|
1
|
Gonzalez GA, Osuji EU, Fiur NC, Clark MG, Ma S, Lukov LL, Zhang C. Alteration of Lipid Metabolism in Hypoxic Cancer Cells. CHEMICAL & BIOMEDICAL IMAGING 2025; 3:25-34. [PMID: 39886224 PMCID: PMC11775851 DOI: 10.1021/cbmi.4c00050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/04/2024] [Accepted: 10/08/2024] [Indexed: 02/01/2025]
Abstract
Due to uncontrolled cell proliferation and disrupted vascularization, many cancer cells in solid tumors have limited oxygen supply. The hypoxic microenvironments of tumors lead to metabolic reprogramming of cancer cells, contributing to therapy resistance and metastasis. To identify better targets for the effective removal of hypoxia-adaptive cancer cells, it is crucial to understand how cancer cells alter their metabolism in hypoxic conditions. Here, we studied lipid metabolic changes in cancer cells under hypoxia using coherent Raman scattering (CRS) microscopy. We discovered the accumulation of lipid droplets (LDs) in the endoplasmic reticulum (ER) in hypoxia. Time-lapse CRS microscopy revealed the release of old LDs and the reaccumulated LDs in the ER during hypoxia exposure. Additionally, we explored the impact of carbon sources on LD formation and found that MIA PaCa2 cells preferred fatty acid uptake for LD formation, while glucose was essential to alleviate lipotoxicity. Hyperspectral-stimulated Raman scattering (SRS) microscopy revealed a reduction in cholesteryl ester content and a decrease in lipid saturation levels of LDs in hypoxic MIA PaCa2 cancer cells. This alteration in LD content is linked to reduced efficacy of treatments targeting cholesteryl ester formation. This study unveils important lipid metabolic changes in hypoxic cancer cells, providing insights that could lead to better treatment strategies for hypoxia-resistant cancer cells.
Collapse
Affiliation(s)
- Gil A. Gonzalez
- Department
of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
| | - Ezinne U. Osuji
- College
of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States
- Purdue
Center for Cancer Research, 201 S. University Street, West Lafayette, Indiana 47907, United States
| | - Natalie C. Fiur
- Department
of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
- Purdue
Center for Cancer Research, 201 S. University Street, West Lafayette, Indiana 47907, United States
| | - Matthew G. Clark
- Department
of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
| | - Seohee Ma
- Department
of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
| | - Laura L. Lukov
- Department
of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
| | - Chi Zhang
- Department
of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
- Purdue
Center for Cancer Research, 201 S. University Street, West Lafayette, Indiana 47907, United States
- Purdue
Institute of Inflammation, Immunology, and Infectious Disease, 207 S. Martin Jischke Drive, West Lafayette, Indiana 47907, United States
| |
Collapse
|
|
2
|
Zhang Z, Wang D, Xu R, Li X, Wang Z, Zhang Y. The Physiological Functions and Therapeutic Potential of Hypoxia-Inducible Factor-1α in Vascular Calcification. Biomolecules 2024; 14:1592. [PMID: 39766299 PMCID: PMC11674127 DOI: 10.3390/biom14121592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/08/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
HIF-1α plays a crucial regulatory role in vascular calcification (VC), primarily influencing the osteogenic differentiation of VSMCs through oxygen-sensing mechanisms. Under hypoxic conditions, the stability of HIF-1α increases, avoiding PHD and VHL protein-mediated degradation, which promotes its accumulation in cells and then activates gene expressions related to calcification. Additionally, HIF-1α modulates the metabolic state of VSMCs by regulating the pathways that govern the switch between glycolysis and oxidative phosphorylation, thereby further advancing the calcification process. The interaction between HIF-1α and other signaling pathways, such as nuclear factor-κB, Notch, and Wnt/β-catenin, creates a complex regulatory network that serves as a critical driving force in VC. Therefore, a deeper understanding of the role and regulatory mechanism of the HIF-1α signaling during the development and progression of VC is of great significance, as it is not only a key molecular marker for understanding the pathological mechanisms of VC but also represents a promising target for future anti-calcification therapies.
Collapse
Affiliation(s)
- Zhenghong Zhang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China; (Z.Z.); (R.X.)
| | - Defan Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen 361102, China;
| | - Renfeng Xu
- Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China; (Z.Z.); (R.X.)
| | - Xiang Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA;
| | - Zhengchao Wang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China; (Z.Z.); (R.X.)
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA;
| | - Yang Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA;
| |
Collapse
|
|
3
|
Khedr MA, Mohamed Z, El-Derby AM, Soliman MM, Edris AAF, Badr E, El-Badri N. Development of hepatocellular carcinoma organoid model recapitulating HIF-1A metabolic signature. Clin Exp Med 2024; 25:9. [PMID: 39567394 PMCID: PMC11579110 DOI: 10.1007/s10238-024-01521-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 11/04/2024] [Indexed: 11/22/2024]
Abstract
Hypoxia is one of the main hallmarks of hepatocellular carcinoma (HCC) resulting from improper oxygenation and insufficient nourishment of the HCC microenvironment. The effect of hypoxia is mediated by hypoxia-inducible factor-1A (HIF-1A) via targeting various downstream pathways, including glycolysis, angiogenesis, and survival signaling. However, HCC cell lines in a 2-dimensional (2D) setting do not resemble the metabolic signature of HCC. Here we aim to overcome these limitations by developing an HCC organoid that recapitulates the HIF-1A metabolic shift. The enrichment analysis of the RNA-Seq data revealed that HIF-1A-driven glycolytic shift is of the significant pathways. The established organoid model, using xeno-free plasma-derived extracellular matrix (ECM) as a scaffold and nutritive biomatrix, maintained its structural integrity and viability for up to 14 days; the comparative analysis of the cobalt (II) chloride (CoCl2)-treated organoids to the untreated ones unveiled reduced size and proliferative capacity. Interestingly, our organoid model showed an elevated expression of HIF-1A and glycolysis enzymes compared to their counterparts in the CoCl2-treated organoids. HIF-1A molecular expression-translated biochemical signature is further assessed in our spontaneously growing organoids showing an increase in glucose uptake, intracellular pyruvate, extracellular lactate dehydrogenase expression, and extracellular lactate production, while hydrogen peroxide (H2O2), a marker for oxidative metabolism, is reduced. Our data confirmed the potency of the established organoid model to mimic the molecular and biochemical HIF-1A-driven metabolism, which validates its potential use as an in vitro HCC model. Our model naturally simulates hypoxic conditions and simultaneous HIF-1A-dependent glycolysis within HCC rather than using of CoCl2-induced hypoxic conditions.
Collapse
Affiliation(s)
- Mennatallah A Khedr
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Zainab Mohamed
- University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Azza M El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Malak M Soliman
- Bioinformatics Group, Center for Informatics Science (CIS), School of Information Technology and Computer Science, Nile University, Giza, 12588, Egypt
| | - Amira Abdel Fattah Edris
- Department of Pediatrics, Cairo University, Cairo, 11956, Egypt
- Faculty of Medicine, Kasr Al Ainy, Cairo University, Giza, 3240020, Egypt
| | - Eman Badr
- University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt.
- Faculty of Computers and Artificial Intelligence, Cairo University, Giza, 12613, Egypt.
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt.
- University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt.
| |
Collapse
|
|
4
|
Slika H, Shahani A, Wahi R, Miller J, Groves M, Tyler B. Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies. Cancers (Basel) 2024; 16:2249. [PMID: 38927954 PMCID: PMC11202166 DOI: 10.3390/cancers16122249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma's response to therapeutic modalities.
Collapse
Affiliation(s)
- Hasan Slika
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
| | - Aanya Shahani
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
| | - Riddhpreet Wahi
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
- Grant Government Medical College and Sir J.J Group of Hospitals, Mumbai 400008, India
| | - Jackson Miller
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
- Department of English, Rhetoric, and Humanistic Studies, Virginia Military Institute, Lexington, VA 24450, USA
| | - Mari Groves
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
- Department of Neurosurgery, University of Maryland Medical Center, Baltimore, MD 21201, USA
| | - Betty Tyler
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (H.S.); (A.S.); (R.W.); (J.M.)
| |
Collapse
|
|
5
|
Manfreda L, Rampazzo E, Persano L, Viola G, Bortolozzi R. Surviving the hunger games: Metabolic reprogramming in medulloblastoma. Biochem Pharmacol 2023; 215:115697. [PMID: 37481140 DOI: 10.1016/j.bcp.2023.115697] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 07/24/2023]
Abstract
Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged as key factors in the development, progression, and response to therapy in various types of cancer. Cancer cells exhibit remarkable adaptability by modulating glucose, lipids, amino acids, and nucleotide metabolism to survive in nutrient- and oxygen-deprived environments. Although medulloblastoma has been extensively studied from a genomic perspective, leading to the identification of four subgroups and their respective subcategories, the investigation of its metabolic phenotype has remained relatively understudied. This review focus on the available literature, aiming to summarize the current knowledge about the main metabolic pathways that are deregulated in medulloblastoma tumors, while emphasizing the controversial aspects and the progress that is yet to be made. Furthermore, we underscored the insights gained so far regarding the impact of metabolism on the development of drug resistance in medulloblastoma and the therapeutic strategies employed to target specific metabolic pathways.
Collapse
Affiliation(s)
- Lorenzo Manfreda
- Department of Women's and Children's Health, University of Padova, Padova, Italy; Pediatric Research Institute, Padova, Italy
| | - Elena Rampazzo
- Department of Women's and Children's Health, University of Padova, Padova, Italy; Pediatric Research Institute, Padova, Italy
| | - Luca Persano
- Department of Women's and Children's Health, University of Padova, Padova, Italy; Pediatric Research Institute, Padova, Italy
| | - Giampietro Viola
- Department of Women's and Children's Health, University of Padova, Padova, Italy; Pediatric Research Institute, Padova, Italy
| | - Roberta Bortolozzi
- Department of Women's and Children's Health, University of Padova, Padova, Italy; Pediatric Research Institute, Padova, Italy; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
| |
Collapse
|
|
6
|
Herrmann A, Meyer AK, Braunschweig L, Wagenfuehr L, Markert F, Kolitsch D, Vukicevic V, Hartmann C, Siebert M, Ehrhart-Bornstein M, Hermann A, Storch A. Notch is Not Involved in Physioxia-Mediated Stem Cell Maintenance in Midbrain Neural Stem Cells. Int J Stem Cells 2023; 16:293-303. [PMID: 37105558 PMCID: PMC10465337 DOI: 10.15283/ijsc22168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 02/10/2023] [Accepted: 03/17/2023] [Indexed: 04/29/2023] Open
Abstract
Background and Objectives The physiological oxygen tension in fetal brains (∼3%, physioxia) is beneficial for the maintenance of neural stem cells (NSCs). Sensitivity to oxygen varies between NSCs from different fetal brain regions, with midbrain NSCs showing selective susceptibility. Data on Hif-1α/Notch regulatory interactions as well as our observations that Hif-1α and oxygen affect midbrain NSCs survival and proliferation prompted our investigations on involvement of Notch signalling in physioxia-dependent midbrain NSCs performance. Methods and Results Here we found that physioxia (3% O2) compared to normoxia (21% O2) increased proliferation, maintained stemness by suppression of spontaneous differentiation and supported cell cycle progression. Microarray and qRT-PCR analyses identified significant changes of Notch related genes in midbrain NSCs after long-term (13 days), but not after short-term physioxia (48 hours). Consistently, inhibition of Notch signalling with DAPT increased, but its stimulation with Dll4 decreased spontaneous differentiation into neurons solely under normoxic but not under physioxic conditions. Conclusions Notch signalling does not influence the fate decision of midbrain NSCs cultured in vitro in physioxia, where other factors like Hif-1α might be involved. Our findings on how physioxia effects in midbrain NSCs are transduced by alternative signalling might, at least in part, explain their selective susceptibility to oxygen.
Collapse
Affiliation(s)
- Anne Herrmann
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Anne K. Meyer
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Lena Braunschweig
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Lisa Wagenfuehr
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Franz Markert
- Department of Neurology, University of Rostock, Rostock, Germany
| | - Deborah Kolitsch
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Vladimir Vukicevic
- Molecular Endocrinology, Medical Clinic III, University Clinic Dresden, Technische Universität Dresden, Dresden, Germany
| | - Christiane Hartmann
- Translational Neurodegeneration Section Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
| | - Marlen Siebert
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Monika Ehrhart-Bornstein
- Molecular Endocrinology, Medical Clinic III, University Clinic Dresden, Technische Universität Dresden, Dresden, Germany
| | - Andreas Hermann
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
- Translational Neurodegeneration Section Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany
| | - Alexander Storch
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
- Department of Neurology, University of Rostock, Rostock, Germany
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany
| |
Collapse
|
|
7
|
Fan Y, Li J, Fang B. A Tale of Two: When Neural Stem Cells Encounter Hypoxia. Cell Mol Neurobiol 2023; 43:1799-1816. [PMID: 36308642 PMCID: PMC11412202 DOI: 10.1007/s10571-022-01293-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 10/02/2022] [Indexed: 11/12/2022]
Abstract
Normoxia is defined as an oxygen concentration of 20.9%, as in room air, whereas hypoxia refers to any oxygen concentration less than this. Any physiological oxygen deficiency or tissue oxygen deficiency relative to demand is called hypoxia. Neural stem cells (NSCs) are multipotent stem cells that can differentiate into multiple cell lines such as neurons, oligodendrocytes, and astrocytes. Under hypoxic conditions, the apoptosis rate of NSCs increases remarkably in vitro or in vivo. However, some hypoxia promotes the proliferation and differentiation of NSCs. The difference is related to the oxygen concentration, the duration of hypoxia, the hypoxia tolerance threshold of the NSCs, and the tissue source of the NSCs. The main mechanism of hypoxia-induced proliferation and differentiation involves an increase in cyclin and erythropoietin concentrations, and hypoxia-inducible factors play a key role. Multiple molecular pathways are activated during hypoxia, including Notch, Wnt/β-catenin, PI3K/Akt, and altered microRNA expression. In addition, we review the protective effect of exogenous NSCs transplantation on ischemic or anoxic organs, the therapeutic potential of hypoxic preconditioning on exogenous NSCs and clinical application of NSCs.
Collapse
Affiliation(s)
- Yiting Fan
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Jinshi Li
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| | - Bo Fang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China.
| |
Collapse
|
|
8
|
Han YP, Lin HW, Li H. Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review. Cancers (Basel) 2023; 15:3154. [PMID: 37370764 DOI: 10.3390/cancers15123154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/30/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Cancer stem cells (CSCs) are a subgroup of cells found in various kinds of tumours with stem cell characteristics, such as self-renewal, induced differentiation, and tumourigenicity. The existence of CSCs is regarded as a major source of tumour recurrence, metastasis, and resistance to conventional chemotherapy and radiation treatment. Tumours of the central nervous system (CNS) are the most common solid tumours in children, which have many different types including highly malignant embryonal tumours and midline gliomas, and low-grade gliomas with favourable prognoses. Stem cells from the CNS tumours have been largely found and reported by researchers in the last decade and their roles in tumour biology have been deeply studied. However, the cross-talk of CSCs among different CNS tumour types and their clinical impacts have been rarely discussed. This article comprehensively reviews the achievements in research on CSCs in paediatric CNS tumours. Biological functions, diagnostic values, and therapeutic perspectives are reviewed in detail. Further investigations into CSCs are warranted to improve the clinical practice in treating children with CNS tumours.
Collapse
Affiliation(s)
- Yi-Peng Han
- Department of Neurosurgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Hou-Wei Lin
- Department of Paediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Department of Paediatric Surgery, Jiaxing Women and Children Hospital Affiliated to Jiaxing University, Jiaxing 314001, China
| | - Hao Li
- Department of Neurosurgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| |
Collapse
|
|
9
|
Liu C, Kuang S, Wu L, Cheng Q, Gong X, Wu J, Zhang L. Radiotherapy and radio-sensitization in H3 K27M -mutated diffuse midline gliomas. CNS Neurosci Ther 2023. [PMID: 37157237 DOI: 10.1111/cns.14225] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/07/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND H3K27M mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%. Radiotherapy is the only established adjuvant treatment of H3K27M DMGs; however, the radio-resistance is commonly observed. METHODS We summarized current understandings of the molecular responses of H3K27M DMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement. RESULTS Ionizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial-mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio-resistance. CONCLUSIONS The advances in mechanisms of radio-resistance in H3K27M DMGs promote the potential targets to enhance the sensitivity to radiotherapy.
Collapse
Affiliation(s)
- Chao Liu
- Departments of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Shuwen Kuang
- Departments of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Lei Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Quan Cheng
- Departments of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xuan Gong
- Departments of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jun Wu
- Departments of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Longbo Zhang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Departments of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Departments of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA
| |
Collapse
|
|
10
|
Lam KHB, Faust K, Yin R, Fiala C, Diamandis P. The Brain Protein Atlas: A conglomerate of proteomics datasets of human neural tissue. Proteomics 2022; 22:e2200127. [PMID: 35971647 DOI: 10.1002/pmic.202200127] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/09/2022] [Accepted: 08/03/2022] [Indexed: 11/06/2022]
Abstract
The human brain represents one of the most complex biological structures with significant spatiotemporal molecular plasticity occurring through early development, learning, aging, and disease. While much progress has been made in mapping its transcriptional architecture, more downstream phenotypic readouts are relatively scarce due to limitations with tissue heterogeneity and accessibility, as well as an inability to amplify protein species prior to global -OMICS analysis. To address some of these barriers, our group has recently focused on using mass-spectrometry workflows compatible with small amounts of formalin-fixed paraffin-embedded tissue samples. This has enabled exploration into spatiotemporal proteomic signatures of the brain and disease across otherwise inaccessible neurodevelopmental timepoints and anatomical niches. Given the similar theme and approaches, we introduce an integrated online portal, "The Brain Protein Atlas (BPA)" (www.brainproteinatlas.org), representing a public resource that allows users to access and explore these amalgamated datasets. Specifically, this portal contains a growing set of peer-reviewed mass-spectrometry-based proteomic datasets, including spatiotemporal profiles of human cerebral development, diffuse gliomas, clinically aggressive meningiomas, and a detailed anatomic atlas of glioblastoma. One barrier to entry in mass spectrometry-based proteomics data analysis is the steep learning curve required to extract biologically relevant data. BPA, therefore, includes several built-in analytical tools to generate relevant plots (e.g., volcano plots, heatmaps, boxplots, and scatter plots) and evaluate the spatiotemporal patterns of proteins of interest. Future iterations aim to expand available datasets, including those generated by the community at large, and analytical tools for exploration. Ultimately, BPA aims to improve knowledge dissemination of proteomic information across the neuroscience community in hopes of accelerating the biological understanding of the brain and various maladies.
Collapse
Affiliation(s)
- K H Brian Lam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.,Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, United States of America
| | - Kevin Faust
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
| | - Richard Yin
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
| | - Clare Fiala
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
| | - Phedias Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.,Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
11
|
Marabitti V, Giansanti M, De Mitri F, Gatto F, Mastronuzzi A, Nazio F. Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma. Front Cell Dev Biol 2022; 10:1007641. [PMID: 36340043 PMCID: PMC9627342 DOI: 10.3389/fcell.2022.1007641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/05/2022] [Indexed: 07/30/2023] Open
Abstract
Tumor-specific alterations in metabolism have been recognized to sustain the production of ATP and macromolecules needed for cell growth, division and survival in many cancer types. However, metabolic heterogeneity poses a challenge for the establishment of effective anticancer therapies that exploit metabolic vulnerabilities. Medulloblastoma (MB) is one of the most heterogeneous malignant pediatric brain tumors, divided into four molecular subgroups (Wingless, Sonic Hedgehog, Group 3 and Group 4). Recent progresses in genomics, single-cell sequencing, and novel tumor models have updated the classification and stratification of MB, highlighting the complex intratumoral cellular diversity of this cancer. In this review, we emphasize the mechanisms through which MB cells rewire their metabolism and energy production networks to support and empower rapid growth, survival under stressful conditions, invasion, metastasis, and resistance to therapy. Additionally, we discuss the potential clinical benefits of currently available drugs that could target energy metabolism to suppress MB progression and increase the efficacy of the current MB therapies.
Collapse
Affiliation(s)
- Veronica Marabitti
- Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Manuela Giansanti
- Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Francesca De Mitri
- Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Francesca Gatto
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Angela Mastronuzzi
- Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Francesca Nazio
- Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| |
Collapse
|
|
12
|
Martín-Rubio P, Espiau-Romera P, Royo-García A, Caja L, Sancho P. Metabolic determinants of stemness in medulloblastoma. World J Stem Cells 2022; 14:587-598. [PMID: 36157911 PMCID: PMC9453267 DOI: 10.4252/wjsc.v14.i8.587] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/26/2022] [Accepted: 08/01/2022] [Indexed: 02/07/2023] Open
Abstract
Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glutathione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.
Collapse
Affiliation(s)
| | | | - Alba Royo-García
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
| | - Laia Caja
- Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Uppsala SE-751, Sweden
| | - Patricia Sancho
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
| |
Collapse
|
|
13
|
Mari V, Angerilli V, Munari G, Scarpa M, Bao QR, Pucciarelli S, Fassan M, Spolverato G. Molecular Determinants of Peritoneal Dissemination in Gastric Adenocarcinoma. Dig Dis 2022; 41:49-65. [PMID: 35940137 DOI: 10.1159/000526333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND Peritoneal dissemination represents a poor prognostic indicator in gastric cancer. Despite a comprehensive molecular characterization of this disease, no peritoneal dissemination-specific signature has been identified, limiting the tailoring of the surgical and oncological treatments. In this review, we outline the available literature focusing on the role of the different molecular pathways involved in the acquisition of peritoneal metastatic dissemination. SUMMARY According to our results, several molecular determinants are associated with peritoneal carcinomatosis and are involved in several cellular and molecular carcinogenetic processes. However, a comprehensive understanding of the complex molecular landscape of gastric carcinosis is still lacking. KEY MESSAGES More efforts should be made toward the integration of molecular and histologic data to perform a risk prediction assessment of peritoneal dissemination based on molecular profiling and histological evaluation.
Collapse
Affiliation(s)
- Valentina Mari
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Valentina Angerilli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Giada Munari
- Veneto Institute of Oncology (I.O.V. IRCSS), Padua, Italy
| | - Marco Scarpa
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Quoc Riccardo Bao
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Salvatore Pucciarelli
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology (I.O.V. IRCSS), Padua, Italy
| | - Gaya Spolverato
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| |
Collapse
|
|
14
|
Inhibiting ALK2/ALK3 Signaling to Differentiate and Chemo-Sensitize Medulloblastoma. Cancers (Basel) 2022; 14:cancers14092095. [PMID: 35565225 PMCID: PMC9102092 DOI: 10.3390/cancers14092095] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Many cancers re-emerge after treatment, despite the sensitivity of the bulk of tumor cells to treatments. This observation has led to the ‘cancer stem cell’ (CSCs) hypothesis, stating that a subpopulation of cancer cells survive therapy and lead to tumor relapse. However, the lack of universal markers to target CSCs is the main constraint to fully eradicate the CSC pool. Differentiation therapy (DT) might in principle suppress tumorigenesis through conversion of undifferentiated cancer cells of high malignancy into differentiated cells of low tumorigenic potential. Here, we provide evidence that CSCs of medulloblastoma can be forced to resume their differentiation potential by inhibiting the BMP4–ALK2/3 axis, providing a new entry point for medulloblastoma treatment. Abstract Background: Medulloblastoma (MB) is a malignant pediatric brain tumor, and it represents the leading cause of death related to cancer in childhood. New perspectives for therapeutic development have emerged with the identification of cancer stem cells (CSCs) displaying tumor initiating capability and chemoresistance. However, the mechanisms responsible for CSCs maintenance are poorly understood. The lack of a universal marker signature represents the main constraints to identify and isolate CSCs within the tumor. Methods: To identify signaling pathways promoting CSC maintenance in MB, we combined tumorsphere assays with targeted neurogenesis PCR pathway arrays. Results: We showed a consistent induction of signaling pathways regulating pluripotency of CSCs in all the screened MB cells. BMP4 signaling was consistently enriched in all tumorsphere(s) independently of their specific stem-cell marker profile. The octamer-binding transcription factor 4 (OCT4), an important regulator of embryonic pluripotency, enhanced CSC maintenance in MBs by inducing the BMP4 signaling pathway. Consistently, inhibition of BMP4 signaling with LDN-193189 reduced stem-cell traits and promoted cell differentiation. Conclusions: Our work suggests that interfering with the BMP4 signaling pathway impaired the maintenance of the CSC pool by promoting cell differentiation. Hence, differentiation therapy might represent an innovative therapeutic to improve the current standard of care in MB patients.
Collapse
|
|
15
|
Yang Y, Meng WJ, Wang ZQ. Cancer Stem Cells and the Tumor Microenvironment in Gastric Cancer. Front Oncol 2022; 11:803974. [PMID: 35047411 PMCID: PMC8761735 DOI: 10.3389/fonc.2021.803974] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/08/2021] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) remains one of the leading causes of cancer-related death worldwide. Cancer stem cells (CSCs) might be responsible for tumor initiation, relapse, metastasis and treatment resistance of GC. The tumor microenvironment (TME) comprises tumor cells, immune cells, stromal cells and other extracellular components, which plays a pivotal role in tumor progression and therapy resistance. The properties of CSCs are regulated by cells and extracellular matrix components of the TME in some unique manners. This review will summarize current literature regarding the effects of CSCs and TME on the progression and therapy resistance of GC, while emphasizing the potential for developing successful anti-tumor therapy based on targeting the TME and CSCs.
Collapse
Affiliation(s)
| | - Wen-Jian Meng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | | |
Collapse
|
|
16
|
Marracino L, Fortini F, Bouhamida E, Camponogara F, Severi P, Mazzoni E, Patergnani S, D’Aniello E, Campana R, Pinton P, Martini F, Tognon M, Campo G, Ferrari R, Vieceli Dalla Sega F, Rizzo P. Adding a "Notch" to Cardiovascular Disease Therapeutics: A MicroRNA-Based Approach. Front Cell Dev Biol 2021; 9:695114. [PMID: 34527667 PMCID: PMC8435685 DOI: 10.3389/fcell.2021.695114] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/09/2021] [Indexed: 12/18/2022] Open
Abstract
Dysregulation of the Notch pathway is implicated in the pathophysiology of cardiovascular diseases (CVDs), but, as of today, therapies based on the re-establishing the physiological levels of Notch in the heart and vessels are not available. A possible reason is the context-dependent role of Notch in the cardiovascular system, which would require a finely tuned, cell-specific approach. MicroRNAs (miRNAs) are short functional endogenous, non-coding RNA sequences able to regulate gene expression at post-transcriptional levels influencing most, if not all, biological processes. Dysregulation of miRNAs expression is implicated in the molecular mechanisms underlying many CVDs. Notch is regulated and regulates a large number of miRNAs expressed in the cardiovascular system and, thus, targeting these miRNAs could represent an avenue to be explored to target Notch for CVDs. In this Review, we provide an overview of both established and potential, based on evidence in other pathologies, crosstalks between miRNAs and Notch in cellular processes underlying atherosclerosis, myocardial ischemia, heart failure, calcification of aortic valve, and arrhythmias. We also discuss the potential advantages, as well as the challenges, of using miRNAs for a Notch-based approach for the diagnosis and treatment of the most common CVDs.
Collapse
Affiliation(s)
- Luisa Marracino
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | | | - Esmaa Bouhamida
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Francesca Camponogara
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Paolo Severi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Elisa Mazzoni
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Simone Patergnani
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Emanuele D’Aniello
- Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Roberta Campana
- Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Paolo Pinton
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Fernanda Martini
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Mauro Tognon
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Gianluca Campo
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
- Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Roberto Ferrari
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
| | | | - Paola Rizzo
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
| |
Collapse
|
|
17
|
Intermittent Hypoxia and Effects on Early Learning/Memory: Exploring the Hippocampal Cellular Effects of Pediatric Obstructive Sleep Apnea. Anesth Analg 2021; 133:93-103. [PMID: 33234943 DOI: 10.1213/ane.0000000000005273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This review provides an update on the neurocognitive phenotype of pediatric obstructive sleep apnea (OSA). Pediatric OSA is associated with neurocognitive deficits involving memory, learning, and executive functioning. Adenotonsillectomy (AT) is presently accepted as the first-line surgical treatment for pediatric OSA, but the executive function deficits do not resolve postsurgery, and the timeline for recovery remains unknown. This finding suggests that pediatric OSA potentially causes irreversible damage to multiple areas of the brain. The focus of this review is the hippocampus, 1 of the 2 major sites of postnatal neurogenesis, where new neurons are formed and integrated into existing circuitry and the mammalian center of learning/memory functions. Here, we review the clinical phenotype of pediatric OSA, and then discuss existing studies of OSA on different cell types in the hippocampus during critical periods of development. This will set the stage for future study using preclinical models to understand the pathogenesis of persistent neurocognitive dysfunction in pediatric OSA.
Collapse
|
|
18
|
Paul MR, Zage PE. Overview and recent advances in the targeting of medulloblastoma cancer stem cells. Expert Rev Anticancer Ther 2021; 21:957-974. [PMID: 34047251 DOI: 10.1080/14737140.2021.1932472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Medulloblastoma, an embryonal small round blue cell tumor primarily arising in the posterior fossa, is the most common malignancy of the central nervous system in children and requires intensive multi-modality therapy for cure. Overall 5-year survival is approximately 75% in children with primary disease, but outcomes for relapsed disease are very poor. Recent advances have identified molecular subgroups with excellent prognosis, with 5-year overall survival rates >90%, and subgroups with very poor prognosis with overall survival rates <50%. Molecular subtyping has allowed for more sophisticated risk stratification of patients, but new treatments for the highest risk patients have not yet improved outcomes. Targeting cancer stem cells may improve outcomes, and several candidate targets and novel drugs are under investigation.Areas covered: We discuss medulloblastoma epidemiology, biology, treatment modalities, risk stratification, and molecular subgroup analysis, links between subgroup and developmental biology, cancer stem cell biology in medulloblastoma including previously described cancer stem cell markers and proposed targeted treatments in the current literature.Expert opinion: The understanding of cancer stem cells in medulloblastoma will advance therapies targeting the most treatment-resistant cells within the tumor and therefore reduce the incidence of treatment refractory and relapsed disease.
Collapse
Affiliation(s)
- Megan Rose Paul
- Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA (M.R.P., P.E.Z.); Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital-San Diego, San Diego, California, USA
| | - Peter E Zage
- Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA (M.R.P., P.E.Z.); Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital-San Diego, San Diego, California, USA
| |
Collapse
|
|
19
|
Liu Z, Zhao Q, Zheng Z, Liu S, Meng L, Dong L, Jiang X. Vascular normalization in immunotherapy: A promising mechanisms combined with radiotherapy. Biomed Pharmacother 2021; 139:111607. [PMID: 33965730 DOI: 10.1016/j.biopha.2021.111607] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/02/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
Leakage and compression of blood vessels may result in deprivation of blood flow to a large number of tumor tissues, which can lead to tumor hypoxia. Hypoxia induces an increase in the expression of hypoxia-inducible factor 1 in tumor cells, which induces angiogenesis in tumors through the high expression of vascular endothelial growth factor, thereby forming a positive feedback vicious circle. Improving hypoxia by normalizing blood vessels and improving radiosensitivity by immunotherapy has emerged as a new application of combined immunotherapy and radiotherapy. Interferon γ produced by CD4 + /CD8 + T cells, induced by immune checkpoint inhibitors, plays an important role in the normalization of blood vessels; tumor-associated eosinophils also play a role in the process of immunotherapy-induced blood vessel normalization. In addition, the reduction in regulatory T cells induced by immune checkpoint inhibitors can increase eosinophil levels, which promotes the further development of vascular normalization mechanisms. This review focuses on the mechanism of immunotherapy to normalize blood vessels, and proposes a good prospect for improving hypoxia. Due to the narrow vascular normalization window of anti-angiogenesis therapy, discovery of the vascular normalization effect of immunotherapy provides a new idea for the combined application of immunotherapy and radiotherapy. The enlarged vascular normalization window and improved hypoxia provide a good opportunity for the subsequent implementation of radiotherapy. The above sorting and analysis may pave the way for a promising strategy for cancer treatment via combined immunotherapy and radiotherapy.
Collapse
Affiliation(s)
- Zijing Liu
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China
| | - Qin Zhao
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China
| | - Zhuangzhuang Zheng
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China
| | - Shiyu Liu
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China
| | - Lingbin Meng
- Department of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Lihua Dong
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China; Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| |
Collapse
|
|
20
|
Chien CH, Hsueh WT, Chuang JY, Chang KY. Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma. J Biomed Sci 2021; 28:18. [PMID: 33685470 PMCID: PMC7938520 DOI: 10.1186/s12929-021-00717-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma is the most common primary malignant brain tumor that is usually considered fatal even with treatment. This is often a result for tumor to develop resistance. Regarding the standard chemotherapy, the alkylating agent temozolomide is effective in disease control but the recurrence will still occur eventually. The mechanism of the resistance is various, and differs in terms of innate or acquired. To date, aberrations in O6-methylguanine-DNA methyltransferase are the clear factor that determines drug susceptibility. Alterations of the other DNA damage repair genes such as DNA mismatch repair genes are also known to affect the drug effect. Together these genes have roles in the innate resistance, but are not sufficient for explaining the mechanism leading to acquired resistance. Recent identification of specific cellular subsets with features of stem-like cells may have role in this process. The glioma stem-like cells are known for its superior ability in withstanding the drug-induced cytotoxicity, and giving the chance to repopulate the tumor. The mechanism is complicated to administrate cellular protection, such as the enhancing ability against reactive oxygen species and altering energy metabolism, the important steps to survive. In this review, we discuss the possible mechanism for these specific cellular subsets to evade cancer treatment, and the possible impact to the following treatment courses. In addition, we also discuss the possibility that can overcome this obstacle.
Collapse
Affiliation(s)
- Chia-Hung Chien
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Wei-Ting Hsueh
- Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Jian-Ying Chuang
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.,The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kwang-Yu Chang
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan. .,Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
| |
Collapse
|
|
21
|
Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy. Molecules 2021; 26:molecules26040972. [PMID: 33673088 PMCID: PMC7917912 DOI: 10.3390/molecules26040972] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/04/2021] [Accepted: 02/09/2021] [Indexed: 12/26/2022] Open
Abstract
The dysregulation of Notch signaling is associated with a wide variety of different human cancers. Notch signaling activation mostly relies on the activity of the γ-secretase enzyme that cleaves the Notch receptors and releases the active intracellular domain. It is well-documented that γ-secretase inhibitors (GSIs) block the Notch activity, mainly by inhibiting the oncogenic activity of this pathway. To date, several GSIs have been introduced clinically for the treatment of various diseases, such as Alzheimer's disease and various cancers, and their impacts on Notch inhibition have been found to be promising. Therefore, GSIs are of great interest for cancer therapy. The objective of this review is to provide a systematic review of in vitro and in vivo studies for investigating the effect of GSIs on various cancer stem cells (CSCs), mainly by modulation of the Notch signaling pathway. Various scholarly electronic databases were searched and relevant studies published in the English language were collected up to February 2020. Herein, we conclude that GSIs can be potential candidates for CSC-targeting therapy. The outcome of our study also indicates that GSIs in combination with anticancer drugs have a greater inhibitory effect on CSCs.
Collapse
|
|
22
|
Wang K, Kievit FM, Chiarelli PA, Stephen ZR, Lin G, Silber JR, Ellenbogen RG, Zhang M. siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model. ADVANCED FUNCTIONAL MATERIALS 2021; 31:2007166. [PMID: 33708035 PMCID: PMC7942690 DOI: 10.1002/adfm.202007166] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Indexed: 05/31/2023]
Abstract
Temozolomide (TMZ) is the standard of care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug resistance mediated by a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here we report the development of an iron oxide nanoparticle (NP) system for targeted delivery of siRNAs to suppress the TMZ-resistance gene (MGMT). We show that our NP is able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially-passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ resulted in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly-prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.
Collapse
Affiliation(s)
- Kui Wang
- Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, United States
| | - Forrest M Kievit
- Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, United States
| | - Peter A Chiarelli
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, United States
| | - Zachary R Stephen
- Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, United States
| | - Guanyou Lin
- Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, United States
| | - John R Silber
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, United States
| | - Richard G Ellenbogen
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, United States
| | - Miqin Zhang
- Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, United States; Department of Neurological Surgery, University of Washington, Seattle, WA 98195, United States
| |
Collapse
|
|
23
|
Lakhan R, Rathinam CV. Deficiency of Rbpj Leads to Defective Stress-Induced Hematopoietic Stem Cell Functions and Hif Mediated Activation of Non-canonical Notch Signaling Pathways. Front Cell Dev Biol 2021; 8:622190. [PMID: 33569384 PMCID: PMC7868433 DOI: 10.3389/fcell.2020.622190] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/31/2020] [Indexed: 12/11/2022] Open
Abstract
Deregulated notch signaling has been associated with human pathobiology. However, functions of notch pathways in hematopoiesis remain incompletely understood. Here, we ablated canonical notch pathways, through genetic deletion of Rbpj, in hematopoietic stem cells (HSCs). Our data identified that loss of canonical notch results in normal adult HSC pool, at steady state conditions. However, HSC maintenance and functions in response to radiation-, chemotherapy-, and cytokine- induced stress were compromised in the absence of canonical notch. Rbpj deficient HSCs exhibit decreased proliferation rates and elevated expression of p57Kip2. Surprisingly, loss of Rbpj resulted in upregulation of key notch target genes and augmented binding of Hes1 to p57 and Gata2 promoters. Further molecular analyses identified an increase in notch activity, elevated expression and nuclear translocation of Hif proteins, and augmented binding of Hif1α to Hes1 promoter in the absence of Rbpj. These studies, for the first time, identify a previously unknown role for non-canonical notch signaling and establish a functional link between Hif and Notch pathways in hematopoiesis.
Collapse
Affiliation(s)
- Ram Lakhan
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Chozha V Rathinam
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States.,Center for Stem Cell and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| |
Collapse
|
|
24
|
Xiu MX, Liu YM, Kuang BH. The Role of DLLs in Cancer: A Novel Therapeutic Target. Onco Targets Ther 2020; 13:3881-3901. [PMID: 32440154 PMCID: PMC7213894 DOI: 10.2147/ott.s244860] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 04/06/2020] [Indexed: 12/18/2022] Open
Abstract
Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.
Collapse
Affiliation(s)
- Meng-Xi Xiu
- Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Yuan-Meng Liu
- Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Bo-Hai Kuang
- Medical School of Nanchang University, Nanchang, People's Republic of China
| |
Collapse
|
|
25
|
Bahmad HF, Poppiti RJ. Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets. J Clin Pathol 2020; 73:243-249. [PMID: 32034059 DOI: 10.1136/jclinpath-2019-206246] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/12/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
Medulloblastoma (MB) is the most common malignant primary intracranial neoplasm diagnosed in childhood. Although numerous efforts have been made during the past few years to exploit novel targeted therapies for this aggressive neoplasm, there still exist substantial hitches hindering successful management of MB. Lately, progress in cancer biology has shown evidence that a subpopulation of cells within the tumour, namely cancer stem cells (CSCs), are thought to be responsible for the resistance to most chemotherapeutic agents and radiation therapy, accounting for cancer recurrence. Hence, it is crucial to identify the molecular signatures and genetic aberrations that characterise those CSCs and develop therapies that specifically target them. In this review, we aim to give an overview of the main genetic and molecular cues that depict MB-CSCs and provide a synopsis of the novel therapeutic approaches that specifically target this population of cells to attain enhanced antitumorous effects and therefore overcome resistance to therapy.
Collapse
Affiliation(s)
- Hisham F Bahmad
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA.,Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Robert J Poppiti
- Arkadi M Rywlin MD Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA .,Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
| |
Collapse
|
|
26
|
Human Medulloblastoma Cell Lines: Investigating on Cancer Stem Cell-Like Phenotype. Cancers (Basel) 2020; 12:cancers12010226. [PMID: 31963405 PMCID: PMC7016648 DOI: 10.3390/cancers12010226] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/13/2020] [Accepted: 01/15/2020] [Indexed: 01/06/2023] Open
Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains significant and the long-term adverse effects in survivors are substantial. The fraction of cancer stem-like cells (CSCs) because of their self-renewal ability and multi-lineage differentiation potential is critical for tumor initiation, growth, and resistance to therapies. For the development of new CSC-targeted therapies, further in-depth studies are needed using enriched and stable MB-CSCs populations. This work, aimed at identifying the amount of CSCs in three available human cell lines (DAOY, D341, and D283), describes different approaches based on the expression of stemness markers. First, we explored potential differences in gene and protein expression patterns of specific stem cell markers. Then, in order to identify and discriminate undifferentiated from differentiated cells, MB cells were characterized using a physical characterization method based on a high-frequency dielectrophoresis approach. Finally, we compared their tumorigenic potential in vivo, through engrafting in nude mice. Concordantly, our findings identified the D283 human cell line as an ideal model of CSCs, providing important evidence on the use of a commercial human MB cell line for the development of new strategic CSC-targeting therapies.
Collapse
|
|
27
|
Oliver JA, Ortiz R, Jimenez-Luna C, Cabeza L, Perazzoli G, Caba O, Mesas C, Melguizo C, Prados J. MMR-proficient and MMR-deficient colorectal cancer cells: 5-Fluorouracil treatment response and correlation to CD133 and MGMT expression. J Biosci 2020; 45:121. [PMID: 33097678 DOI: 10.1007/s12038-020-00093-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/25/2020] [Indexed: 12/24/2022]
Abstract
Cancer stem cells (CSCs) from colorectal cancer (CRC), characterized by CD133 expression, have been associated with 5-fluorouracile (5-FU) chemoresistance. DNA repair mechanisms, such as O6-alkylguanine DNA alkyltransferase (MGMT) and mismatch repair (MMR) systems, have also been correlated to 5-FU resistance in CRC. The aim of this study was to evaluate the modulation of CD133 and MGMT in MMRproficient and MMR-deficient CRC cells under 5-FU treatment and the effect of this drug in CSCs. CD133 and MGMT methylation status were determined in MMR-proficient (SW480 and HT29) and MMR-deficient (RKO and HCT116) cell lines by methylation-specific PCRs. SW480 and RKO were selected to determine modulation of CD133, MGMT and MMR expression after 5-FU treatment by qPCR. In addition, CD133, MGMT and MMR were analyze in SW480 and RKO CSCs. No association between promoter methylation and MGMT and CD133 expression was found. 5-FU treatment increased CD133 expression independently to MMR status in SW480 and RKO and was able to increase hMLH1 expression in RKO, a MMR-deficient cell line. RKO/ CSCs overexpressed CD133 and MMR (hMSH2 and hMSH6) while SW480/CSCs showed a significant increase in CD133, MMR (hMLH1, hMSH2 and hMSH6) and MGMT, moreover 5-FU resistance than parental cell lines. Thus, although CSCs 5-FU chemoresistance appears to be independently to MMR status, hMLH1 might play a key role in CSC response to 5-FU. New drugs exploding these differences could benefit the prognostic of patients with CRC.
Collapse
Affiliation(s)
- Jaime A Oliver
- Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Kim S, Lee M, Choi YK. The Role of a Neurovascular Signaling Pathway Involving Hypoxia-Inducible Factor and Notch in the Function of the Central Nervous System. Biomol Ther (Seoul) 2020; 28:45-57. [PMID: 31484285 PMCID: PMC6939687 DOI: 10.4062/biomolther.2019.119] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/06/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022] Open
Abstract
In the neurovascular unit, the neuronal and vascular systems communicate with each other. O2 and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O2 and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson’s disease, and Alzheimer’s disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.
Collapse
Affiliation(s)
- Seunghee Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Minjae Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Yoon Kyung Choi
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| |
Collapse
|
|
29
|
Chien CH, Chuang JY, Yang ST, Yang WB, Chen PY, Hsu TI, Huang CY, Lo WL, Yang KY, Liu MS, Chu JM, Chung PH, Liu JJ, Chou SW, Chen SH, Chang KY. Enrichment of superoxide dismutase 2 in glioblastoma confers to acquisition of temozolomide resistance that is associated with tumor-initiating cell subsets. J Biomed Sci 2019; 26:77. [PMID: 31629402 PMCID: PMC6800988 DOI: 10.1186/s12929-019-0565-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/10/2019] [Indexed: 12/13/2022] Open
Abstract
Background Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance. Methods Resistant cell lines derived from U87MG and A172 were established through long-term co-incubation of TMZ. Primary tumors obtained from patients were maintained as patient-derived xenograft for studies of tumor-initating cell (TIC) features. The cell manifestations were assessed in the gene modulated cells for relevance to drug resistance. Results Among the mitochondria-related genes in the gene expression databases, superoxide dismutase 2 (SOD2) was a significant factor in resistance and patient survival. SOD2 in the resistant cells functionally determined the cell fate by limiting TMZ-stimulated superoxide reaction and cleavage of caspase-3. Genetic inhibition of the protein led to retrieval of drug effect in mouse study. SOD2 was also associated with the TIC features, which enriched in the resistant cells. The CD133+ specific subsets in the resistant cells exhibited superior superoxide regulation and the SOD2-related caspase-3 reaction. Experiments applying SOD2 modulation showed a positive correlation between the TIC features and the protein expression. Finally, co-treatment with TMZ and the SOD inhibitor sodium diethyldithiocarbamate trihydrate in xenograft mouse models with the TMZ-resistant primary tumor resulted in lower tumor proliferation, longer survival, and less CD133, Bmi-1, and SOD2 expression. Conclusion SOD2 plays crucial roles in the tumor-initiating features that are related to TMZ resistance. Inhibition of the protein is a potential therapeutic strategy that can be used to enhance the effects of chemotherapy. Graphical abstract ![]()
Collapse
Affiliation(s)
- Chia-Hung Chien
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Jian-Ying Chuang
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.,The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shun-Tai Yang
- Division of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Wen-Bin Yang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pin-Yuan Chen
- Department of Neurosurgery, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
| | - Tsung-I Hsu
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan
| | - Chih-Yuan Huang
- Division of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Wei-Lun Lo
- Division of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ka-Yen Yang
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Sheng Liu
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan.,Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan
| | - Jui-Mei Chu
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Pei-Hsuan Chung
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Jr-Jiun Liu
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.,The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shao-Wen Chou
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Shang-Hung Chen
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan.,Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kwang-Yu Chang
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan. .,Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| |
Collapse
|
|
30
|
Pan W, Song XY, Hu QB, Zhang M, Xu XH. TSP2 acts as a suppresser of cell invasion, migration and angiogenesis in medulloblastoma by inhibiting the Notch signaling pathway. Brain Res 2019; 1718:223-230. [PMID: 31063715 DOI: 10.1016/j.brainres.2019.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/10/2019] [Accepted: 05/04/2019] [Indexed: 10/26/2022]
Abstract
Medulloblastoma (MB) represents a fatal malignancy often occurring in children. Angiogenesis is a hallmark of the progression of MB. Over the past decade, investigators have attempted to develop more effective and less toxic anti-angiogenic strategies to treat MB. Thrombospondin (TSP) family is observed to be a key regulator of angiogenesis. Thus, the current study aimed to elucidate the function of TSP2 in patients with MB and the underlying mechanism. The expression of TSP2, Notch1 and VEGF in MB and adjacent tissues collected from clinical samples as well as a MB cell line (Daoy) was examined. The results demonstrated that in the MB tissues and Daoy cells, TSP2 was downregulated, while Notch1 and VEGF were upregulated. Then, after the Daoy cells were treated with TSP2 silencing, TSP2 overexpression, or Notch signaling pathway inhibition, a series of in vitro cell experiments were performed to verify the interaction between TSP2 and Notch signaling pathway, and to examine the abilities of cell proliferation, migration, invasion, and tube formation. Upregulation of TSP2 was observed to lead to the downregulation of the Notch signaling pathway. Moreover, cells overexpressing TSP2 exhibited diminished proliferation, invasion, migration, and tube formation. In addition, a significant attenuation of tumor growth and angiogenesis was identified in vivo in the Daoy cells overexpressing TSP2 inoculated in nude mice. Taken together, the key findings of this study revealed the inhibitory role of TSP2 in the development of MB via blockade of the Notch signaling pathway, highlighting its potential as a treatment target for MB treatment.
Collapse
Affiliation(s)
- Wei Pan
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Xing-Yu Song
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Qi-Bo Hu
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Meng Zhang
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Xiao-Heng Xu
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun 130041, PR China.
| |
Collapse
|
|
31
|
Trotta T, Panaro MA, Prifti E, Porro C. Modulation of Biological Activities in Glioblastoma Mediated by Curcumin. Nutr Cancer 2019; 71:1241-1253. [PMID: 31007066 DOI: 10.1080/01635581.2019.1604978] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Curcumin is an alkaloid with various pharmacologic properties; numerous investigations have suggested that in the Central Nervous System, Curcumin has anti-inflammatory, antimicrobial, antioxidant, and antitumor effects. Gliomas are the most common primary intracranial tumors in adults. The prognosis of glioblastoma is still dismal. In this review, we profile that Curcumin could suppress cell proliferation and induce apoptosis of cancer cells and genomic modulation. In particular, Curcumin could exert its therapeutic effect via modulating miRNA, affecting a variety of miRNAs involved in the response to cancer therapy. The combination of Curcumin with chemotherapeutic drugs or radiotherapy could prime the sensitivity of cancer cells to chemotherapy or radiotherapy. We also discuss the use of exosomes as Curcumin delivery vehicles. In this context, exosomes containing Curcumin may change the behavior of recipient cells by targeting a sequence of cellular and molecular pathways. Hence, the application of exosomes containing Curcumin may prove to be an emerging area of research in cancer therapy.
Collapse
Affiliation(s)
- Teresa Trotta
- Department of Clinical and Experimental Medicine, University of Foggia , Foggia , Italy
| | - Maria A Panaro
- Department of Biosciences, Biotechnologies and Biopharmaceutics University of Bari , Bari , Italy
| | - Elona Prifti
- Department of Clinical Materies, University of Elbasan "Aleksander Xhuvani", Faculty of Medical and Technical Science , Albania
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia , Foggia , Italy
| |
Collapse
|
|
32
|
Mazor G, Levin L, Picard D, Ahmadov U, Carén H, Borkhardt A, Reifenberger G, Leprivier G, Remke M, Rotblat B. The lncRNA TP73-AS1 is linked to aggressiveness in glioblastoma and promotes temozolomide resistance in glioblastoma cancer stem cells. Cell Death Dis 2019; 10:246. [PMID: 30867410 PMCID: PMC6416247 DOI: 10.1038/s41419-019-1477-5] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 02/06/2019] [Accepted: 02/12/2019] [Indexed: 12/19/2022]
Abstract
Glioblastoma multiform (GBM) is the most common brain tumor characterized by a dismal prognosis. GBM cancer stem cells (gCSC) or tumor-initiating cells are the cell population within the tumor-driving therapy resistance and recurrence. While temozolomide (TMZ), an alkylating agent, constitutes the first-line chemotherapeutic significantly improving survival in GBM patients, resistance against this compound commonly leads to GBM recurrence and treatment failure. Although the roles of protein-coding transcripts, proteins and microRNA in gCSC, and therapy resistance have been comprehensively investigated, very little is known about the role of long noncoding RNAs (lncRNAs) in this context. Using nonoverlapping, independent RNA sequencing and gene expression profiling datasets, we reveal that TP73-AS1 constitutes a clinically relevant lncRNA in GBM. Specifically, we demonstrate significant overexpression of TP73-AS1 in primary GBM samples, which is particularly increased in the gCSC. More importantly, we demonstrate that TP73-AS1 comprises a prognostic biomarker in glioma and in GBM with high expression identifying patients with particularly poor prognosis. Using CRISPRi to downregulate our candidate lncRNA in gCSC, we demonstrate that TP73-AS1 promotes TMZ resistance in gCSC and is linked to regulation of the expression of metabolism- related genes and ALDH1A1, a protein known to be expressed in cancer stem cell markers and protects gCSC from TMZ treatment. Taken together, our results reveal that high TP73-AS1 predicts poor prognosis in primary GBM cohorts and that this lncRNA promotes tumor aggressiveness and TMZ resistance in gCSC.
Collapse
Affiliation(s)
- Gal Mazor
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Liron Levin
- Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Daniel Picard
- Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Germany
| | - Ulvi Ahmadov
- Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Germany
| | - Helena Carén
- Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Arndt Borkhardt
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Guido Reifenberger
- Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Gabriel Leprivier
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Marc Remke
- Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Germany
| | - Barak Rotblat
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
| |
Collapse
|
|
33
|
Fu Y, Du P, Zhao J, Hu C, Qin Y, Huang G. Gastric Cancer Stem Cells: Mechanisms and Therapeutic Approaches. Yonsei Med J 2018; 59:1150-1158. [PMID: 30450848 PMCID: PMC6240570 DOI: 10.3349/ymj.2018.59.10.1150] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/11/2018] [Accepted: 10/12/2018] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC stem-like cells (GCSCs), with unlimited self-renewal, differentiation, and tumor-regenerating capacities, contribute significantly to the refractory features of GC and have gained increasing attention for their role in GC drug resistance, relapse, and metastasis. Therapies targeting GCSCs seem to be one of the most promising methods to improve the outcomes of GC patients. Extensive investigations have attempted to outline the regulatory mechanisms in GCSCs and to develop GCSCs-targeting therapies with which to diminish GC drug resistance, metastasis and relapse. To the best of our knowledge, there is a lack of reviews summarizing these studies. In this review, we systematically recapitulated findings regarding the regulatory mechanisms of GCSCs, as well as therapies that target GCSCs, hoping to support the development of prognostic biomarkers and GCSCs-targeting anticancer therapies in GC.
Collapse
Affiliation(s)
- Yan Fu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Peizhun Du
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Cheng'en Hu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yunyun Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Guangjian Huang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
34
|
Tumour heterogeneity and metastasis at single-cell resolution. Nat Cell Biol 2018; 20:1349-1360. [PMID: 30482943 DOI: 10.1038/s41556-018-0236-7] [Citation(s) in RCA: 399] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/24/2018] [Indexed: 02/07/2023]
Abstract
Tumours comprise a heterogeneous collection of cells with distinct genetic and phenotypic properties that can differentially promote progression, metastasis and drug resistance. Emerging single-cell technologies provide a new opportunity to profile individual cells within tumours and investigate what roles they play in these processes. This Review discusses key technological considerations for single-cell studies in cancer, new findings using single-cell technologies and critical open questions for future applications.
Collapse
|
|
35
|
Paul MS, Dutta D, Singh A, Mutsuddi M, Mukherjee A. Regulation of Notch signaling in the developing
Drosophila
eye by a T‐box containing transcription factor, Dorsocross. Genesis 2018; 56:e23251. [DOI: 10.1002/dvg.23251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 09/11/2018] [Accepted: 09/16/2018] [Indexed: 12/29/2022]
Affiliation(s)
- Maimuna S. Paul
- Department of Molecular and Human GeneticsBanaras Hindu University Varanasi India
| | - Debdeep Dutta
- Department of Molecular and Human GeneticsBanaras Hindu University Varanasi India
| | - Ankita Singh
- Department of Molecular and Human GeneticsBanaras Hindu University Varanasi India
| | - Mousumi Mutsuddi
- Department of Molecular and Human GeneticsBanaras Hindu University Varanasi India
| | - Ashim Mukherjee
- Department of Molecular and Human GeneticsBanaras Hindu University Varanasi India
| |
Collapse
|
|
36
|
Li Y, Wu L, Yu M, Yang F, Wu B, Lu S, Tu M, Xu H. HIF-1α is Critical for the Activation of Notch Signaling in Neurogenesis During Acute Epilepsy. Neuroscience 2018; 394:206-219. [PMID: 30394322 DOI: 10.1016/j.neuroscience.2018.10.037] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 09/30/2018] [Accepted: 10/22/2018] [Indexed: 01/01/2023]
Abstract
Emerging evidence suggests that hypoxia-inducible factors (specifically, HIF-1α) and Notch signaling are involved in epileptogenesis and that cross-coupling exists between HIF-1α and Notch signaling in other diseases, including tumors and ischemia. However, the exact molecular mechanisms by which HIF-1α and Notch signaling affect the development of epilepsy, especially regarding neurogenesis, remain unclear. In the present study, we investigated the role of HIF-1α in neurogenesis and whether Notch signaling is involved in this process during epileptogenesis by assessing hippocampal apoptosis, neuronal injury, and the proliferation and differentiation of neural stem cells (NSCs) in four groups, including control, epilepsy, epilepsy+2-methoxyestradiol (2ME2) and epilepsy+GSI-IX (DAPT) groups. Our data demonstrated that HIF-1α mediated neurogenesis during acute epilepsy, which required the participation of Notch signaling. The immunoprecipitation data illustrated that HIF-1α activated Notch signaling by physically interacting with the Notch intracellular domain (NICD) in epilepsy. In conclusion, our results suggested that HIF-1α-Notch signaling enhanced neurogenesis in acute epilepsy and that neurogenesis during epileptogenesis was reduced once this pathway was blocked; thus, members of this pathway might be potential therapeutic targets for epilepsy.
Collapse
Affiliation(s)
- Yushuang Li
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
| | - Lei Wu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
| | - Minhua Yu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
| | - Fei Yang
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
| | - Bo Wu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
| | - Shuting Lu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
| | - Mengqi Tu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
| | - Haibo Xu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China.
| |
Collapse
|
|
37
|
Association of Notch-1, osteopontin and stem-like cells in ENU-glioma malignant process. Oncotarget 2018; 9:31330-31341. [PMID: 30140373 PMCID: PMC6101132 DOI: 10.18632/oncotarget.25808] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Accepted: 07/12/2018] [Indexed: 12/13/2022] Open
Abstract
Notch-1 and osteopontin (OPN) mediate angiogenesis and glioma stem-like cell (GSLC) maintenance. However, the relationship between these molecules and GSLCs during the development of glioma is unknown. We investigate the expression of Notch-1, OPN and vascular endothelial growth factor (VEGF) associated to the stemness markers nestin and CD133 in three stages of murine gliomas induced by N-ethyl-N-nitrosourea (ENU). Notch-1 and OPN overexpress in the intermediate stage (II), which corresponds to the "angiogenesis switch". Nestin+ cells appear in all stages of ENU-glioma but CD133 only from stage II on. In stage III, neoplastic cells expressing nestin, CD133 and nestin/CD133 reside in spheroid-like aggregates (SAs) and in the neoangiogenic border. These aggregates show Notch-1 and VEGF+ surrounding cells and a significant size and density increase with respect to stage I (3.3 ± 1.5 to 22.4 ± 6.3 µm2, n° = 0.3 ± 0.1 to 4.2 ± 0.9, from stage I to stage III, respectively). OPN expression increases in correlation to the glioma malignancy from 4.5 ± 1.8% (I) to 12.3 ± 1.2% of OPN+ cells (III). It predominates in astrocyte-like cells of the neoangiogenic border, displaying co-location with VEGF and CD133. The OPN immunopositivity distribution correlates with the CD133 distribution. In conclusion, OPN co-expressing with CD133 contributes to the identification of GSLCs in the neoangiogenic border, while Notch-1 is present around SAs in advanced stages. The ENU-glioma, mainly in stage II, is a useful tool for assessing new antitumour therapies against these molecules.
Collapse
|
|
38
|
Notch signaling promotes a HIF2α-driven hypoxic response in multiple tumor cell types. Oncogene 2018; 37:6083-6095. [PMID: 29993038 PMCID: PMC6237764 DOI: 10.1038/s41388-018-0400-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 05/07/2018] [Accepted: 06/12/2018] [Indexed: 01/16/2023]
Abstract
Hyperactivation of Notch signaling and the cellular hypoxic response are frequently observed in cancers, with increasing reports of connections to tumor initiation and progression. The two signaling mechanisms are known to intersect, but while it is well established that hypoxia regulates Notch signaling, less is known about whether Notch can regulate the cellular hypoxic response. We now report that Notch signaling specifically controls expression of HIF2α, a key mediator of the cellular hypoxic response. Transcriptional upregulation of HIF2α by Notch under normoxic conditions leads to elevated HIF2α protein levels in primary breast cancer cells as well as in human breast cancer, medulloblastoma, and renal cell carcinoma cell lines. The elevated level of HIF2α protein was in certain tumor cell types accompanied by downregulation of HIF1α protein levels, indicating that high Notch signaling may drive a HIF1α-to-HIF2α switch. At the transcriptome level, the presence of HIF2α was required for approximately 21% of all Notch-induced genes: among the 1062 genes that were upregulated by Notch in medulloblastoma cells during normoxia, upregulation was abrogated in 227 genes when HIF2α expression was knocked down by HIF2α siRNA. In conclusion, our data show that Notch signaling affects the hypoxic response via regulation of HIF2α, which may be important for future cancer therapies.
Collapse
|
|
39
|
Aulestia FJ, Néant I, Dong J, Haiech J, Kilhoffer MC, Moreau M, Leclerc C. Quiescence status of glioblastoma stem-like cells involves remodelling of Ca 2+ signalling and mitochondrial shape. Sci Rep 2018; 8:9731. [PMID: 29950651 PMCID: PMC6021377 DOI: 10.1038/s41598-018-28157-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 06/14/2018] [Indexed: 12/31/2022] Open
Abstract
Quiescence is a reversible cell-cycle arrest which allows cancer stem-like cells to evade killing following therapies. Here, we show that proliferating glioblastoma stem-like cells (GSLCs) can be induced and maintained in a quiescent state by lowering the extracellular pH. Through RNAseq analysis we identified Ca2+ signalling genes differentially expressed between proliferating and quiescent GSLCs. Using the bioluminescent Ca2+ reporter EGFP-aequorin we observed that the changes in Ca2+ homeostasis occurring during the switch from proliferation to quiescence are controlled through store-operated channels (SOC) since inhibition of SOC drives proliferating GSLCs to quiescence. We showed that this switch is characterized by an increased capacity of GSLCs’ mitochondria to capture Ca2+ and by a dramatic and reversible change of mitochondrial morphology from a tubular to a donut shape. Our data suggest that the remodelling of the Ca2+ homeostasis and the reshaping of mitochondria might favours quiescent GSLCs’ survival and their aggressiveness in glioblastoma.
Collapse
Affiliation(s)
- Francisco J Aulestia
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, F-31062, Toulouse, France
| | - Isabelle Néant
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, F-31062, Toulouse, France
| | - Jihu Dong
- Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000, Strasbourg, France
| | - Jacques Haiech
- Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000, Strasbourg, France
| | - Marie-Claude Kilhoffer
- Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000, Strasbourg, France
| | - Marc Moreau
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, F-31062, Toulouse, France
| | - Catherine Leclerc
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, F-31062, Toulouse, France.
| |
Collapse
|
|
40
|
Rivero-Hinojosa S, Lau LS, Stampar M, Staal J, Zhang H, Gordish-Dressman H, Northcott PA, Pfister SM, Taylor MD, Brown KJ, Rood BR. Proteomic analysis of Medulloblastoma reveals functional biology with translational potential. Acta Neuropathol Commun 2018; 6:48. [PMID: 29880060 PMCID: PMC5992829 DOI: 10.1186/s40478-018-0548-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 05/17/2018] [Indexed: 12/14/2022] Open
Abstract
Genomic characterization has begun to redefine diagnostic classifications of cancers. However, it remains a challenge to infer disease phenotypes from genomic alterations alone. To help realize the promise of genomics, we have performed a quantitative proteomics investigation using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and 41 tissue samples spanning the 4 genomically based subgroups of medulloblastoma and control cerebellum. We have identified and quantitated thousands of proteins across these groups and find that we are able to recapitulate the genomic subgroups based upon subgroup restricted and differentially abundant proteins while also identifying subgroup specific protein isoforms. Integrating our proteomic measurements with genomic data, we calculate a poor correlation between mRNA and protein abundance. Using EPIC 850 k methylation array data on the same tissues, we also investigate the influence of copy number alterations and DNA methylation on the proteome in an attempt to characterize the impact of these genetic features on the proteome. Reciprocally, we are able to use the proteome to identify which genomic alterations result in altered protein abundance and thus are most likely to impact biology. Finally, we are able to assemble protein-based pathways yielding potential avenues for clinical intervention. From these, we validate the EIF4F cap-dependent translation pathway as a novel druggable pathway in medulloblastoma. Thus, quantitative proteomics complements genomic platforms to yield a more complete understanding of functional tumor biology and identify novel therapeutic targets for medulloblastoma.
Collapse
|
|
41
|
Abstract
The concept that progression of cancer is regulated by interactions of cancer cells with their microenvironment was postulated by Stephen Paget over a century ago. Contemporary tumour microenvironment (TME) research focuses on the identification of tumour-interacting microenvironmental constituents, such as resident or infiltrating non-tumour cells, soluble factors and extracellular matrix components, and the large variety of mechanisms by which these constituents regulate and shape the malignant phenotype of tumour cells. In this Timeline article, we review the developmental phases of the TME paradigm since its initial description. While illuminating controversies, we discuss the importance of interactions between various microenvironmental components and tumour cells and provide an overview and assessment of therapeutic opportunities and modalities by which the TME can be targeted.
Collapse
Affiliation(s)
- Shelly Maman
- Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Isaac P Witz
- Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
| |
Collapse
|
|
42
|
Wei ZZ, Zhu YB, Zhang JY, McCrary MR, Wang S, Zhang YB, Yu SP, Wei L. Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy. Chin Med J (Engl) 2018; 130:2361-2374. [PMID: 28937044 PMCID: PMC5634089 DOI: 10.4103/0366-6999.215324] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. Data Sources: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: “stem cells,” “hypoxic preconditioning,” “ischemic preconditioning,” and “cell transplantation.” Study Selection: Original articles and critical reviews on the topics were selected. Results: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. Conclusions: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.
Collapse
Affiliation(s)
- Zheng Z Wei
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Yan-Bing Zhu
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - James Y Zhang
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Myles R McCrary
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Song Wang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Yong-Bo Zhang
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shan-Ping Yu
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Ling Wei
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University; Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| |
Collapse
|
|
43
|
Glioblastoma niches: from the concept to the phenotypical reality. Neurol Sci 2018; 39:1161-1168. [PMID: 29736738 DOI: 10.1007/s10072-018-3408-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 04/05/2018] [Indexed: 12/24/2022]
Abstract
Recently, the concept of niches as sites of tumor progression, invasion, and angiogenesis in glioblastoma (GB) has been extensively debated. Niches, considered the sites in which glioblastoma stem cells (GSCs) reside, have been classified as perivascular, perinecrotic, and invasive. However, from a neuropathological point of view, it is not easy to establish when a tumor structure can be considered a niche. The relevant literature has been reviewed in the light of our recent experience on the subject. As for perinecrotic niches, the occurrence of GSCs around necrosis is interpreted as triggered by hypoxia through HIF-1α. Our alternative hypothesis is that, together with progenitors, they are the cell constituents of hyper-proliferative areas of GB, where perinecrotic niches have developed, and they would, therefore, represent the remnants of GSCs/progenitors spared by the developing necrosis. Perivascular structures originate from both transport vessels and exchange vessels, i.e., venules, arterioles, or the undefinable neo-formed small vessels, but only those in which a direct contact between GSCs/progenitors and endothelial cells occurs can be called niches. Both pericytes and microglia/macrophages play a role in niche function: Macrophages of blood origin invade GB only after the appearance of "mother vessels" with consequent blood-brain barrier disruption. Not all vessel/tumor cell structures can be considered niches, that is, crucial sites of tumor progression, invasion, and angiogenesis.
Collapse
|
|
44
|
Hira VV, Aderetti DA, van Noorden CJ. Glioma Stem Cell Niches in Human Glioblastoma Are Periarteriolar. J Histochem Cytochem 2018; 66:349-358. [PMID: 29328867 PMCID: PMC5958355 DOI: 10.1369/0022155417752676] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 12/11/2017] [Indexed: 12/22/2022] Open
Abstract
Survival of primary brain tumor (glioblastoma) patients is seriously hampered by glioma stem cells (GSCs) that are distinct therapy-resistant self-replicating pluripotent cancer cells. GSCs reside in GSC niches, which are specific protective microenvironments in glioblastoma tumors. We have recently found that GSC niches are hypoxic periarteriolar, whereas in most studies, GSC niches are identified as hypoxic perivascular. The aim of this review is to critically evaluate the literature on perivascular GSC niches to establish whether these are periarteriolar, pericapillary, perivenular, and/or perilymphatic. We found six publications showing images of human glioblastoma tissue containing perivascular GSC niches without any specification of the vessel type. However, it is frequently assumed that these vessels are capillaries which are exchange vessels, whereas arterioles and venules are transport vessels. Closer inspection of the figures of these publications showed vessels that were not capillaries. Whether these vessels were arterioles or venules was difficult to determine in one case, but in the other cases, these were clearly arterioles and their perivascular niches were similar to the periarteriolar niches we have found. Therefore, we conclude that in human glioblastoma tumors, GSC niches are hypoxic periarteriolar and are structurally and functionally look-alikes of hematopoietic stem cell niches in the bone marrow.
Collapse
Affiliation(s)
- Vashendriya V.V. Hira
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Diana A. Aderetti
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis J.F. van Noorden
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
45
|
Carballo GB, Honorato JR, de Lopes GPF, Spohr TCLDSE. A highlight on Sonic hedgehog pathway. Cell Commun Signal 2018; 16:11. [PMID: 29558958 PMCID: PMC5861627 DOI: 10.1186/s12964-018-0220-7] [Citation(s) in RCA: 312] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/16/2018] [Indexed: 12/25/2022] Open
Abstract
Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. It is already known that Sonic hedgehog (Shh) pathway is important for the evolution of radio and chemo-resistance of several types of tumors. Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. So, a better knowledge of the Shh pathway opens an opportunity for targeted therapies against brain tumors considering a multi-factorial molecular overview. Therefore, emerging studies are being conducted in order to find new inhibitors for Shh signaling pathway, which could be safely used in clinical trials. Shh can signal through a canonical and non-canonical way, and it also has important points of interaction with other pathways during brain tumorigenesis. So, a better knowledge of Shh signaling pathway opens an avenue of possibilities for the treatment of not only for brain tumors but also for other types of cancers. In this review, we will also highlight some clinical trials that use the Shh pathway as a target for treating brain cancer.
Collapse
Affiliation(s)
- Gabriela Basile Carballo
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.,Programa de Pós-Gradução em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jéssica Ribeiro Honorato
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.,Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), RJ, Brazil.,Programa de Pós-Gradução em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Giselle Pinto Farias de Lopes
- Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), RJ, Brazil
| | - Tania Cristina Leite de Sampaio E Spohr
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.
| |
Collapse
|
|
46
|
Li L, Ren F, Qi C, Xu L, Fang Y, Liang M, Feng J, Chen B, Ning W, Cao J. Intermittent hypoxia promotes melanoma lung metastasis via oxidative stress and inflammation responses in a mouse model of obstructive sleep apnea. Respir Res 2018; 19:28. [PMID: 29433520 PMCID: PMC5809953 DOI: 10.1186/s12931-018-0727-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 01/23/2018] [Indexed: 12/23/2022] Open
Abstract
Background Recently, increased tumor incidence and cancer-related mortality have been reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), the hallmark feature of OSA, contributes to the metastasis of tumors. However, the molecular mechanisms by which tumor metastasis is accelerated by OSA-like IH remain to be elucidated. Methods C57BL/6 J male mice were subjected to intravenous injection of B16F10 melanoma cells before receiving IH treatment. Then, the animals were randomly distributed into three groups (n = 8 each): normoxia (N) group, IH group, and antioxidant tempol group (IHT, exposed to IH after treatment with tempol). After the mice were sacrificed, the number and weight of lung metastatic colonies were assessed. The lung tissues with tumor metastasis were analyzed for markers of oxidative stress and inflammation and for HIF-1α using western blotting and real-time PCR (qRT-PCR). The level of reactive oxygen species (ROS) in B16F10 cell was also assessed after N, IH and IH with tempol treatments. Results Compared with normoxia, IH significantly increased the number and weight of mouse lung metastatic colonies. Treatment of B16F10 cells with IH significantly enhanced ROS generation. Lung tissues with tumor metastasis provided evidence of increased oxidative stress, as assessed by p22phox and SOD mRNA levels and the NRF2 protein level, as well as increased inflammation, as assessed by TNF-α and IL-6 mRNA levels and the NF-κB P65 protein level. HIF-1α protein levels were increased in response to IH treatment. Tempol, an important antioxidant, ameliorated IH-induced melanoma lung metastasis in mice and reduced oxidative stress and inflammation responses. Conclusions These results support the hypothesis that oxidative stress and inflammation responses play an important role in the pathogenesis of OSA-like IH-induced melanoma lung metastasis in mice. Antioxidant intervention provides a novel strategy for the prevention and treatment of cancer in OSA populations.
Collapse
Affiliation(s)
- Lian Li
- Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Fangyuan Ren
- Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Chao Qi
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Leiqian Xu
- Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Yinshan Fang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Maoli Liang
- Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing Feng
- Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Baoyuan Chen
- Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Wen Ning
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
| | - Jie Cao
- Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China.
| |
Collapse
|
|
47
|
A Microdevice Platform Recapitulating Hypoxic Tumor Microenvironments. Sci Rep 2017; 7:15233. [PMID: 29123197 PMCID: PMC5680268 DOI: 10.1038/s41598-017-15583-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 10/30/2017] [Indexed: 12/19/2022] Open
Abstract
Hypoxia plays a central role in cancer progression and resistance to therapy. We have engineered a microdevice platform to recapitulate the intratumor oxygen gradients that drive the heterogeneous hypoxic landscapes in solid tumors. Our design features a "tumor section"-like culture by incorporating a cell layer between two diffusion barriers, where an oxygen gradient is established by cellular metabolism and physical constraints. We confirmed the oxygen gradient by numerical simulation and imaging-based oxygen sensor measurement. We also demonstrated spatially-resolved hypoxic signaling in cancer cells through immunostaining, gene expression assay, and hypoxia-targeted drug treatment. Our platform can accurately generate and control oxygen gradients, eliminates complex microfluidic handling, allows for incorporation of additional tumor components, and is compatible with high-content imaging and high-throughput applications. It is well suited for understanding hypoxia-mediated mechanisms in cancer disease and other biological processes, and discovery of new therapeutics.
Collapse
|
|
48
|
Pistollato F, Calderón Iglesias R, Ruiz R, Aparicio S, Crespo J, Dzul Lopez L, Giampieri F, Battino M. The use of natural compounds for the targeting and chemoprevention of ovarian cancer. Cancer Lett 2017; 411:191-200. [PMID: 29017913 DOI: 10.1016/j.canlet.2017.09.050] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 09/25/2017] [Accepted: 09/25/2017] [Indexed: 12/21/2022]
Abstract
Among gynaecological cancers, ovarian cancer represents the leading cause of death in women. Current treatment for ovarian cancer entails surgery followed by combined chemotherapy with platinum and taxane, which are associated, particularly cisplatin, with severe side effects. While this treatment approach appears to be initially effective in a high number of patients, nearly 70% of them suffer a relapse within a few months after initial treatment. Therefore, more effective and better-tolerated treatment options are clearly needed. In recent years, several natural compounds (such as curcumin, epigallocatechin 3-gallate (EGCG), resveratrol, sulforaphane and Withaferin-A), characterized by long-term safety and negligible and/or inexistent side effects, have been proposed as possible adjuvants of traditional chemotherapy. Indeed, several in vitro and in vivo studies have shown that phytocompounds can effectively inhibit tumor cell proliferation, stimulate autophagy, induce apoptosis, and specifically target ovarian cancer stem cells (CSCs), which are generally considered to be responsible for tumor recurrence in several types of cancer. Here we review current literature on the role of natural products in ovarian cancer chemoprevention, highlighting their effects particularly on the regulation of inflammation, autophagy, proliferation and apoptosis, chemotherapy resistance, and ovarian CSC growth.
Collapse
Affiliation(s)
- Francesca Pistollato
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | | | - Roberto Ruiz
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | - Silvia Aparicio
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | - Jorge Crespo
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | - Luis Dzul Lopez
- Universidad Internacional Iberoamericana (UNINI), Campeche, Mexico
| | - Francesca Giampieri
- Dipartimento di Scienze Cliniche Specialistiche Ed Odontostomatologiche, Sez. Biochimica, Università Politecnica Delle Marche, Ancona, Italy.
| | - Maurizio Battino
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain; Dipartimento di Scienze Cliniche Specialistiche Ed Odontostomatologiche, Sez. Biochimica, Università Politecnica Delle Marche, Ancona, Italy.
| |
Collapse
|
|
49
|
Han N, Hu G, Shi L, Long G, Yang L, Xi Q, Guo Q, Wang J, Dong Z, Zhang M. Notch1 ablation radiosensitizes glioblastoma cells. Oncotarget 2017; 8:88059-88068. [PMID: 29152141 PMCID: PMC5675693 DOI: 10.18632/oncotarget.21409] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 09/04/2017] [Indexed: 11/25/2022] Open
Abstract
Broad specific Notch1 inhibitors suppress glioblastoma multiforme (GBM) growth but have significant gastrointestinal toxicities. Here, we examined Notch1 expression in GBM tissue specimens and its correlation with the overall survival (OS) of GBM patients. Furthermore, using the CRISPR/Cas9 system, we investigated the effects of Notch1 downregulation on clonogenic growth and angiogenesis of GBM cells and xenografts. Immunohistochemistry showed positive Notch1 expression in 71% (49/69) of GBM tissues. Our multivariate Cox regression analysis further revealed that Notch1 expression was an independent adverse prognostic factor for OS. Notch1 downregulation suppressed the growth of GBM cells U87MG and U251. The mean duration to reach 6 x the starting volume was 18.3 days for xenografts with Notch1 downregulation and 13.4 days for the control xenografts. Immunofluorescent staining further disclosed that Notch1 downregulation markedly increased the number of γH2AX foci and radiosensitized GBM cells. Notch1 downregulation also impaired angiogenesis and attenuated VEGF and hypoxic response to irradiation in xenografts. In conclusion, Notch1 ablation inhibited GBM cell proliferation and neovascularization and radiosensitized GBM cells and xenografts, suggesting a pivotal role of Notch1 in tumor growth, angiogenesis, and radioresistance in GBM.
Collapse
Affiliation(s)
- Na Han
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Guangyuan Hu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Lei Shi
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Guoxian Long
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Lin Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Qingsong Xi
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Qiuyun Guo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Jianhua Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Zhen Dong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Mengxian Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| |
Collapse
|
|
50
|
Aghazadeh S, Yazdanparast R. Activation of STAT3/HIF-1α/Hes-1 axis promotes trastuzumab resistance in HER2-overexpressing breast cancer cells via down-regulation of PTEN. Biochim Biophys Acta Gen Subj 2017; 1861:1970-1980. [DOI: 10.1016/j.bbagen.2017.05.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 04/22/2017] [Accepted: 05/08/2017] [Indexed: 01/13/2023]
|