-3 and proinflammatory cytokines, TGF-β downregulation and lower counts of leukocytes influence the SC duration. Gal-3 likely manifests indirect immunometabolic regulation of cognition in SC.
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Affiliation(s)
| | - Ivan P Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Nevena M Gajovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Milena M Jurisevic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
| | - Nebojsa N Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Milica M Borovcanin
- Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
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12
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Guda MR, Tsung AJ, Asuthkar S, Velpula KK. Galectin-1 activates carbonic anhydrase IX and modulates glioma metabolism. Cell Death Dis 2022; 13:574. [PMID: 35773253 PMCID: PMC9247167 DOI: 10.1038/s41419-022-05024-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 01/21/2023]
Abstract
Galectins are a family of β-galactose-specific binding proteins residing within the cytosol or nucleus, with a highly conserved carbohydrate recognition domain across many species. Accumulating evidence shows that Galectin 1 (Gal-1) plays an essential role in cancer, and its expression correlates with tumor aggressiveness and progression. Our preliminary data showed Gal-1 promotes glioma stem cell (GSC) growth via increased Warburg effect. mRNA expression and clinical data were obtained from The Cancer Genome Atlas database. The immunoblot analysis conducted using our cohort of human glioblastoma patient specimens (hGBM), confirmed Gal-1 upregulation in GBM. GC/MS analysis to evaluate the effects of Gal-1 depletion showed elevated levels of α-ketoglutaric acid, and citric acid with a concomitant reduction in lactic acid levels. Using Biolog microplate-1 mitochondrial functional assay, we confirmed that the depletion of Gal-1 increases the expression levels of the enzymes from the TCA cycle, suggesting a reversal of the Warburg phenotype. Manipulation of Gal-1 using RNA interference showed reduced ATP, lactate levels, cell viability, colony-forming abilities, and increased expression levels of genes implicated in the induction of apoptosis. Gal-1 exerts its metabolic role via regulating the expression of carbonic anhydrase IX (CA-IX), a surrogate marker for hypoxia. CA-IX functions downstream to Gal-1, and co-immunoprecipitation experiments along with proximity ligation assays confirm that Gal-1 physically associates with CA-IX to regulate its expression. Further, silencing of Gal-1 in mice models showed reduced tumor burden and increased survival compared to the mice implanted with GSC controls. Further investigation of Gal-1 in GSC progression and metabolic reprogramming is warranted.
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Affiliation(s)
- Maheedhara R. Guda
- grid.430852.80000 0001 0741 4132Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL USA
| | - Andrew J. Tsung
- grid.430852.80000 0001 0741 4132Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL USA ,grid.430852.80000 0001 0741 4132Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL USA ,Illinois Neurological Institute, Peoria, IL USA
| | - Swapna Asuthkar
- grid.430852.80000 0001 0741 4132Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL USA
| | - Kiran K. Velpula
- grid.430852.80000 0001 0741 4132Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL USA ,grid.430852.80000 0001 0741 4132Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL USA ,grid.430852.80000 0001 0741 4132Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL USA
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13
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Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma. Int J Mol Sci 2022; 23:ijms23116312. [PMID: 35682991 PMCID: PMC9181495 DOI: 10.3390/ijms23116312] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/23/2022] [Accepted: 06/03/2022] [Indexed: 02/04/2023] Open
Abstract
Despite diagnostic and therapeutic improvements, glioblastoma (GB) remains one of the most threatening brain tumor in adults, underlining the urgent need of new therapeutic targets. Lectins are glycan-binding proteins that regulate several biological processes through the recognition of specific sugar motifs. Lectins and their ligands are found on immune cells, endothelial cells and, also, tumor cells, pointing out a strong correlation among immunity, tumor microenvironment and vascularization. In GB, altered glycans and lectins contribute to tumor progression and immune evasion, shaping the tumor-immune landscape promoting immunosuppressive cell subsets, such as myeloid-derived suppressor cells (MDSCs) and M2-macrophages, and affecting immunoeffector populations, such as CD8+ T cells and dendritic cells (DCs). Here, we discuss the latest knowledge on the immune cells, immune related lectin receptors (C-type lectins, Siglecs, galectins) and changes in glycosylation that are involved in immunosuppressive mechanisms in GB, highlighting their interest as possible novel therapeutical targets.
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14
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Gopinath P, Natarajan A, Sathyanarayanan A, Veluswami S, Gopisetty G. The multifaceted role of Matricellular Proteins in health and cancer, as biomarkers and therapeutic targets. Gene 2022; 815:146137. [PMID: 35007686 DOI: 10.1016/j.gene.2021.146137] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.
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Affiliation(s)
- Prarthana Gopinath
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | - Aparna Natarajan
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India
| | | | - Sridevi Veluswami
- Deaprtment of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
| | - Gopal Gopisetty
- Department of Molecular Oncology, Cancer Institute WIA, Chennai, Tamil Nadu, India.
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15
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Scuto M, Ontario ML, Salinaro AT, Caligiuri I, Rampulla F, Zimbone V, Modafferi S, Rizzolio F, Canzonieri V, Calabrese EJ, Calabrese V. Redox modulation by plant polyphenols targeting vitagenes for chemoprevention and therapy: Relevance to novel anti-cancer interventions and mini-brain organoid technology. Free Radic Biol Med 2022; 179:59-75. [PMID: 34929315 DOI: 10.1016/j.freeradbiomed.2021.12.267] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/07/2021] [Accepted: 12/16/2021] [Indexed: 12/26/2022]
Abstract
The scientific community, recently, has focused notable attention on the chemopreventive and therapeutic effects of dietary polyphenols for human health. Emerging evidence demonstrates that polyphenols, flavonoids and vitamins counteract and neutralize genetic and environmental stressors, particularly oxidative stress and inflammatory process closely connected to cancer initiation, promotion and progression. Interestingly, polyphenols can exert antioxidant or pro-oxidant cytotoxic effects depending on their endogenous concentration. Notably, polyphenols at high dose act as pro-oxidants in a wide type of cancer cells by inhibiting Nrf2 pathway and the expression of antioxidant vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), GPx, heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system which play an essential role in the metabolism of reactive oxygen species (ROS), detoxification of xenobiotics and inhibition of cancer progression, by inducing apoptosis and cell cycle arrest according to the hormesis approach. Importantly, mutagenesis of Nrf2 pathway can exacerbate its "dark side" role, representing a crucial event in the initiation stage of carcinogenesis. Herein, we review the hormetic effects of polyphenols and nanoincapsulated-polyphenols in chemoprevention and treatment of brain tumors via activation or inhibition of Nrf2/vitagenes to suppress carcinogenesis in the early stages, and thus inhibit its progression. Lastly, we discuss innovative preclinical approaches through mini-brain tumor organoids to study human carcinogenesis, from basic cancer research to clinical practice, as promising tools to recapitulate the arrangement of structural neuronal tissues and biological functions of the human brain, as well as test drug toxicity and drive personalized and precision medicine in brain cancer.
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Affiliation(s)
- Maria Scuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124, Catania, Italy; Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy
| | - Maria Laura Ontario
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124, Catania, Italy
| | - Angela Trovato Salinaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124, Catania, Italy.
| | - Isabella Caligiuri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy
| | - Francesco Rampulla
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124, Catania, Italy
| | - Vincenzo Zimbone
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124, Catania, Italy
| | - Sergio Modafferi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124, Catania, Italy
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy; Department of Molecular Sciences and Nanosystems, Ca'Foscari University of Venice, 30123, Venezia, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, 34127, Trieste, Italy
| | - Edward J Calabrese
- Department of Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA, 01003, USA
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124, Catania, Italy.
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Videla-Richardson GA, Morris-Hanon O, Torres NI, Esquivel MI, Vera MB, Ripari LB, Croci DO, Sevlever GE, Rabinovich GA. Galectins as Emerging Glyco-Checkpoints and Therapeutic Targets in Glioblastoma. Int J Mol Sci 2021; 23:ijms23010316. [PMID: 35008740 PMCID: PMC8745137 DOI: 10.3390/ijms23010316] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 02/08/2023] Open
Abstract
Despite recent advances in diagnosis and treatment, glioblastoma (GBM) represents the most common and aggressive brain tumor in the adult population, urging identification of new rational therapeutic targets. Galectins, a family of glycan-binding proteins, are highly expressed in the tumor microenvironment (TME) and delineate prognosis and clinical outcome in patients with GBM. These endogenous lectins play key roles in different hallmarks of cancer by modulating tumor cell proliferation, oncogenic signaling, migration, vascularization and immunity. Additionally, they have emerged as mediators of resistance to different anticancer treatments, including chemotherapy, radiotherapy, immunotherapy, and antiangiogenic therapy. Particularly in GBM, galectins control tumor cell transformation and proliferation, reprogram tumor cell migration and invasion, promote vascularization, modulate cell death pathways, and shape the tumor-immune landscape by targeting myeloid, natural killer (NK), and CD8+ T cell compartments. Here, we discuss the role of galectins, particularly galectin-1, -3, -8, and -9, as emerging glyco-checkpoints that control different mechanisms associated with GBM progression, and discuss possible therapeutic opportunities based on inhibition of galectin-driven circuits, either alone or in combination with other treatment modalities.
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Affiliation(s)
- Guillermo A. Videla-Richardson
- Laboratorio de Investigación Aplicada en Neurociencias (LIAN), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Belén de Escobar B1625, Argentina; (G.A.V.-R.); (O.M.-H.); (M.I.E.); (M.B.V.); (L.B.R.); (G.E.S.)
| | - Olivia Morris-Hanon
- Laboratorio de Investigación Aplicada en Neurociencias (LIAN), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Belén de Escobar B1625, Argentina; (G.A.V.-R.); (O.M.-H.); (M.I.E.); (M.B.V.); (L.B.R.); (G.E.S.)
| | - Nicolás I. Torres
- Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1428, Argentina;
| | - Myrian I. Esquivel
- Laboratorio de Investigación Aplicada en Neurociencias (LIAN), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Belén de Escobar B1625, Argentina; (G.A.V.-R.); (O.M.-H.); (M.I.E.); (M.B.V.); (L.B.R.); (G.E.S.)
| | - Mariana B. Vera
- Laboratorio de Investigación Aplicada en Neurociencias (LIAN), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Belén de Escobar B1625, Argentina; (G.A.V.-R.); (O.M.-H.); (M.I.E.); (M.B.V.); (L.B.R.); (G.E.S.)
| | - Luisina B. Ripari
- Laboratorio de Investigación Aplicada en Neurociencias (LIAN), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Belén de Escobar B1625, Argentina; (G.A.V.-R.); (O.M.-H.); (M.I.E.); (M.B.V.); (L.B.R.); (G.E.S.)
| | - Diego O. Croci
- Laboratorio de Inmunopatología, Instituto de Histología y Embriología de Mendoza (IHEM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza C5500, Argentina;
| | - Gustavo E. Sevlever
- Laboratorio de Investigación Aplicada en Neurociencias (LIAN), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Belén de Escobar B1625, Argentina; (G.A.V.-R.); (O.M.-H.); (M.I.E.); (M.B.V.); (L.B.R.); (G.E.S.)
| | - Gabriel A. Rabinovich
- Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1428, Argentina;
- Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428, Argentina
- Correspondence: ; Tel.: +54-11-4783-2869 (ext. 266)
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Rana R, Chauhan K, Gautam P, Kulkarni M, Banarjee R, Chugh P, Chhabra SS, Acharya R, Kalra SK, Gupta A, Jain S, Ganguly NK. Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma. Front Oncol 2021; 11:778754. [PMID: 34900729 PMCID: PMC8661035 DOI: 10.3389/fonc.2021.778754] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022] Open
Abstract
Gliomas are the most common type of the malignant brain tumor, which arise from glial cells. They make up about 40% of all primary brain tumors and around 70% of all primary malignant brain tumors. They can occur anywhere in the central nervous system (CNS) and have a poor prognosis. The average survival of glioma patients is approximately 6-15 months with poor aspects of life. In this edge, identification of proteins secreted by cancer cells is of special interest because it may provide a better understanding of tumor progression and provide early diagnosis of the diseases. Extracellular vesicles (EVs) were isolated from pooled plasma of healthy controls (n=03) and patients with different grades of glioma (Grade I or II or III, n=03 each). Nanoparticle tracking analysis, western blot, and flow cytometry were performed to determine the size, morphology, the concentration of glioma-derived vesicles and EV marker, CD63. Further, iTRAQ-based LC-MS/MS analysis of EV protein was performed to determine the differential protein abundance in extracellular vesicles across different glioma grades. We further verified galectin-3 binding protein (LGALS3BP) by ELISA in individual blood plasma and plasma-derived vesicles from control and glioma patients (n=40 each). Analysis by Max Quant identified 123 proteins from the pooled patient exosomes, out of which 34, 21, and 14 proteins were found to be differentially abundant by more than 1.3-fold in the different grades of glioma grade I, pilocytic astrocytoma; grade II, diffuse astrocytoma; grade III, anaplastic astrocytoma, respectively, in comparison with the control samples. A total of seven proteins-namely, CRP, SAA2, SERPINA3, SAA1, C4A, LV211, and KV112-showed differential abundance in all the three grades. LGALS3BP was seen to be upregulated across the different grades, and ELISA analysis from individual blood plasma and plasma-derived extracellular vesicles confirmed the increased expression of LGALS3BP in glioma patients (p<0.001). The present study provides LGALS3BP as a potential biomarker for early detection of glioma and improve survival outcome of the patient. The present study further provides the information of progression and monitoring the tumor grades (grade 1, grade II, grade III).
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Affiliation(s)
- Rashmi Rana
- Department of Research, Sir Ganga Ram Hospital, New Delhi, India
| | - Kirti Chauhan
- Department of Research, Sir Ganga Ram Hospital, New Delhi, India
| | - Poonam Gautam
- Laboratory of Molecular Oncology, National Institute of Pathology, Indian Council of Medical Research (ICMR), New Delhi, India
| | - Mahesh Kulkarni
- Biochemical Sciences Division, National Chemical Laboratory, Council of Scientific and Industrial Research (CSIR), Pune, India
| | - Reema Banarjee
- Biochemical Sciences Division, National Chemical Laboratory, Council of Scientific and Industrial Research (CSIR), Pune, India
| | - Parul Chugh
- Department of Research, Sir Ganga Ram Hospital, New Delhi, India
| | | | - Rajesh Acharya
- Department of Neurosurgery, Sir Ganga Ram Hospital, New Delhi, India
| | - Samir Kumar Kalra
- Department of Neurosurgery, Sir Ganga Ram Hospital, New Delhi, India
| | - Anshul Gupta
- Department of Neurosurgery, Sir Ganga Ram Hospital, New Delhi, India
| | - Sunila Jain
- Department of Histopathology, Sir Ganga Ram Hospital, New Delhi, India
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18
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Gomes MC, Chen J, Cunha A, Trindade T, Zheng G, Tomé JPC. Complex cellular environments imaged by SERS nanoprobes using sugars as an all-in-one vector. J Mater Chem B 2021; 9:9285-9294. [PMID: 34709285 DOI: 10.1039/d1tb01360b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Raman spectroscopy coupled with confocal microscopy offers an alternative bioimaging technique overcoming limitations associated with sensitivity, tissue penetration and image resolution. Allied to the surface-enhanced Raman scattering (SERS) properties of gold nanoparticles (AuNP), we designed SERS nanoprobes with enhanced properties and straightforward application as bio-labelling agents for gliomas. The ensuing nanoprobes coated with simple sugar units (galactose or glucose) allowed assessing information about their intracellular localization (vesicular structures), with impressive sensitivity towards complex environments and proved the ability to overcome biological auto-fluorescence and high penetration in tissues. We validate the use of sugars as an all-in-one vector (Raman reporter, conferring high stability, biocompatibility and affinity to glioma cells) as imaging agents using an impressive technique.
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Affiliation(s)
- Maria C Gomes
- LAQV-REQUINTE and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.,Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
| | - Juan Chen
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
| | - Angela Cunha
- CESAM and Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Tito Trindade
- CICECO-Aveiro Institute of Materials and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Gang Zheng
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - João P C Tomé
- LAQV-REQUINTE and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.,CQE and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.
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19
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Ajarrag S, St-Pierre Y. Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment. Cancers (Basel) 2021; 13:cancers13215533. [PMID: 34771696 PMCID: PMC8582867 DOI: 10.3390/cancers13215533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 11/29/2022] Open
Abstract
Simple Summary Glioblastomas are among the most common and aggressive brain tumors. The high rate of recurrence and mortality associated with this cancer underscores the need for the development of new therapeutical targets. Galectins are among the new targets that have attracted the attention of many scientists working in the field of cancer. They form a group of small proteins found in many tissues where they accomplish various physiological roles, including regulation of immune response and resistance to cell death. In many types of cancer, however, production of abnormally high levels of galectins by cancer cells can be detrimental to patients. Elevated levels of galectins can, for example, suppress the ability of the host’s immune system to kill cancer cells. They can also provide cancer cells with resistance to drugs-induced cell death. Here, we review the recent progress that has contributed to a better understanding of the mechanisms of actions of galectins in glioblastoma. We also discuss recent development of anti-galectin drugs and the challenges associated with their use in clinical settings, with particular attention to their role in reducing the efficacy of immunotherapy, a promising treatment that exploits the capacity of the immune system to recognize and kill cancer cells. Abstract Traditional wisdom suggests that galectins play pivotal roles at different steps in cancer progression. Galectins are particularly well known for their ability to increase the invasiveness of cancer cells and their resistance to drug-induced cell death. They also contribute to the development of local and systemic immunosuppression, allowing cancer cells to escape the host’s immunological defense. This is particularly true in glioma, the most common primary intracranial tumor. Abnormally high production of extracellular galectins in glioma contributes to the establishment of a strong immunosuppressive environment that favors immune escape and tumor progression. Considering the recent development and success of immunotherapy in halting cancer progression, it is logical to foresee that galectin-specific drugs may help to improve the success rate of immunotherapy for glioma. This provides a new perspective to target galectins, whose intracellular roles in cancer progression have already been investigated thoroughly. In this review, we discuss the mechanisms of action of galectins at different steps of glioma progression and the potential of galectin-specific drugs for the treatment of glioma.
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20
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da Silva Filho AF, Tavares LB, Pitta MGR, Beltrão EIC, Rêgo MJBM. Galectin-3 is modulated in pancreatic cancer cells under hypoxia and nutrient deprivation. Biol Chem 2021; 401:1153-1165. [PMID: 32755098 DOI: 10.1515/hsz-2019-0413] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 04/28/2020] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive tumors with a microenvironment marked by hypoxia and starvation. Galectin-3 has been evaluated in solid tumors and seems to present both pro/anti-tumor effects. So, this study aims to characterize the expression of Galectin-3 from pancreatic tumor cells and analyze its influence for cell survive and motility in mimetic microenvironment. For this, cell cycle and cell death were accessed through flow cytometry. Characterization of inside and outside Galectin-3 was performed through Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), immunofluorescence, Western blot, and ELISA. Consequences of Galectin-3 extracellular inhibition were investigated using cell death and scratch assays. PANC-1 showed increased Galectin-3 mRNA expression when cultivated in hypoxia for 24 and 48 h. After 24 h in simultaneously hypoxic/deprived incubation, PANC-1 shows increased Galectin-3 protein and secreted levels. For Mia PaCa-2, cultivation in deprivation was determinant for the increasing in Galectin-3 mRNA expression. When cultivated in simultaneously hypoxic/deprived condition, Mia PaCa-2 also presented increasing for the Galectin-3 secreted levels. Treatment of PANC-1 cells with lactose increased the death rate when cells were incubated simultaneously hypoxic/deprived condition. Therefore, it is possible to conclude that the microenvironmental conditions modulate the Galectin-3 expression on the transcriptional and translational levels for pancreatic cancer cells.
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Affiliation(s)
- Antônio F da Silva Filho
- Immunomodulation and New Therapy Approach Laboratory (LINAT), Biochemistry Department, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil.,Therapeutic Innovation Research Center- Suelly Galdino (NUPIT-SG), Biochemistry Departament, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Lucas B Tavares
- Immunomodulation and New Therapy Approach Laboratory (LINAT), Biochemistry Department, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil.,Therapeutic Innovation Research Center- Suelly Galdino (NUPIT-SG), Biochemistry Departament, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Maira G R Pitta
- Immunomodulation and New Therapy Approach Laboratory (LINAT), Biochemistry Department, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil.,Therapeutic Innovation Research Center- Suelly Galdino (NUPIT-SG), Biochemistry Departament, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Eduardo I C Beltrão
- Laboratory of Biomarkers in Cancer (BmC), Biochemistry Department, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Moacyr J B M Rêgo
- Immunomodulation and New Therapy Approach Laboratory (LINAT), Biochemistry Department, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil.,Therapeutic Innovation Research Center- Suelly Galdino (NUPIT-SG), Biochemistry Departament, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
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21
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Jafari SH, Rabiei N, Taghizadieh M, Mirazimi SMA, Kowsari H, Farzin MA, Razaghi Bahabadi Z, Rezaei S, Mohammadi AH, Alirezaei Z, Dashti F, Nejati M. Joint application of biochemical markers and imaging techniques in the accurate and early detection of glioblastoma. Pathol Res Pract 2021; 224:153528. [PMID: 34171601 DOI: 10.1016/j.prp.2021.153528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/09/2021] [Accepted: 06/14/2021] [Indexed: 11/28/2022]
Abstract
Glioblastoma is a primary brain tumor with the most metastatic effect in adults. Despite the wide range of multidimensional treatments, tumor heterogeneity is one of the main causes of tumor spread and gives great complexity to diagnostic and therapeutic methods. Therefore, featuring noble noninvasive prognostic methods that are focused on glioblastoma heterogeneity is perceived as an urgent need. Imaging neuro-oncological biomarkers including MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation status, tumor grade along with other tumor characteristics and demographic features (e.g., age) are commonly referred to during diagnostic, therapeutic and prognostic processes. Therefore, the use of new noninvasive prognostic methods focused on glioblastoma heterogeneity is considered an urgent need. Some neuronal biomarkers, including the promoter methylation status of the promoter MGMT, the characteristics and grade of the tumor, along with the patient's demographics (such as age and sex) are involved in diagnosis, treatment, and prognosis. Among the wide array of imaging techniques, magnetic resonance imaging combined with the more physiologically detailed technique of H-magnetic resonance spectroscopy can be useful in diagnosing neurological cancer patients. In addition, intracranial tumor qualitative analysis and sometimes tumor biopsies help in accurate diagnosis. This review summarizes the evidence for biochemical biomarkers being a reliable biomarker in the early detection and disease management in GBM. Moreover, we highlight the correlation between Imaging techniques and biochemical biomarkers and ask whether they can be combined.
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Affiliation(s)
- Seyed Hamed Jafari
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sayad Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Kowsari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Amin Farzin
- Department of Laboratory Medicine, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Razaghi Bahabadi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Samaneh Rezaei
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Hossein Mohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Alirezaei
- Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Paramedical School, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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22
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Seguin L, Odouard S, Corlazzoli F, Haddad SA, Moindrot L, Calvo Tardón M, Yebra M, Koval A, Marinari E, Bes V, Guérin A, Allard M, Ilmjärv S, Katanaev VL, Walker PR, Krause KH, Dutoit V, Sarkaria JN, Dietrich PY, Cosset É. Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells. Commun Biol 2021; 4:718. [PMID: 34112916 PMCID: PMC8192788 DOI: 10.1038/s42003-021-02258-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 05/21/2021] [Indexed: 12/11/2022] Open
Abstract
Recently, we involved the carbohydrate-binding protein Galectin-3 (Gal-3) as a druggable target for KRAS-mutant-addicted lung and pancreatic cancers. Here, using glioblastoma patient-derived stem cells (GSCs), we identify and characterize a subset of Gal-3high glioblastoma (GBM) tumors mainly within the mesenchymal subtype that are addicted to Gal-3-mediated macropinocytosis. Using both genetic and pharmacologic inhibition of Gal-3, we showed a significant decrease of GSC macropinocytosis activity, cell survival and invasion, in vitro and in vivo. Mechanistically, we demonstrate that Gal-3 binds to RAB10, a member of the RAS superfamily of small GTPases, and β1 integrin, which are both required for macropinocytosis activity and cell survival. Finally, by defining a Gal-3/macropinocytosis molecular signature, we could predict sensitivity to this dependency pathway and provide proof-of-principle for innovative therapeutic strategies to exploit this Achilles' heel for a significant and unique subset of GBM patients.
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Affiliation(s)
- Laetitia Seguin
- University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging (IRCAN), Nice, France
| | - Soline Odouard
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Francesca Corlazzoli
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Sarah Al Haddad
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Laurine Moindrot
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Marta Calvo Tardón
- Laboratory of Immunobiology of brain tumors, Center for Translational Research in Onco-Hematology, Geneva University Hospitals, and University of Geneva, Geneva, Switzerland
| | - Mayra Yebra
- Department of Surgery, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Alexey Koval
- Department of Cell Physiology and Metabolism, Medical School, University of Geneva, Geneva, Switzerland
| | - Eliana Marinari
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Viviane Bes
- Laboratory of Immunobiology of brain tumors, Center for Translational Research in Onco-Hematology, Geneva University Hospitals, and University of Geneva, Geneva, Switzerland
| | - Alexandre Guérin
- Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Geneva, Switzerland
| | - Mathilde Allard
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Sten Ilmjärv
- Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Geneva, Switzerland
| | - Vladimir L Katanaev
- Department of Cell Physiology and Metabolism, Medical School, University of Geneva, Geneva, Switzerland
| | - Paul R Walker
- Laboratory of Immunobiology of brain tumors, Center for Translational Research in Onco-Hematology, Geneva University Hospitals, and University of Geneva, Geneva, Switzerland
| | - Karl-Heinz Krause
- Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Geneva, Switzerland
| | - Valérie Dutoit
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Pierre-Yves Dietrich
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Érika Cosset
- Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
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23
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Knudsen AM, Rudkjøbing SJ, Sørensen MD, Dahlrot RH, Kristensen BW. Expression and Prognostic Value of the Immune Checkpoints Galectin-9 and PD-L1 in Glioblastomas. J Neuropathol Exp Neurol 2021; 80:541-551. [PMID: 33990845 DOI: 10.1093/jnen/nlab041] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Immunotherapeutic targeting of the PD-1/PD-L1 axis has been widely implemented for treatment of several cancer types but shown disappointing results in glioblastomas (GBMs), potentially due to compensatory mechanisms of other expressed immune checkpoints. Galectin-9 is an immune-checkpoint protein that facilitates T-cell exhaustion and apoptosis and could be a potential target for immune-checkpoint inhibition. A total of 163 GBMs IDH wildtype were immunostained with anti-Galectin-9 and PD-L1 antibodies. Software-based quantitation of immunostainings was performed and co-expression was investigated using double immunofluorescence. Both Galectin-9 and PD-L1 protein expression were found in all 163 tumors and showed a significant positive correlation (p = 0.0017). Galectin-9 expression varied from 0.01% to 32% (mean = 6.61%), while PD-L1 membrane expression ranged from 0.003% to 0.14% (mean = 0.048%) of total tumor area. Expression of Galectin-9 and PD-L1 was found on both microglia/macrophages and tumor cells, and colocalization of both markers was found in 88.3% of tumors. In multivariate analysis, neither Galectin-9 (HR = 0.99), PD-L1 (HR = 1.05), nor their combinations showed prognostic value. Galectin-9 and PD-L1 were expressed in all investigated GBMs and the majority of patients had co-expression, which may provide rationale for multi-targeted immune checkpoint inhibition.
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Affiliation(s)
- Arnon Møldrup Knudsen
- From the Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Sisse Josephine Rudkjøbing
- From the Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Mia Dahl Sørensen
- From the Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Rikke Hedegaard Dahlrot
- From the Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Oncology, Odense University Hospital, Odense, Denmark
| | - Bjarne Winther Kristensen
- From the Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark.,Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Clinical Medicine and Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
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24
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Navarro P, Martínez-Bosch N, Blidner AG, Rabinovich GA. Impact of Galectins in Resistance to Anticancer Therapies. Clin Cancer Res 2020; 26:6086-6101. [DOI: 10.1158/1078-0432.ccr-18-3870] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/27/2020] [Accepted: 07/22/2020] [Indexed: 11/16/2022]
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25
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Araújo JRC, Coelho CB, Campos AR, de Azevedo Moreira R, de Oliveira Monteiro-Moreira AC. Animal Galectins and Plant Lectins as Tools for Studies in Neurosciences. Curr Neuropharmacol 2019; 18:202-215. [PMID: 31622208 PMCID: PMC7327950 DOI: 10.2174/1570159x17666191016092221] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 09/13/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022] Open
Abstract
Lectins are proteins or glycoproteins of non-immunological origin capable of reversibly and specifically binding to glycoconjugates. They exist in free form or associated with cells and are widely distributed in nature, being found in plants, microorganisms, and animals. Due to their characteristics and mainly due to the possibility of reversible binding to glycoconjugates, lectins have stood out as important tools in research involving Neurobiology. These proteins have the ability to modulate molecular targets in the central nervous system (CNS) which may be involved with neuroplasticity, neurobehavioral effects, and neuroprotection. The present report integrates existing information on the activity of animal and plant lectins in different areas of Neuroscience, presenting perspectives to direct new research on lectin function in the CNS, providing alternatives for understanding neurological diseases such as mental disorders, neurodegenerative, and neuro-oncological diseases, and for the development of new drugs, diagnoses and therapies in the field of Neuroscience.
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Affiliation(s)
| | - Cauê Barbosa Coelho
- Programa de Pos-Graduacao em Ciencia e Tecnologia Ambiental para o Semiarido (PPGCTAS), State University of Pernambuco, Petrolina, Pernambuco, Brazil
| | - Adriana Rolim Campos
- Experimental Biology Centre (NUBEX), University of Fortaleza (UNIFOR), Fortaleza, Ceara, Brazil
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26
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Carvalho A, Viaene J, Vandenbussche G, De Braekeleer K, Masereel B, Wouters J, Souard F, Vander Heyden Y, Van Antwerpen P, Delporte C, Mathieu V. A new potential anti-cancer beta-carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation. Drug Dev Res 2019; 81:32-42. [PMID: 31498913 DOI: 10.1002/ddr.21600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 07/08/2019] [Accepted: 08/14/2019] [Indexed: 12/15/2022]
Abstract
Gliomas remain highly fatal due to their high resistance to current therapies. Deregulation of protein synthesis contributes to cancer onset and progression and is a source of rising interest for new drugs. CM16, a harmine derivative with predicted high blood-brain barrier penetration, exerts antiproliferative effects partly through translation inhibition. We evaluated herein how CM16 alters the proteome of glioma cells. The analysis of the gel-free LC/MS and auto-MS/MS data showed that CM16 induces time- and concentration-dependent significant changes in the total ion current chromatograms. In addition, we observed spontaneous clustering of the samples according to their treatment condition and their proper classification by unsupervised and supervised analyses, respectively. A two-dimensional gel-based approach analysis allowed us to identify that treatment with CM16 may downregulate four key proteins involved in glioma aggressiveness and associated with poor patient survival (HspB1, BTF3, PGAM1, and cofilin), while it may upregulate galectin-1 and Ebp1. Consistently with the protein synthesis inhibition properties of CM16, HspB1, Ebp1, and BTF3 exert known roles in protein synthesis. In conclusion, the downregulation of HspB1, BTF3, PGAM1 and cofilin bring new insights in CM16 antiproliferative effects, further supporting CM16 as an interesting protein synthesis inhibitor to combat glioma.
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Affiliation(s)
- Annelise Carvalho
- Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.,ULB Cancer Research Center, Université Libre de Bruxelles, Brussels, Belgium
| | - Johan Viaene
- VUB - Analytical Chemistry, Applied Chemometrics and Molecular Modeling, Pharmaceutical Institute, Vrije Universiteit Brussel - VUB, Brussels, Belgium
| | - Guy Vandenbussche
- Laboratory for the Structure and Function of Biological Membranes, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium
| | - Kris De Braekeleer
- Unit of Pharmacognosy, Bioanalysis and Drug Discovery, Department of Research in Drug Development (RD3), Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium
| | - Bernard Masereel
- NAMEDIC, Department of Pharmacy, University of Namur, Namur, Belgium
| | - Johan Wouters
- NAMEDIC, Department of Pharmacy, University of Namur, Namur, Belgium
| | - Florence Souard
- Unit of Pharmacognosy, Bioanalysis and Drug Discovery, Department of Research in Drug Development (RD3), Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.,Université Grenoble Alpes, CNRS, DPM, Grenoble, France
| | - Yvan Vander Heyden
- VUB - Analytical Chemistry, Applied Chemometrics and Molecular Modeling, Pharmaceutical Institute, Vrije Universiteit Brussel - VUB, Brussels, Belgium
| | - Pierre Van Antwerpen
- Unit of Pharmacognosy, Bioanalysis and Drug Discovery, Department of Research in Drug Development (RD3), Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.,Analytical Platform of the Faculty of Pharmacy and Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium
| | - Cédric Delporte
- Unit of Pharmacognosy, Bioanalysis and Drug Discovery, Department of Research in Drug Development (RD3), Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.,Analytical Platform of the Faculty of Pharmacy and Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium
| | - Véronique Mathieu
- Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.,ULB Cancer Research Center, Université Libre de Bruxelles, Brussels, Belgium
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27
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He X, Zhang S, Chen J, Li D. Increased LGALS3 expression independently predicts shorter overall survival in patients with the proneural subtype of glioblastoma. Cancer Med 2019; 8:2031-2040. [PMID: 30848102 PMCID: PMC6536958 DOI: 10.1002/cam4.2075] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/05/2019] [Accepted: 02/15/2019] [Indexed: 11/24/2022] Open
Abstract
In the current study, we tried to study the expression of LGALS3 and LGALS3BP, their potential as prognostic markers and the possible genetic/epigenetic mechanisms underlying their dysregulation in different subtypes of glioblastoma (GBM). An in silico retrospective study was performed using large online databases. Results showed that LGALS3 and LGALS3BP were upregulated at both RNA and protein levels in GBM tissue and were generally associated with shorter overall survival (OS) in GBM patients. However, in subgroup analysis, we only found the association in proneural subtype. The copy number alterations did not necessarily lead to LGALS3/LGALS3BP dysregulation. In the proneural subtype of GBM patients, hypermethylation of the two CpG sites (cg19099850 and cg17403875) was associated with significantly lower expression of LGALS3. In univariate and multivariate analysis, LGALS3 expression independently predicted shorter OS in the proneural subtype of GBM (HR: 1.487, 95% CI: 1.229‐1.798, P < 0.001), after adjustment of age, gender, IDH1 mutations, temozolomide chemotherapy, radiotherapy and LGALS3BP expression. In comparison, LGALS3BP lost the prognostic value in multivariate analysis. Based on these findings, we infer that LGALS3 expression serves as an independent biomarker of shorter OS in the proneural subtype of GBM, the expression of which might be regulated in an epigenetic manner.
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Affiliation(s)
- Xia He
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Bayi Rehabilitation Center/Sichuan Provincial Rehabilitation Hospital, Chengdu, China
| | - Sunfu Zhang
- Department of Neurosurgery, The First People's Hospital of Yibin, Yibin, China
| | - Junchen Chen
- Department of Neurosurgery, Sichuan Bayi Rehabilitation Center/Sichuan Provincial Rehabilitation Hospital, Chengdu, China
| | - Dekang Li
- Department of Neurosurgery, The First People's Hospital of Yibin, Yibin, China
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Transcriptome profiling reveals PDZ binding kinase as a novel biomarker in peritumoral brain zone of glioblastoma. J Neurooncol 2018; 141:315-325. [PMID: 30460633 DOI: 10.1007/s11060-018-03051-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/12/2018] [Indexed: 12/25/2022]
Abstract
PURPOSE Peritumoural brain zone (PT) of glioblastoma (GBM) is the area where tumour recurrence is often observed. We aimed to identify differentially regulated genes between tumour core (TC) and PT to understand the underlying molecular characteristics of infiltrating tumour cells in PT. METHODS 17 each histologically characterised TC and PT tissues of GBM along with eight control tissues were subjected to cDNA Microarray. PT tissues contained 25-30% infiltrating tumour cells. Data was analysed using R Bioconductor software. Shortlisted genes were validated using qRT-PCR. Expression of one selected candidate gene, PDZ Binding Kinase (PBK) was correlated with patient survival, tumour recurrence and functionally characterized in vitro using gene knock-down approach. RESULTS Unsupervised hierarchical clustering showed that TC and PT have distinct gene expression profiles compared to controls. Further, comparing TC with PT, we observed a significant overlap in gene expression profile in both, despite PT having fewer infiltrating tumour cells. qRT-PCR for 13 selected genes validated the microarray data. Expression of PBK was higher in PT as compared to TC and recurrent when compared to newly diagnosed GBM tumours. PBK knock-down showed a significant reduction in cell proliferation, migration and invasion with increase in sensitivity to radiation and Temozolomide treatment. CONCLUSIONS We show that several genes of TC are expressed even in PT contributing to the vulnerability of PT for tumour recurrence. PBK is identified as a novel gene up-regulated in PT of GBM with a strong role in conferring aggressiveness, including radio-chemoresistance, thus contributing to recurrence in GBM tumours.
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Sulforaphane from Cruciferous Vegetables: Recent Advances to Improve Glioblastoma Treatment. Nutrients 2018; 10:nu10111755. [PMID: 30441761 PMCID: PMC6267435 DOI: 10.3390/nu10111755] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/09/2018] [Accepted: 11/12/2018] [Indexed: 02/07/2023] Open
Abstract
Sulforaphane (SFN), an isothiocyanate (ITC) derived from cruciferous vegetables, particularly broccoli and broccoli sprouts, has been widely investigated due to its promising health-promoting properties in disease, and low toxicity in normal tissue. Although not yet fully understood, many mechanisms of anticancer activity at each step of cancer development have been attributed to this ITC. Given the promising data available regarding SFN, this review aimed to provide an overview on the potential activities of SFN related to the cellular mechanisms involved in glioblastoma (GBM) progression. GBM is the most frequent malignant brain tumor among adults and is currently an incurable disease due mostly to its highly invasive phenotype, and the poor efficacy of the available therapies. Despite all efforts, the median overall survival of GBM patients remains approximately 1.5 years under therapy. Therefore, there is an urgent need to provide support for translating the progress in understanding the molecular background of GBM into more complex, but promising therapeutic strategies, in which SFN may find a leading role.
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Wang H, Song X, Huang Q, Xu T, Yun D, Wang Y, Hu L, Yan Y, Chen H, Lu D, Chen J. LGALS3 Promotes Treatment Resistance in Glioblastoma and Is Associated with Tumor Risk and Prognosis. Cancer Epidemiol Biomarkers Prev 2018; 28:760-769. [PMID: 30341098 DOI: 10.1158/1055-9965.epi-18-0638] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 07/28/2018] [Accepted: 10/15/2018] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND LGALS3 promotes tumor progression in diverse cancers. However, the involvement of LGALS3 in glioblastoma has not yet been broadly illuminated. METHODS Microarray was performed to detect the gene expression profiles of radioresistance in T98G cells and identified a universally upregulated gene, LGALS3. The impact of LGALS3 on the survival of glioblastoma cells facing ionizing irradiation or temozolomide was investigated by the Cell Counting Kit-8 (CCK-8). A total of 120 glioblastoma cases were collected to analyze the relationship between LGALS3 expression and patient prognosis. Another 961 patients with glioma and 1,351 healthy controls were recruited to study the association of SNPs across the LGALS3 gene with glioblastoma susceptibility. The functional SNP sites were also studied in cellular experiments. RESULTS An effective protection of LGALS3 from ionizing irradiation or temozolomide-induced cell death in T98G and U251 cells was found. In addition, high expression of LGALS3 could work as an independent risk factor for survival of patients with glioblastoma. Two SNP sites (rs4644 and rs4652) across the LGALS3 gene were associated with increased risk for glioblastoma, and the C allele of rs4652 and the A allele of rs4644 could enhance glioblastoma resistance to radio-chemotherapy, but not cell proliferation. CONCLUSIONS Our results suggest that LGALS3 is an important biomarker influencing glioblastoma risk and prognosis and a potential target for treating the malignancy, especially ones with resistance against the standard therapy. IMPACT LGALS3 promotes glioblastoma cells' resistance to ionizing irradiation and temozolomide and predicts poor prognosis. Targeting LGALS3 may limit the therapeutic resistance in glioblastoma and increase patient survival.
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Affiliation(s)
- Hongxiang Wang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiao Song
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Qilin Huang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tao Xu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dapeng Yun
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuqi Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Lingna Hu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yong Yan
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hongyan Chen
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Daru Lu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
| | - Juxiang Chen
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
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31
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A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma. Nat Cell Biol 2018; 20:1203-1214. [PMID: 30202050 DOI: 10.1038/s41556-018-0183-3] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 07/27/2018] [Indexed: 02/08/2023]
Abstract
Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignalling and a bulky glycocalyx, implying a causal link towards a mesenchymal, stem-like phenotype in GBMs. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM.
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Simão D, Silva MM, Terrasso AP, Arez F, Sousa MFQ, Mehrjardi NZ, Šarić T, Gomes-Alves P, Raimundo N, Alves PM, Brito C. Recapitulation of Human Neural Microenvironment Signatures in iPSC-Derived NPC 3D Differentiation. Stem Cell Reports 2018; 11:552-564. [PMID: 30057262 PMCID: PMC6094163 DOI: 10.1016/j.stemcr.2018.06.020] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 06/25/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
Brain microenvironment plays an important role in neurodevelopment and pathology, where the extracellular matrix (ECM) and soluble factors modulate multiple cellular processes. Neural cell culture typically relies on heterologous matrices poorly resembling brain ECM. Here, we employed neurospheroids to address microenvironment remodeling during neural differentiation of human stem cells, without the confounding effects of exogenous matrices. Proteome and transcriptome dynamics revealed significant changes at cell membrane and ECM during 3D differentiation, diverging significantly from the 2D differentiation. Structural proteoglycans typical of brain ECM were enriched during 3D differentiation, in contrast to basement membrane constituents in 2D. Moreover, higher expression of synaptic and ion transport machinery was observed in 3D cultures, suggesting higher neuronal maturation in neurospheroids. This work demonstrates that 3D neural differentiation as neurospheroids promotes the expression of cellular and extracellular features found in neural tissue, highlighting its value to address molecular defects in cell-ECM interactions associated with neurological disorders.
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Affiliation(s)
- Daniel Simão
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Marta M Silva
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Ana P Terrasso
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Francisca Arez
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Marcos F Q Sousa
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Narges Z Mehrjardi
- Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, Cologne 50931, Germany
| | - Tomo Šarić
- Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, Cologne 50931, Germany
| | - Patrícia Gomes-Alves
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Nuno Raimundo
- Universitätsmedizin Göttingen, Institut für Zellbiochemie, Göttingen, Germany
| | - Paula M Alves
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Catarina Brito
- iBET, Instituto de Biologia Experimental e Biológica, Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.
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Abstract
Polymeric nanoparticles have tremendous potential to improve the efficacy of therapeutic cancer treatments by facilitating targeted delivery to a desired site. The physical and chemical properties of polymers can be tuned to accomplish delivery across the multiple biological barriers required to reach diverse subsets of cells. The use of biodegradable polymers as nanocarriers is especially attractive, as these materials can be designed to break down in physiological conditions and engineered to exhibit triggered functionality when at a particular location or activated by an external source. We present how biodegradable polymers can be engineered as drug delivery systems to target the tumor microenvironment in multiple ways. These nanomedicines can target cancer cells directly, the blood vessels that supply the nutrients and oxygen that support tumor growth, and immune cells to promote anticancer immunotherapy.
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Affiliation(s)
- Johan Karlsson
- Department of Biomedical Engineering, Translational Tissue Engineering Center, and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA;
- Department of Chemistry, Ångström Laboratory, Uppsala University, Uppsala SE-75121, Sweden
| | - Hannah J Vaughan
- Department of Biomedical Engineering, Translational Tissue Engineering Center, and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA;
| | - Jordan J Green
- Department of Biomedical Engineering, Translational Tissue Engineering Center, and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA;
- Departments of Materials Science and Engineering, Chemical and Biomolecular Engineering, Neurosurgery, Oncology, and Ophthalmology and the Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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Wang L, Zhao Y, Wang Y, Wu X. The Role of Galectins in Cervical Cancer Biology and Progression. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2175927. [PMID: 29854732 PMCID: PMC5964433 DOI: 10.1155/2018/2175927] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 03/18/2018] [Accepted: 03/27/2018] [Indexed: 02/06/2023]
Abstract
Cervical cancer is one of the malignant tumors with high incidence and high mortality among women in developing countries. The main factors affecting the prognosis of cervical cancer are the late recurrence and metastasis and the effective adjuvant treatment, which is radiation and chemotherapy or combination therapy. Galectins, a family containing many carbohydrate binding proteins, are closely involved in the occurrence and development of tumor. They are involved in tumor cells transformation, angiogenesis, metastasis, immune escape, and sensitivity against radiation and chemotherapy. Therefore, galectins are deemed as the targets of multifunctional cancer treatment. In this review, we mainly focus on the role of galectins, especially galectin-1, galectin-3, galectin-7, and galectin-9 in cervical cancer, and provide theoretical basis for potential targeted treatment of cervical cancer.
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Affiliation(s)
- Lufang Wang
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yanyan Zhao
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yanshi Wang
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xin Wu
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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35
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Gragnano F, Crisci M, Bigazzi MC, Bianchi R, Sperlongano S, Natale F, Fimiani F, Concilio C, Cesaro A, Pariggiano I, Diana V, Limongelli G, Cirillo P, Russo M, Golia E, Calabrò P. Von Willebrand Factor as a Novel Player in Valvular Heart Disease: From Bench to Valve Replacement. Angiology 2018; 69:103-112. [PMID: 28481153 DOI: 10.1177/0003319717708070] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
von Willebrand Factor (vWF) is a well-known mediator of hemostasis and vascular inflammation. Its dynamic modulation in the bloodstream, according to hemodynamic conditions, makes it an appealing biomarker in patients with valvular heart disease (VHD). Recent studies highlight the close connection between vWF and VHD, with possible implications in the pathogenesis of VHD, promoting valve aging and calcification or favoring the development of infective endocarditis. Moreover, vWF has been recently proposed as a new diagnostic and prognostic tool in patients with valve stenosis or regurgitation, showing a strict correlation with severity of valve disease, outcome, and bleeding (Heyde syndrome). A novel role for vWF is also emerging in patients undergoing percutaneous or surgical valve repair/replacement to select and stratify patients, evaluate periprocedural bleeding risk, and detect procedural complications. We also report our single-center experience, suggesting, for the first time, possible clinical implications for vWF in percutaneous mitral valve repair (MitraClip). This review summarizes recent advances in the role of vWF in VHD with an updated overview going from bench to operating room.
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Affiliation(s)
- Felice Gragnano
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Mario Crisci
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maurizio Cappelli Bigazzi
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Renatomaria Bianchi
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Simona Sperlongano
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Francesco Natale
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fabio Fimiani
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Claudia Concilio
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Arturo Cesaro
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ivana Pariggiano
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Vincenzo Diana
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Limongelli
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Plinio Cirillo
- 2 Department of Advanced Biological Sciences, Federico II University, Naples, Italy
| | - Mariagiovanna Russo
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Enrica Golia
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Paolo Calabrò
- 1 Division of Cardiology, Department of Cardio-thoracic and Respiratory Sciences, A.O. dei Colli Monaldi Hospital, University of Campania "Luigi Vanvitelli", Naples, Italy
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Veillon L, Fakih C, Abou-El-Hassan H, Kobeissy F, Mechref Y. Glycosylation Changes in Brain Cancer. ACS Chem Neurosci 2018; 9:51-72. [PMID: 28982002 DOI: 10.1021/acschemneuro.7b00271] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Protein glycosylation is a posttranslational modification that affects more than half of all known proteins. Glycans covalently bound to biomolecules modulate their functions by both direct interactions, such as the recognition of glycan structures by binding partners, and indirect mechanisms that contribute to the control of protein conformation, stability, and turnover. The focus of this Review is the discussion of aberrant glycosylation related to brain cancer. Altered sialylation and fucosylation of N- and O-glycans play a role in the development and progression of brain cancer. Additionally, aberrant O-glycan expression has been implicated in brain cancer. This Review also addresses the clinical potential and applications of aberrant glycosylation for the detection and treatment of brain cancer. The viable roles glycans may play in the development of brain cancer therapeutics are addressed as well as cancer-glycoproteomics and personalized medicine. Glycoprotein alterations are considered as a hallmark of cancer while high expression in body fluids represents an opportunity for cancer assessment.
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Affiliation(s)
- Lucas Veillon
- Department
of Chemistry and Biochemistry, Texas Tech University, Lubbock Texas 79409, United States
| | - Christina Fakih
- Department
of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hadi Abou-El-Hassan
- Department
of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Firas Kobeissy
- Department
of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Yehia Mechref
- Department
of Chemistry and Biochemistry, Texas Tech University, Lubbock Texas 79409, United States
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Fischöder T, Laaf D, Dey C, Elling L. Enzymatic Synthesis of N-Acetyllactosamine (LacNAc) Type 1 Oligomers and Characterization as Multivalent Galectin Ligands. Molecules 2017; 22:molecules22081320. [PMID: 28796164 PMCID: PMC6152129 DOI: 10.3390/molecules22081320] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 08/07/2017] [Accepted: 08/08/2017] [Indexed: 01/05/2023] Open
Abstract
Repeats of the disaccharide unit N-acetyllactosamine (LacNAc) occur as type 1 (Galβ1, 3GlcNAc) and type 2 (Galβ1, 4GlcNAc) glycosylation motifs on glycoproteins and glycolipids. The LacNAc motif acts as binding ligand for lectins and is involved in many biological recognition events. To the best of our knowledge, we present, for the first time, the synthesis of LacNAc type 1 oligomers using recombinant β1,3-galactosyltransferase from Escherichia coli and β1,3-N-acetylglucosaminyltranferase from Helicobacter pylori. Tetrasaccharide glycans presenting LacNAc type 1 repeats or LacNAc type 1 at the reducing or non-reducing end, respectively, were conjugated to bovine serum albumin as a protein scaffold by squarate linker chemistry. The resulting multivalent LacNAc type 1 presenting neo-glycoproteins were further studied for specific binding of the tumor-associated human galectin 3 (Gal-3) and its truncated counterpart Gal-3∆ in an enzyme-linked lectin assay (ELLA). We observed a significantly increased affinity of Gal-3∆ towards the multivalent neo-glycoprotein presenting LacNAc type 1 repeating units. This is the first evidence for differences in glycan selectivity of Gal-3∆ and Gal-3 and may be further utilized for tracing Gal-3∆ during tumor progression and therapy.
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Affiliation(s)
- Thomas Fischöder
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany.
| | - Dominic Laaf
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany.
| | - Carina Dey
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany.
| | - Lothar Elling
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany.
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Bianco J, Bastiancich C, Jankovski A, des Rieux A, Préat V, Danhier F. On glioblastoma and the search for a cure: where do we stand? Cell Mol Life Sci 2017; 74:2451-2466. [PMID: 28210785 PMCID: PMC11107640 DOI: 10.1007/s00018-017-2483-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 01/30/2017] [Indexed: 01/25/2023]
Abstract
Although brain tumours have been documented and recorded since the nineteenth century, 2016 marked 90 years since Percival Bailey and Harvey Cushing coined the term "glioblastoma multiforme". Since that time, although extensive developments in diagnosis and treatment have been made, relatively little improvement on prognosis has been achieved. The resilience of GBM thus makes treating this tumour one of the biggest challenges currently faced by neuro-oncology. Aggressive and robust development, coupled with difficulties of complete resection, drug delivery and therapeutic resistance to treatment are some of the main issues that this nemesis presents today. Current treatments are far from satisfactory with poor prognosis, and focus on palliative management rather than curative intervention. However, therapeutic research leading to developments in novel treatment stratagems show promise in combating this disease. Here we present a review on GBM, looking at the history and advances which have shaped neurosurgery over the last century that cumulate to the present day management of GBM, while also exploring future perspectives in treatment options that could lead to new treatments on the road to a cure.
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Affiliation(s)
- John Bianco
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier 73, bte B1 73.12, 1200, Brussels, Belgium.
| | - Chiara Bastiancich
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier 73, bte B1 73.12, 1200, Brussels, Belgium
| | - Aleksander Jankovski
- Institute of Neuroscience, Université catholique de Louvain, Avenue Hippocrate B1.54.10, 1200, Brussels, Belgium
- Department of Neurosurgery, CHU UCL Namur, Avenue G. Thérasse 1, 5530, Yvoir, Belgium
| | - Anne des Rieux
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier 73, bte B1 73.12, 1200, Brussels, Belgium
- Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, 1348, Louvain-la-Neuve, Belgium
| | - Véronique Préat
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier 73, bte B1 73.12, 1200, Brussels, Belgium.
| | - Fabienne Danhier
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier 73, bte B1 73.12, 1200, Brussels, Belgium
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Dion J, Deshayes F, Storozhylova N, Advedissian T, Lambert A, Viguier M, Tellier C, Dussouy C, Poirier F, Grandjean C. Lactosamine-Based Derivatives as Tools to Delineate the Biological Functions of Galectins: Application to Skin Tissue Repair. Chembiochem 2017; 18:782-789. [DOI: 10.1002/cbic.201600673] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Indexed: 11/08/2022]
Affiliation(s)
- Johann Dion
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2 chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Frédérique Deshayes
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Nataliya Storozhylova
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2 chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Tamara Advedissian
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Annie Lambert
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2 chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Mireille Viguier
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Charles Tellier
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2 chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Christophe Dussouy
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2 chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Françoise Poirier
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Cyrille Grandjean
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2 chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
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John S, Mishra R. mRNA Transcriptomics of Galectins Unveils Heterogeneous Organization in Mouse and Human Brain. Front Mol Neurosci 2016; 9:139. [PMID: 28018170 PMCID: PMC5159438 DOI: 10.3389/fnmol.2016.00139] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 11/23/2016] [Indexed: 12/22/2022] Open
Abstract
Background: Galectins, a family of non-classically secreted, β-galactoside binding proteins is involved in several brain disorders; however, no systematic knowledge on the normal neuroanatomical distribution and functions of galectins exits. Hence, the major purpose of this study was to understand spatial distribution and predict functions of galectins in brain and also compare the degree of conservation vs. divergence between mouse and human species. The latter objective was required to determine the relevance and appropriateness of studying galectins in mouse brain which may ultimately enable us to extrapolate the findings to human brain physiology and pathologies. Results: In order to fill this crucial gap in our understanding of brain galectins, we analyzed the in situ hybridization and microarray data of adult mouse and human brain respectively, from the Allen Brain Atlas, to resolve each galectin-subtype’s spatial distribution across brain distinct cytoarchitecture. Next, transcription factors (TFs) that may regulate galectins were identified using TRANSFAC software and the list obtained was further curated to sort TFs on their confirmed transcript expression in the adult brain. Galectin-TF cluster analysis, gene-ontology annotations and co-expression networks were then extrapolated to predict distinct functional relevance of each galectin in the neuronal processes. Data shows that galectins have highly heterogeneous expression within and across brain sub-structures and are predicted to be the crucial targets of brain enriched TFs. Lgals9 had maximal spatial distribution across mouse brain with inferred predominant roles in neurogenesis while LGALS1 was ubiquitously expressed in human. Limbic region associated with learning, memory and emotions and substantia nigra associated with motor movements showed strikingly high expression of LGALS1 and LGALS8 in human vs. mouse brain. The overall expression profile of galectin-8 was most preserved across both these species, however, galectin-9 showed maximal preservation only in the cerebral cortex. Conclusion: It is for the first time that a comprehensive description of galectins’ mRNA expression profile in brain is presented. Results suggests that spatial transcriptome changes in galectins may contribute to differential brain functions and evolution across species that highlights galectins as novel signatures of brain heterogeneity and functions, which if disturbed, can promote several brain disorders.
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Affiliation(s)
- Sebastian John
- Disease Biology Program, Department of Neurobiology and Genetics, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram, India
| | - Rashmi Mishra
- Disease Biology Program, Department of Neurobiology and Genetics, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram, India
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Nio-Kobayashi J. Tissue- and cell-specific localization of galectins, β-galactose-binding animal lectins, and their potential functions in health and disease. Anat Sci Int 2016; 92:25-36. [PMID: 27590897 DOI: 10.1007/s12565-016-0366-6] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 08/17/2016] [Indexed: 01/13/2023]
Abstract
Fifteen galectins, β-galactose-binding animal lectins, are known to be distributed throughout the body. We herein summarize current knowledge on the tissue- and cell-specific localization of galectins and their potential functions in health and disease. Galectin-3 is widely distributed in epithelia, including the simple columnar epithelium in the gut, stratified squamous epithelium in the gut and skin, and transitional epithelium and several regions in nephrons in the urinary tract. Galectin-2 and galectin-4/6 are gut-specific, while galectin-7 is found in the stratified squamous epithelium in the gut and skin. The reproductive tract mainly contains galectin-1 and galectin-3, and their expression markedly changes during the estrous/menstrual cycle. The galectin subtype expressed in the corpus luteum (CL) changes in association with luteal function. The CL of women and cows displays a "galectin switch" with coordinated changes in the major galectin subtype and its ligand glycoconjugate structure. Macrophages express galectin-3, which may be involved in phagocytotic activity. Lymphoid tissues contain galectin-3-positive macrophages, which are not always stained with the macrophage marker, F4/80. Subsets of neurons in the brain and dorsal root ganglion express galectin-1 and galectin-3, which may contribute to the regeneration of damaged axons, stem cell differentiation, and pain control. The subtype-specific contribution of galectins to implantation, fibrosis, and diabetes are also discussed. The function of galectins may differ depending on the tissues or cells in which they act. The ligand glycoconjugate structures mediated by glycosyltransferases including MGAT5, ST6GAL1, and C2GnT are important for revealing the functions of galectins in healthy and disease states.
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Affiliation(s)
- Junko Nio-Kobayashi
- Laboratory of Histology and Cytology, Hokkaido University Graduate School of Medicine, Kita 15-Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
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Metz C, Döger R, Riquelme E, Cortés P, Holmes C, Shaughnessy R, Oyanadel C, Grabowski C, González A, Soza A. Galectin-8 promotes migration and proliferation and prevents apoptosis in U87 glioblastoma cells. Biol Res 2016; 49:33. [PMID: 27459991 PMCID: PMC4962418 DOI: 10.1186/s40659-016-0091-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 06/10/2016] [Indexed: 12/19/2022] Open
Abstract
Background Glioblastoma is one of the most aggressive cancers of the brain. Malignant traits of glioblastoma cells include elevated migration, proliferation and survival capabilities. Galectins are unconventionally secreted glycan-binding proteins that modulate processes of cell adhesion, migration, proliferation and apoptosis by interacting with beta-galactosides of cell surface glycoproteins and the extracellular matrix. Galectin-8 is one of the galectins highly expressed in glioblastoma cells. It has a unique selectivity for terminally sialylated glycans recently found enhanced in these highly malignant cells. A previous study in glioblastoma cell lines reported that Gal-8 coating a plastic surface stimulates two-dimensional motility. Because in other cells Gal-8 arrests proliferation and induces apoptosis, here we extend its study by analyzing all of these processes in a U87 glioblastoma cell model. Methods We used immunoblot and RT-PCR for Gal-8 expression analysis, recombinant Gal-8 produced in a bacteria system for Gal-8 treatment of the cells, and shRNA in lentivirus transduction for Gal-8 silencing. Cell migration as assessed in transwell filters. Cell proliferation, cell cycle and apoptosis were analyzed by FACS. Results Gal-8 as a soluble stimulus triggered chemotactic migration of U87 cells across the polycarbonate filter of transwell chambers, almost as intensively as fetal bovine serum. Unexpectedly, Gal-8 also enhanced U87 cell growth. Co-incubation of Gal-8 with lactose, which blocks galectin–glycan interactions, abrogated both effects. Immunoblot showed Gal-8 in conditioned media reflecting its secretion. U87 cells transduced with silencing shRNA in a lentiviral vector expressed and secreted 30–40 % of their normal Gal-8 levels. These cells maintained their migratory capabilities, but decreased their proliferation rate and underwent higher levels of apoptosis, as revealed by flow cytometry analysis of cell cycle, CFSE and activated caspase-3 staining. Proliferation seemed to be more sensitive than migration to Gal-8 expression levels. Conclusions Gal-8, either secreted or exogenously enriched in the media, and acting through extracellular glycan interactions, constitutes a strong stimulus of directional migration in glioblastoma U87 cells and for the first time emerges as a factor that promotes proliferation and prevents apoptosis in cancerous cells. These properties could potentially contribute to the exaggerated malignancy of glioblastoma cells.
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Affiliation(s)
- Claudia Metz
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Remziye Döger
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Elizabeth Riquelme
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Priscilla Cortés
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Christopher Holmes
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Ronan Shaughnessy
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Claudia Oyanadel
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Fundación Ciencia y Vida, Av. Zañartu 1482, 77803444, Santiago, Chile
| | - Catalina Grabowski
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Alfonso González
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile
| | - Andrea Soza
- Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile. .,Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, 8331010, Santiago, Chile.
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Van Woensel M, Wauthoz N, Rosière R, Mathieu V, Kiss R, Lefranc F, Steelant B, Dilissen E, Van Gool SW, Mathivet T, Gerhardt H, Amighi K, De Vleeschouwer S. Development of siRNA-loaded chitosan nanoparticles targeting Galectin-1 for the treatment of glioblastoma multiforme via intranasal administration. J Control Release 2016; 227:71-81. [DOI: 10.1016/j.jconrel.2016.02.032] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 02/18/2016] [Accepted: 02/18/2016] [Indexed: 11/25/2022]
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Zhang Z, Li C, Shang L, Zhang Y, Zou R, Zhan Y, Bi B. Sulforaphane induces apoptosis and inhibits invasion in U251MG glioblastoma cells. SPRINGERPLUS 2016; 5:235. [PMID: 27026929 PMCID: PMC4771656 DOI: 10.1186/s40064-016-1910-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/17/2016] [Indexed: 12/18/2022]
Abstract
In recent studies, sulforaphane (SFN) has been seen to demonstrate antioxidant and anti-tumor activities. In the present study, the viability inhibition effects of SFN in U251MG glioblastoma cells were analyzed by MTS. Morphology changes were observed by microscope. Apoptotic effects of SFN were evaluated by annexin V binding capacity with flow cytometric analysis. Invasion inhibition effects of SFN were tested by the invasion assay. The molecular mechanisms of apoptotic effects and invasion inhibition effects of SFN were detected by western blot and gelatin zymography. The results indicated that SFN has potent apoptotic effects and invasion inhibition effects against U251MG glioblastoma cells. These effects are both dose dependent. Taken together, SFN possessed apoptotic activity on U251MG cells indicated by increased annexin V-binding capacity, Bad, Bax, cytochrome C expression, and decreased Bcl-2 and survivin expressions. SFN inhibited invasion in U251MG cells via upregulation of E-cadherin and downregulation of MMP-2, MMP-9 and Galectin-3.
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Affiliation(s)
- Zhen Zhang
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100 China
| | - Chunliu Li
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100 China
| | - Li Shang
- Affiliated Hospital of Binzhou Medical University, Binzhou, China
| | | | - Rong Zou
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100 China
| | - Yan Zhan
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100 China
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Sirko S, Irmler M, Gascón S, Bek S, Schneider S, Dimou L, Obermann J, De Souza Paiva D, Poirier F, Beckers J, Hauck SM, Barde YA, Götz M. Astrocyte reactivity after brain injury-: The role of galectins 1 and 3. Glia 2015; 63:2340-61. [PMID: 26250529 PMCID: PMC5042059 DOI: 10.1002/glia.22898] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 07/14/2015] [Accepted: 07/22/2015] [Indexed: 01/18/2023]
Abstract
Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins-Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere-forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes.
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Affiliation(s)
- Swetlana Sirko
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany.,Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Sergio Gascón
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany.,Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Sarah Bek
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany
| | - Sarah Schneider
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany.,Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Leda Dimou
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany.,Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Jara Obermann
- Research Unit Protein Science, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Daisylea De Souza Paiva
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany.,Department of Physiology, Federal University of Sao Paulo, Sao Paulo, Brazil
| | - Francoise Poirier
- Institut Jacques Monod, CNRS-University Paris Diderot, Paris, France
| | - Johannes Beckers
- Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Yves-Alain Barde
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Magdalena Götz
- Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Germany.,Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,SYNERGY, Excellence Cluster of Systems Neurology, Ludwig-Maximilians-University Munich, Germany
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Böcker S, Laaf D, Elling L. Galectin Binding to Neo-Glycoproteins: LacDiNAc Conjugated BSA as Ligand for Human Galectin-3. Biomolecules 2015. [PMID: 26213980 PMCID: PMC4598770 DOI: 10.3390/biom5031671] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Carbohydrate-lectin interactions are relatively weak. As they play an important role in biological recognition processes, multivalent glycan ligands are designed to enhance binding affinity and inhibitory potency. We here report on novel neo-glycoproteins based on bovine serum albumin as scaffold for multivalent presentation of ligands for galectins. We prepared two kinds of tetrasaccharides (N-acetyllactosamine and N,N-diacetyllactosamine terminated) by multi-step chemo-enzymatic synthesis utilizing recombinant glycosyltransferases. Subsequent conjugation of these glycans to lysine groups of bovine serum albumin via squaric acid diethyl ester yielded a set of 22 different neo-glycoproteins with tuned ligand density. The neo-glycoproteins were analyzed by biochemical and chromatographic methods proving various modification degrees. The neo-glycoproteins were used for binding and inhibition studies with human galectin-3 showing high affinity. Binding strength and inhibition potency are closely related to modification density and show binding enhancement by multivalent ligand presentation. At galectin-3 concentrations comparable to serum levels of cancer patients, we detect the highest avidities. Selectivity of N,N-diacetyllactosamine terminated structures towards galectin-3 in comparison to galectin-1 is demonstrated. Moreover, we also see strong inhibitory potency of our scaffolds towards galectin-3 binding. These novel neo-glycoproteins may therefore serve as selective and strong galectin-3 ligands in cancer related biomedical research.
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Affiliation(s)
- Sophia Böcker
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
| | - Dominic Laaf
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
| | - Lothar Elling
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
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Messaoudi K, Clavreul A, Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today 2015; 20:899-905. [PMID: 25744176 DOI: 10.1016/j.drudis.2015.02.011] [Citation(s) in RCA: 175] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 02/05/2015] [Accepted: 02/24/2015] [Indexed: 02/05/2023]
Abstract
Glioblastoma multiforme (GBM) is a devastating disease and the most lethal of adult brain tumors. Treatment is based on surgery, radiotherapy and chemotherapy by oral temozolomide (TMZ), which is the most potent chemotherapy agent for the treatment of GBM. Despite TMZ efficiency, the prognosis of these tumors remains poor. This is because of inherent or acquired resistance of glioma tumor cells to TMZ. This resistance is caused by DNA repair enzyme activity, overexpression of epidermal growth factor receptor (EGFR), galectin-1, murine double minute 2 (Mdm2), p53 and phosphatase and tensin homolog (PTEN) mutations. Many strategies to overcome this resistance have been developed. In this review, we will describe the main mechanisms of GBM resistance to TMZ and different strategies developed to reverse the phenotype of these tumor cells. Finally, we will discuss the drawbacks and limitations of these strategies.
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Affiliation(s)
- Khaled Messaoudi
- LUNAM Université, Angers, France; Inserm U1066, Micro et Nanomedecines Biomimétiques, IBS, Angers Cedex 9, France
| | - Anne Clavreul
- LUNAM Université, Angers, France; Inserm U1066, Micro et Nanomedecines Biomimétiques, IBS, Angers Cedex 9, France
| | - Frédéric Lagarce
- LUNAM Université, Angers, France; Inserm U1066, Micro et Nanomedecines Biomimétiques, IBS, Angers Cedex 9, France; Service Pharmacie, CHU Angers, France.
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Bailey LA, Jamshidi-Parsian A, Patel T, Koonce NA, Diekman AB, Cifarelli CP, Marples B, Griffin RJ. Combined temozolomide and ionizing radiation induces galectin-1 and galectin-3 expression in a model of human glioma. ACTA ACUST UNITED AC 2015. [DOI: 10.1515/tumor-2015-0002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
AbstractBackground Despite aggressive treatment for glioblastoma multiforme (GBM), including surgical resection, radiotherapy and temozolomide (TMZ) chemotherapy, over 90% of patients experience tumor recurrence. Galectins are carbohydrate-binding proteins that are overexpressed in the stroma of GBM tumors, and are potent modulators of GBM cell migration and angiogenesis. The objective of this study was to analyze glioma and endothelial cell galectin expression in response to combined chemoradiation. Methodology The effects of TMZ, ionizing radiation, or combined chemoradiation on galectin protein secretion and expression were assessed in U87 orthotopically grown GBM tumors in mice, as well as in vitro in U87 human glioma cells and human umbilical vein endothelial cells (HUVECs). Results We found that combination chemoradiation increased galectin-1 and galectin-3 protein expression in U87 glioma cells. In response to radiation alone, U87 cells secreted significant levels of galectin-1 and galectin-3 into the microenvironment. HUVEC co-culture increased U87 galectin-1 and galectin-3 protein expression 14 - 20% following chemoradiation, and conferred a radioprotective benefit to U87 glioma cells. In vivo, radiation alone and combination chemoradiation significantly increased tumor galectin-1 expression in an orthotopic murine model of GBM. Conclusions Glioma cell galectin expression increased following combined chemoradiation, both in vitro and in vivo. The presence of endothelial cells further increased glioma cell galectin expression and survival, suggesting that crosstalk between tumor and endothelial cells in response to standard chemoradiation may be an important factor in mediating glioma recurrence, potentially via galectin upregulation.
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Ikemori RY, Machado CML, Furuzawa KM, Nonogaki S, Osinaga E, Umezawa K, de Carvalho MA, Verinaud L, Chammas R. Galectin-3 up-regulation in hypoxic and nutrient deprived microenvironments promotes cell survival. PLoS One 2014; 9:e111592. [PMID: 25369297 PMCID: PMC4219723 DOI: 10.1371/journal.pone.0111592] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 10/06/2014] [Indexed: 01/20/2023] Open
Abstract
Galectin-3 (gal-3) is a β-galactoside binding protein related to many tumoral aspects, e.g. angiogenesis, cell growth and motility and resistance to cell death. Evidence has shown its upregulation upon hypoxia, a common feature in solid tumors such as glioblastoma multiformes (GBM). This tumor presents a unique feature described as pseudopalisading cells, which accumulate large amounts of gal-3. Tumor cells far from hypoxic/nutrient deprived areas express little, if any gal-3. Here, we have shown that the hybrid glioma cell line, NG97ht, recapitulates GBM growth forming gal-3 positive pseudopalisades even when cells are grafted subcutaneously in nude mice. In vitro experiments were performed exposing these cells to conditions mimicking tumor areas that display oxygen and nutrient deprivation. Results indicated that gal-3 transcription under hypoxic conditions requires previous protein synthesis and is triggered in a HIF-1α and NF-κB dependent manner. In addition, a significant proportion of cells die only when exposed simultaneously to hypoxia and nutrient deprivation and demonstrate ROS induction. Inhibition of gal-3 expression using siRNA led to protein knockdown followed by a 1.7–2.2 fold increase in cell death. Similar results were also found in a human GBM cell line, T98G. In vivo, U87MG gal-3 knockdown cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and increased time for tumor engraftment. These results indicate that gal-3 protected cells from cell death under hypoxia and nutrient deprivation in vitro and that gal-3 is a key factor in tumor growth and engraftment in hypoxic and nutrient-deprived microenvironments. Overexpression of gal-3, thus, is part of an adaptive program leading to tumor cell survival under these stressing conditions.
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Affiliation(s)
- Rafael Yamashita Ikemori
- Faculdade de Medicina da Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
- * E-mail: (RYI); (RC)
| | - Camila Maria Longo Machado
- Faculdade de Medicina da Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
- Laboratório de Investigação Médica em Medicina Nuclear – LIM43, São Paulo, SP, Brazil
| | - Karina Mie Furuzawa
- Faculdade de Medicina da Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
| | - Suely Nonogaki
- Departamento de Patologia do Instituto Adolfo Lutz, São Paulo, SP, Brazil
| | - Eduardo Osinaga
- Facultad de Medicina de La Universidad de La Republica, Montevideo, Uruguay
| | | | | | - Liana Verinaud
- Departamento de Microbiologia e Imunologia, Instituto de Biologia, UNICAMP, Campinas, SP, Brazil
| | - Roger Chammas
- Faculdade de Medicina da Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brazil
- * E-mail: (RYI); (RC)
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Rieger DK, Cunha RMS, Lopes MW, Costa AP, Budni J, Rodrigues ALS, Walz R, Teixeira EH, Nascimento KS, Cavada BS, Leal RB. ConBr, a lectin fromCanavalia brasiliensisseeds, modulates signaling pathways and increases BDNF expression probably via a glycosylated target. J Mol Recognit 2014; 27:746-54. [DOI: 10.1002/jmr.2401] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 05/29/2014] [Accepted: 06/01/2014] [Indexed: 01/02/2023]
Affiliation(s)
- Débora K. Rieger
- Departamento de Bioquímica, Centro de Ciências Biológicas; Universidade Federal de Santa Catarina; Florianópolis SC 88040-900 Brazil
| | | | - Mark William Lopes
- Departamento de Bioquímica, Centro de Ciências Biológicas; Universidade Federal de Santa Catarina; Florianópolis SC 88040-900 Brazil
| | - Ana Paula Costa
- Departamento de Bioquímica, Centro de Ciências Biológicas; Universidade Federal de Santa Catarina; Florianópolis SC 88040-900 Brazil
| | - Josiani Budni
- Departamento de Bioquímica, Centro de Ciências Biológicas; Universidade Federal de Santa Catarina; Florianópolis SC 88040-900 Brazil
| | - Ana Lúcia S. Rodrigues
- Departamento de Bioquímica, Centro de Ciências Biológicas; Universidade Federal de Santa Catarina; Florianópolis SC 88040-900 Brazil
| | - Roger Walz
- Departamento de Clínica Médica, Hospital Universitário (HU), Centro de Ciências da Saúde; Universidade Federal de Santa Catarina; Florianópolis SC Brazil
| | - Edson H. Teixeira
- BioMolLab; Universidade Federal do Ceará; Fortaleza CE 60455-970 Brazil
| | | | - Benildo S. Cavada
- BioMolLab; Universidade Federal do Ceará; Fortaleza CE 60455-970 Brazil
| | - Rodrigo B. Leal
- Departamento de Bioquímica, Centro de Ciências Biológicas; Universidade Federal de Santa Catarina; Florianópolis SC 88040-900 Brazil
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