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Trojan A, Lone YC, Briceno I, Trojan J. Anti-Gene IGF-I Vaccines in Cancer Gene Therapy: A Review of a Case of Glioblastoma. Curr Med Chem 2024; 31:1983-2002. [PMID: 38031775 DOI: 10.2174/0109298673237968231106095141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 06/27/2023] [Accepted: 10/10/2023] [Indexed: 12/01/2023]
Abstract
OBJECTIVE Vaccines for the deadliest brain tumor - glioblastoma (GBM) - are generally based on targeting growth factors or their receptors, often using antibodies. The vaccines described in the review were prepared to suppress the principal cancer growth factor - IGF-I, using anti-gene approaches either of antisense (AS) or of triple helix (TH) type. Our objective was to increase the median survival of patients treated with AS and TH cell vaccines. METHODOLOGY The cells were transfected in vitro by both constructed IGF-I AS and IGF-I TH expression episomal vectors; part of these cells was co-cultured with plant phytochemicals, modulating IGF-I expression. Both AS and TH approaches completely suppressed IGF-I expression and induced MHC-1 / B7 immunogenicity related to the IGF-I receptor signal. RESULTS This immunogenicity proved to be stronger in IGF-I TH than in IGF-I AS-prepared cell vaccines, especially in TH / phytochemical cells. The AS and TH vaccines generated an important TCD8+ and TCD8+CD11b- immune response in treated GBM patients and increased the median survival of patients up to 17-18 months, particularly using TH vaccines; in some cases, 2- and 3-year survival was reported. These clinical results were compared with those obtained in therapies targeting other growth factors. CONCLUSION The anti-gene IGF-I vaccines continue to be applied in current GBM personalized medicine. Technical improvements in the preparation of AS and TH vaccines to increase MHC-1 and B7 immunogenicity have, in parallel, allowed to increase in the median survival of patients.
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Affiliation(s)
- Annabelle Trojan
- INSERM UMR 1197, Cancer Center & University of Paris / Saclay, PO Box: 94802 Villejuif, France
- Faculty of Medicine, University of Cartagena, PO Box: 130014 Cartagena de Indias, Colombia
| | - Yu-Chun Lone
- INSERM UMR 1197, Cancer Center & University of Paris / Saclay, PO Box: 94802 Villejuif, France
- CEDEA / ICGT - Center of Oncological Diseases Diagnosis, PO Box: 110231 Bogota, Colombia
| | - Ignacio Briceno
- Faculty of Medicine, University of La Sabana, PO Box: 250008 Chia, Colombia
| | - Jerzy Trojan
- INSERM UMR 1197, Cancer Center & University of Paris / Saclay, PO Box: 94802 Villejuif, France
- CEDEA / ICGT - Center of Oncological Diseases Diagnosis, PO Box: 110231 Bogota, Colombia
- National Academy of Medicine - ANM, PO Box: 75272 Paris, France
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Macvanin M, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER. New insights on the cardiovascular effects of IGF-1. Front Endocrinol (Lausanne) 2023; 14:1142644. [PMID: 36843588 PMCID: PMC9947133 DOI: 10.3389/fendo.2023.1142644] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023] Open
Abstract
INTRODUCTION Cardiovascular (CV) disorders are steadily increasing, making them the world's most prevalent health issue. New research highlights the importance of insulin-like growth factor 1 (IGF-1) for maintaining CV health. METHODS We searched PubMed and MEDLINE for English and non-English articles with English abstracts published between 1957 (when the first report on IGF-1 identification was published) and 2022. The top search terms were: IGF-1, cardiovascular disease, IGF-1 receptors, IGF-1 and microRNAs, therapeutic interventions with IGF-1, IGF-1 and diabetes, IGF-1 and cardiovascular disease. The search retrieved original peer-reviewed articles, which were further analyzed, focusing on the role of IGF-1 in pathophysiological conditions. We specifically focused on including the most recent findings published in the past five years. RESULTS IGF-1, an anabolic growth factor, regulates cell division, proliferation, and survival. In addition to its well-known growth-promoting and metabolic effects, there is mounting evidence that IGF-1 plays a specialized role in the complex activities that underpin CV function. IGF-1 promotes cardiac development and improves cardiac output, stroke volume, contractility, and ejection fraction. Furthermore, IGF-1 mediates many growth hormones (GH) actions. IGF-1 stimulates contractility and tissue remodeling in humans to improve heart function after myocardial infarction. IGF-1 also improves the lipid profile, lowers insulin levels, increases insulin sensitivity, and promotes glucose metabolism. These findings point to the intriguing medicinal potential of IGF-1. Human studies associate low serum levels of free or total IGF-1 with an increased risk of CV and cerebrovascular illness. Extensive human trials are being conducted to investigate the therapeutic efficacy and outcomes of IGF-1-related therapy. DISCUSSION We anticipate the development of novel IGF-1-related therapy with minimal side effects. This review discusses recent findings on the role of IGF-1 in the cardiovascular (CVD) system, including both normal and pathological conditions. We also discuss progress in therapeutic interventions aimed at targeting the IGF axis and provide insights into the epigenetic regulation of IGF-1 mediated by microRNAs.
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Affiliation(s)
- Mirjana Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Clinic for Internal Medicine, Department of Endocrinology and Diabetes, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Magbubah Essack
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Xin Gao
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Werner H, LeRoith D. Hallmarks of cancer: The insulin-like growth factors perspective. Front Oncol 2022; 12:1055589. [PMID: 36479090 PMCID: PMC9720135 DOI: 10.3389/fonc.2022.1055589] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/07/2022] [Indexed: 08/30/2023] Open
Abstract
The identification of a series of attributes or hallmarks that are shared by virtually all cancer cells constitutes a true milestone in cancer research. The conceptualization of a catalogue of common genetic, molecular, biochemical and cellular events under a unifying Hallmarks of Cancer idea had a major impact in oncology. Furthermore, the fact that different types of cancer, ranging from pediatric tumors and leukemias to adult epithelial cancers, share a large number of fundamental traits reflects the universal nature of the biological events involved in oncogenesis. The dissection of a complex disease like cancer into a finite directory of hallmarks is of major basic and translational relevance. The role of insulin-like growth factor-1 (IGF1) as a progression/survival factor required for normal cell cycle transition has been firmly established. Similarly well characterized are the biochemical and cellular activities of IGF1 and IGF2 in the chain of events leading from a phenotypically normal cell to a diseased one harboring neoplastic traits, including growth factor independence, loss of cell-cell contact inhibition, chromosomal abnormalities, accumulation of mutations, activation of oncogenes, etc. The purpose of the present review is to provide an in-depth evaluation of the biology of IGF1 at the light of paradigms that emerge from analysis of cancer hallmarks. Given the fact that the IGF1 axis emerged in recent years as a promising therapeutic target, we believe that a careful exploration of this signaling system might be of critical importance on our ability to design and optimize cancer therapies.
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Affiliation(s)
- Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Sahu U, Barth RF, Otani Y, McCormack R, Kaur B. Rat and Mouse Brain Tumor Models for Experimental Neuro-Oncology Research. J Neuropathol Exp Neurol 2022; 81:312-329. [PMID: 35446393 PMCID: PMC9113334 DOI: 10.1093/jnen/nlac021] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Rodent brain tumor models have been useful for developing effective therapies for glioblastomas (GBMs). In this review, we first discuss the 3 most commonly used rat brain tumor models, the C6, 9L, and F98 gliomas, which are all induced by repeated injections of nitrosourea to adult rats. The C6 glioma arose in an outbred Wistar rat and its potential to evoke an alloimmune response is a serious limitation. The 9L gliosarcoma arose in a Fischer rat and is strongly immunogenic, which must be taken into consideration when using it for therapy studies. The F98 glioma may be the best of the 3 but it does not fully recapitulate human GBMs because it is weakly immunogenic. Next, we discuss a number of mouse models. The first are human patient-derived xenograft gliomas in immunodeficient mice. These have failed to reproduce the tumor-host interactions and microenvironment of human GBMs. Genetically engineered mouse models recapitulate the molecular alterations of GBMs in an immunocompetent environment and “humanized” mouse models repopulate with human immune cells. While the latter are rarely isogenic, expensive to produce, and challenging to use, they represent an important advance. The advantages and limitations of each of these brain tumor models are discussed. This information will assist investigators in selecting the most appropriate model for the specific focus of their research.
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Affiliation(s)
- Upasana Sahu
- From the Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Rolf F Barth
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Yoshihiro Otani
- From the Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Ryan McCormack
- From the Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Balveen Kaur
- From the Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
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5
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Lipopeptides in promoting signals at surface/interface of micelles: Their roles in repairing cellular and nuclear damages. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2021.101522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Samani AA, Nalbantoglu J, Brodt P. Glioma Cells With Genetically Engineered IGF-I Receptor Downregulation Can Persist in the Brain in a Dormant State. Front Oncol 2020; 10:555945. [PMID: 33072581 PMCID: PMC7539665 DOI: 10.3389/fonc.2020.555945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 08/24/2020] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma multiforme is an aggressive malignancy, resistant to standard treatment modalities and associated with poor prognosis. We analyzed the role of the IGF system in intracerebral glioma growth using human and rat glioma cells. The glioma cells C6 and U87MG were transduced with a genetically engineered retrovirus expressing type 1 insulin-like growth factor (IGF-IR) antisense RNA, either before or after intra-cerebral implantation of the cells into Sprague Dawley rats or nude mice, respectively and tumor growth and animal survival were monitored. Rat glioma cells transduced prior to orthotopic, intra-cerebral implantation had a significantly increased apoptotic rate in vivo and a significantly reduced tumor volume as seen 24 days post implantation (p < 0.0015). This resulted in increased survival, as greater than 70% of the rats were still alive 182 days after tumor implantation (p < 0.01), as compared to 80% mortality by day 24 in the control group. Histomorphology and histochemical studies performed on brain tissue that was obtained from rats that survived for 182 days revealed numerous single cells that were widely disseminated throughout the brain. These cells expressed the β-galactosidase marker protein, but were Ki67negative, suggesting that they acquired a dormant phenotype. Direct targeting of the C6 cells with retroviral particles in vivo was effective and reduced tumor volumes by 22% relative to controls. A significant effect on tumor growth was also seen with human glioma U87MG cells that were virally transduced and implanted intra-cerebrally in nude mice. We observed in these mice a significant reduction in tumor volumes and 70% of the animals were still alive 6 months after tumor implantation, as compared to 100% mortality in the control group by day 63. Our results show that IGF-IR targeting can inhibit the intracerebral growth of glioma cells. They also suggest that IGF-IR expression levels may determine a delicate balance between glioma cell growth, death and the acquisition of a dormant state in the brain.
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Affiliation(s)
- Amir A Samani
- Department of Medicine, McGill University, Montreal, QC, Canada
| | - Josephine Nalbantoglu
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Pnina Brodt
- Department of Medicine, McGill University, Montreal, QC, Canada.,Department of Surgery, McGill University, Montreal, QC, Canada.,Department of Oncology, McGill University, Montreal, QC, Canada.,The Research Institute of the McGill University Health Center, Montreal, QC, Canada
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Zheng T, Wang W, Ashley J, Zhang M, Feng X, Shen J, Sun Y. Self-Assembly Protein Superstructures as a Powerful Chemodynamic Therapy Nanoagent for Glioblastoma Treatment. NANO-MICRO LETTERS 2020; 12:151. [PMID: 34138164 PMCID: PMC7770858 DOI: 10.1007/s40820-020-00490-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/18/2020] [Indexed: 06/12/2023]
Abstract
Glioblastoma (GBM) remains a formidable challenge in oncology. Chemodynamic therapy (CDT) that triggers tumor cell death by reactive oxygen species (ROS) could open up a new door for GBM treatment. Herein, we report a novel CDT nanoagent. Hemoglobin (Hb) and glucose oxidase (GOx) were employed as powerful CDT catalysts. Instead of encapsulating the proteins in drug delivery nanocarriers, we formulate multimeric superstructures as self-delivery entities by crosslinking techniques. Red blood cell (RBC) membranes are camouflaged on the protein superstructures to promote the delivery across blood-brain barrier. The as-prepared RBC@Hb@GOx nanoparticles (NPs) offer superior biocompatibility, simplified structure, and high accumulation at the tumor site. We successfully demonstrated that the NPs could efficiently produce toxic ROS to kill U87MG cancer cells in vitro and inhibit the growth of GBM tumor in vivo, suggesting that the new CDT nanoagent holds great promise for treating GBM.
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Affiliation(s)
- Tao Zheng
- Department of Health Technology, Technical University of Denmark, 2800, Kongens Lyngby, Denmark.
| | - Wentao Wang
- Department of Health Technology, Technical University of Denmark, 2800, Kongens Lyngby, Denmark
| | - Jon Ashley
- Department of Health Technology, Technical University of Denmark, 2800, Kongens Lyngby, Denmark
| | - Ming Zhang
- Department of Health Technology, Technical University of Denmark, 2800, Kongens Lyngby, Denmark.
| | - Xiaotong Feng
- Department of Health Technology, Technical University of Denmark, 2800, Kongens Lyngby, Denmark
| | - Jian Shen
- Jiangsu Collaborative Innovation Center for Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, People's Republic of China
- Key Laboratory of High Performance Polymer Material and Technology of Ministry of Education, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, People's Republic of China
| | - Yi Sun
- Department of Health Technology, Technical University of Denmark, 2800, Kongens Lyngby, Denmark.
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8
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Manipulation of Metabolic Pathways and Its Consequences for Anti-Tumor Immunity: A Clinical Perspective. Int J Mol Sci 2020; 21:ijms21114030. [PMID: 32512898 PMCID: PMC7312891 DOI: 10.3390/ijms21114030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
In the relatively short history of anti-tumor treatment, numerous medications have been developed against a variety of targets. Intriguingly, although many anti-tumor strategies have failed in their clinical trials, metformin, an anti-diabetic medication, demonstrated anti-tumor effects in observational studies and even showed its synergistic potential with immune checkpoint inhibitors (ICIs) in subsequent clinical studies. Looking back from bedside-to-bench, it may not be surprising that the anti-tumor effect of metformin derives largely from its ability to rewire aberrant metabolic pathways within the tumor microenvironment. As one of the most promising breakthroughs in oncology, ICIs were also found to exert their immune-stimulatory effects at least partly via rewiring metabolic pathways. These findings underscore the importance of correcting metabolic pathways to achieve sufficient anti-tumor immunity. Herein, we start by introducing the tumor microenvironment, and then we review the implications of metabolic syndrome and treatments for targeting metabolic pathways in anti-tumor therapies. We further summarize the close associations of certain aberrant metabolic pathways with impaired anti-tumor immunity and introduce the therapeutic effects of targeting these routes. Lastly, we go through the metabolic effects of ICIs and conclude an overall direction to manipulate metabolic pathways in favor of anti-tumor responses.
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9
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Yang S, Ou C, Wang L, Liu X, Yang J, Wang X, Wang M, Shen M, Wu Q, Gong C. Virus-esque nucleus-targeting nanoparticles deliver trojan plasmid for release of anti-tumor shuttle protein. J Control Release 2020; 320:253-264. [DOI: 10.1016/j.jconrel.2020.01.037] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/14/2020] [Accepted: 01/19/2020] [Indexed: 11/29/2022]
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10
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Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. ACTA ACUST UNITED AC 2020; 1:75-85. [DOI: 10.1038/s43018-019-0007-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/14/2019] [Indexed: 01/31/2023]
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Osher E, Macaulay VM. Therapeutic Targeting of the IGF Axis. Cells 2019; 8:E895. [PMID: 31416218 PMCID: PMC6721736 DOI: 10.3390/cells8080895] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/04/2019] [Accepted: 08/09/2019] [Indexed: 12/17/2022] Open
Abstract
The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement of IGF signaling in the pathogenesis of cancer, endocrine disorders including acromegaly, diabetes and thyroid eye disease, skin diseases such as acne and psoriasis, and the frailty that accompanies aging. We discuss the use of IGF axis inhibitors, focusing on the different approaches that have been taken to develop effective and tolerable ways to block this important signaling pathway. We outline the advantages and disadvantages of each approach, and discuss progress in evaluating these agents, including factors that contributed to the failure of many of these novel therapeutics in early phase cancer trials. Finally, we summarize grounds for cautious optimism for ongoing and future studies of IGF blockade in cancer and non-malignant disorders including thyroid eye disease and aging.
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Affiliation(s)
- Eliot Osher
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
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12
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Simpson A, Petnga W, Macaulay VM, Weyer-Czernilofsky U, Bogenrieder T. Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies. Target Oncol 2017; 12:571-597. [PMID: 28815409 PMCID: PMC5610669 DOI: 10.1007/s11523-017-0514-5] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair. Consequently, combining IGF-targeted agents with standard cytotoxic agents, other targeted agents, endocrine therapies, or immunotherapies represents an attractive therapeutic approach. Anti-IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti-proliferative activity. In addition, due to their lack of specificity, IGF-1R tyrosine kinase inhibitors are associated with hyperglycemia as a result of interference with signaling through the classical metabolic INSR-B isoform; this may preclude their use at clinically effective doses. Conversely, IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/anti-apoptotic signaling via IGF-1R and INSR-A, without compromising the metabolic function of INSR-B. Therefore, combination regimens that include these agents may be more efficacious and tolerable versus IGF-1R-targeted combinations. Herein, we review the preclinical and clinical experience with IGF-targeted therapies to-date, and discuss the rationale for future combination approaches as a means to overcome treatment resistance.
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Affiliation(s)
- Aaron Simpson
- Department of Oncology, University of Oxford, Oxford, UK
| | | | | | | | - Thomas Bogenrieder
- Boehringer Ingelheim RCV, Dr. Boehringer Gasse 5-11, 1121, Vienna, Austria.
- Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377, Munich, Germany.
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Tornatore C, Rabin S, Baker-Cairns B, Keir S, Mocchetti I. Engraftment of C6-2B Cells into the Striatum of Aci Nude Rats as a Tool for Comparison of the in Vitro and in Vivo Phenotype of a Glioma Cell Line. Cell Transplant 2017; 6:317-26. [PMID: 9171164 DOI: 10.1177/096368979700600314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The C6-2B is a well-characterized glioma cell line used extensively in the study of malignant glial biology. While the C6-2B cell line has traditionally been thought of as a homogenous cell line, the in vitro phenotype of the C6-2B cell line can vary considerably depending on the culture technique used and the stratum on which the cells are grown. Thus, we asked whether the in vitro phenotype of the C6-2B cell line was significantly different than the in vivo phenotype of the cell line once it was engrafted into the striatum of nude rats. Under culture conditions used in our laboratory, 100% of the C6 cells were found to express p75, the low-affinity nerve growth factor (NGF) receptor, and Major Histocompatability Class I (MHC Class I), while only 10-15% demonstrated vimentin reactivity. Immunohistochemistry was consistently negative for GFAP, trkA (the high-affinity receptor for NGF), CD4, CD8, and a macrophage specific marker (Ox-41). Once engrafted into the striatum of nude rats, the cells remained 100% p75 and MHC Class I positive, and again, only 15% of the cells demonstrated vimentin reactivity. The grafted cells retained this characteristic for 28 days in vivo. Although an immunoincompetent host was selected to minimize the effects an inflammatory response would have on the graft, a transient inflammatory response was detected. During the first week of engraftment, numerous MHC class II cells, some of which were macrophages, were seen infiltrating the graft. However, by 4 weeks postengraftment, no inflammatory cells were appreciated in the graft and surprisingly little reactive gliosis was seen in the penumbra of the tumor mass. Thus, the limited number of in vitro phe-notypic characteristics we examined in the C6-2B cell line remained constant once the cells were engrafted into the striatum of athymic nude rats.
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Affiliation(s)
- C Tornatore
- Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA
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14
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Osuka S, Sampetrean O, Shimizu T, Saga I, Onishi N, Sugihara E, Okubo J, Fujita S, Takano S, Matsumura A, Saya H. IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. Stem Cells 2013; 31:627-40. [PMID: 23335250 DOI: 10.1002/stem.1328] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 12/20/2012] [Indexed: 01/07/2023]
Abstract
Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.
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Affiliation(s)
- Satoru Osuka
- Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Park MY, Kim DR, Eo EY, Lim HJ, Park JS, Cho YJ, Yoon HI, Lee JH, Lee CT. Genetic blockade of insulin-like growth factor-1 receptor via recombinant adenovirus in lung cancer can be enhanced by the histone deacetylase inhibitor, vorinostat. J Gene Med 2013; 15:115-22. [DOI: 10.1002/jgm.2699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Revised: 12/24/2012] [Accepted: 01/29/2013] [Indexed: 11/09/2022] Open
Affiliation(s)
- Mi-Young Park
- Department of Internal Medicine, Respiratory Center; Seoul National University Bundang Hospital; Seongnam; Korea
| | - Dal Rae Kim
- Department of Internal Medicine, Respiratory Center; Seoul National University Bundang Hospital; Seongnam; Korea
| | - Eun Young Eo
- Department of Internal Medicine, Respiratory Center; Seoul National University Bundang Hospital; Seongnam; Korea
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Pan Y, Trojan J, Guo Y, Anthony DD. Rescue of MHC-1 antigen processing machinery by down-regulation in expression of IGF-1 in human glioblastoma cells. PLoS One 2013; 8:e58428. [PMID: 23526983 PMCID: PMC3603982 DOI: 10.1371/journal.pone.0058428] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 02/05/2013] [Indexed: 11/18/2022] Open
Abstract
Escape from immune recognition has been hypothesized to be a factor in carcinogenesis. It may be mediated for many cancers through down-regulation in the MHC class 1 antigen processing and presentation pathway. TAP-1, TAP-2, tightly linked to LMP-2 and LMP-7 are multiple components of the endogenous, antigen presentation pathway machinery. We addressed the question of alterations in this pathway in human Glioblastoma (HGB) and of its relationship to modulation in expression of IGF-1 that is highly expressed in this cancer. Deficiencies in expression of TAP-1 were demonstrated by RT-PCR and/or by immuno-flow cytometry in the HGB cell line T98G obtained from ATCC, and in 3 of 4 human cell lines established from patients with Glioblastoma Multiforme. Deficiencies in expression of TAP-2 were observed in 3 of 4, deficiencies in expression of LMP-2 in 4 of 4 and deficiencies in LMP-7 in 3 of 4 HGB cell lines examined by RT-PCR and Western blot. Following down-regulation of IGF-1 by transfection with the pAnti IGF-1 vector that expresses IGF-1 RNA in antisense orientation, or by the exogenous addition of IGF-1 receptor monoclonal antibody to cell culture media, the deficiencies in components of the MHC-1 antigen presentation pathway were up-regulated and/or rescued in all HGB cell lines tested. Moreover, this up-regulation in expression was aborted by addition of 100 ng/ml of IGF-1 to the culture media. Unlike in the case of IFN-γ, the restoration of TAP-1 and LMP-2 by down-regulation of IGF-1 in Glioblastoma cells was not correlated to the tyrosine phosphorylation of STAT 1. In summary, the simultaneous reversion in expression of the multiple constituents of MHC-1 antigen processing path and up-regulation in expression of MHC-1 occurring with down-regulation in IGF-1 may have a role in reinforcement of immunity against tumor antigen(s) in some animal cancers and in humans with Glioblastoma Multiforme.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 2
- ATP Binding Cassette Transporter, Subfamily B, Member 3
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Antigen Presentation/genetics
- Antigens, Neoplasm/metabolism
- B7-1 Antigen/metabolism
- Cell Line, Tumor
- Cysteine Endopeptidases/genetics
- Cysteine Endopeptidases/metabolism
- Down-Regulation
- Glioblastoma/genetics
- Glioblastoma/immunology
- Glioblastoma/metabolism
- Histocompatibility Antigens Class I/metabolism
- Humans
- Insulin-Like Growth Factor I/antagonists & inhibitors
- Insulin-Like Growth Factor I/genetics
- Proteasome Endopeptidase Complex/genetics
- Proteasome Endopeptidase Complex/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
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Affiliation(s)
- Yuexin Pan
- Division of General Medical Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Department of Medicine, University Hospitals of Cleveland, Cleveland, Ohio, United States of America
| | - Jerzy Trojan
- INSERM U542 and U602, Paul-Brousse Hospital, Paris XI University, Villejuif, France
| | - Yajun Guo
- International Joint Cancer Institute, Second Military Medical University, Shanghai, China
| | - Donald D. Anthony
- Division of General Medical Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
- Department of Medicine, University Hospitals of Cleveland, Cleveland, Ohio, United States of America
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17
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Seccareccia E, Brodt P. The role of the insulin-like growth factor-I receptor in malignancy: an update. Growth Horm IGF Res 2012; 22:193-199. [PMID: 23098677 DOI: 10.1016/j.ghir.2012.09.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 08/27/2012] [Accepted: 09/19/2012] [Indexed: 12/13/2022]
Abstract
In the past three decades, evidence has been accumulating that the IGF-I receptor/ligand system plays an important role in malignant disease. This has led to a search for specific inhibitors of the IGF receptor for cancer therapy, revealing some predictable, but also unexpected challenges. Here we review recent data that highlight the essential role of the IGF axis in several important steps in cancer cell progression and metastasis and highlight cellular processes that have been the focus of much interest and new insight in recent years. Strategies used to target the IGF axis clinically are summarized and the obstacles encountered are discussed.
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18
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Ojima Y, Hongo A, Liu Y, Zhu L, Kusumoto T, Nakamura K, Seki N, Hiramatsu Y. Antitumor effects of novel shorter truncated insulin-like growth factor I receptors. Cancer Biol Ther 2012; 13:559-66. [PMID: 22406993 DOI: 10.4161/cbt.19609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
We generated novel truncated insulin-like growth factor I receptors (IGF-IRs) designated as 126/STOP, 223/STOP and 325/STOP in order to establish shorter soluble IGF-IRs than previously reported 486/STOP without abrogating the same antitumor effects. Stable transfection of 223/STOP and 325/STOP, but not 126/STOP caused inhibition of anchorage-independent growth of CaOV-3 ovarian cancer cells in vitro. This antitumor effect was reproduced when we used recombinant proteins of these constructs, suggesting a bystander effect of these shorter truncated IGF-IRs. Tumorigenesis in vivo of CaOV-3 cells tranfected with 223/STOP or 325/STOP was strictly inhibited, and inoculation of these cells in nude mice caused massive apoptosis exclusively in vivo. Phosphorylations of IGF-IR and Akt, but not Erk were attenuated in 223/STOP- or 325/STOP-transfected CaOV-3 cells, and downregulations of IGF-IR and Akt phosphorylation seemed to play at least a partial role in the anti-tumor effect of these novel truncated IGF-IRs. Since 223/STOP and 325/STOP are smaller in size than previously reported 486/STOP, and they retain the same antitumor effects, they could be good candidates for clinical application in the future.
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Affiliation(s)
- Yojiro Ojima
- Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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19
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Methodology for Anti-Gene Anti-IGF-I Therapy of Malignant Tumours. CHEMOTHERAPY RESEARCH AND PRACTICE 2012; 2012:721873. [PMID: 22400112 PMCID: PMC3287029 DOI: 10.1155/2012/721873] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Revised: 10/25/2011] [Accepted: 10/31/2011] [Indexed: 01/26/2023]
Abstract
The aim of this study was to establish the criteria for methodology of cellular “anti-IGF-I” therapy of malignant tumours and particularly for glioblastoma multiforme. The treatment of primary glioblastoma patients using surgery, radiotherapy, and chemotherapy was followed by subcutaneous injection of autologous cancer cells transfected by IGF-I antisense/triple helix expression vectors. The prepared cell “vaccines” should it be in the case of glioblastomas or other tumours, have shown a change of phenotype, the absence of IGF-I protein, and expression of MHC-I and B7. The peripheral blood lymphocytes, PBL cells, removed after each of two successive vaccinations, have demonstrated for all the types of tumour tested an increasing level of CD8+ and CD8+28+ molecules and a switch from CD8+11b+ to CD8+11. All cancer patients were supervised for up to 19 months, the period corresponding to minimum survival of glioblastoma patients. The obtained results have permitted to specify the common criteria for “anti-IGF-I” strategy: characteristics sine qua non of injected “vaccines” (cloned cells IGF-I(−) and MHC-I(+)) and of PBL cells (CD8+ increased level).
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20
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Dmitrenko VV, Kavsan VM, Boyko OI, Rymar VI, Stepanenko AA, Balynska OV, Mausheva TA, Rozumenko VD, Zozulya YP. Expression of genes belonging to the IGF-system in glial tumors. CYTOL GENET+ 2011. [DOI: 10.3103/s0095452711050021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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21
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Nieto-Sampedro M, Valle-Argos B, Gómez-Nicola D, Fernández-Mayoralas A, Nieto-Díaz M. Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System. Clin Med Insights Oncol 2011; 5:265-314. [PMID: 22084619 PMCID: PMC3201112 DOI: 10.4137/cmo.s7685] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells.The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 μM or higher.At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step.
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Affiliation(s)
- Manuel Nieto-Sampedro
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
| | - Beatriz Valle-Argos
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
| | - Diego Gómez-Nicola
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
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22
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Mazzoccoli G, Tarquini R, Durfort T, Francois JC. Chronodisruption in lung cancer and possible therapeutic approaches. Biomed Pharmacother 2011; 65:500-8. [PMID: 21993005 DOI: 10.1016/j.biopha.2011.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Accepted: 06/05/2011] [Indexed: 01/05/2023] Open
Abstract
A customary temporal organization of physiological functions and biological processes is necessary to maintain body homeostasis and an altered body time structure may favour carcinogenesis. There is growing evidence that GH stimulates cancer growth, IGF1 may have a role in carcinogenesis and cancer promotion, GH-IGF1 axis, TRH, TSH, thyroxine, melatonin and cortisol modulate immune cell function and the immune system is often dysfunctional in patients with malignancies. The aim of our study was to evaluate GH-IGF1 axis, hypothalamus-pituitary-thyroid axis, melatonin, cortisol, lymphocyte subsets and IL2 in lung cancer patients. Peripheral blood samples were collected at 4-hour intervals in a 24-hour period from eleven healthy male subjects (age range 35-53 years) and nine male patients suffering from non-small cell lung cancer (age range 43-63 years). In each blood sample, lymphocyte subpopulations (CD3+, CD4+, CD8+, CD16+, CD20+, CD25+, HLA-DR+, γδTcR bearing cells) were analyzed and GH, IGF1, TRH, TSH, FT4, melatonin, cortisol and IL2 were measured. Circadian rhythmicity was evaluated and MESOR, amplitude and acrophase values were compared. In healthy subjects a significant circadian rhythm could be demonstrated with midday peaks for CD8+, CD16+, γδTCR expressing cells and cortisol, and peaks during the night for CD3+, CD4+, GH, TSH and melatonin. A borderline significant rhythm was also observed for CD20+, with a peak late in the evening. IGF1, TRH, FT4 and IL2 values did not show rhythmic variation. In cancer patients a significant circadian rhythm could be demonstrated with diurnal peak for CD16+ and peaks during the night for CD4+ and melatonin. GH, IGF1, TRH, TSH, FT4, cortisol and IL2 values did not show rhythmic variation. MESOR of CD8+ (P<0.0001), CD20+ (P=0.05), γδTCR expressing cells (P=0.01), IGF1 (P<0.001) and TSH (P=0.032) was higher in healthy subjects, whereas MESOR of CD16+ (P<0.0001), CD25+ (P=0.001), GH (P<0.001), TRH (P=0.002), FT4 (P=0.030), cortisol (P=0.01) and IL2 (P=0.02) was higher in cancer patients. Amplitude of circadian variation of γδTCR expressing cells (P=0.01), TSH (P<0.001) and cortisol (P=0.01) was higher in healthy subjects, whereas amplitude of circadian variation of CD4+ was higher in cancer patients (P=0.02). In conclusion, non-small cell lung cancer patients show severe alterations of periodic and quantitative characteristics of neuroendocrine and immune parameters with loss of circadian rhythmicity and internal desynchronization, leading to chronodisruption.
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Affiliation(s)
- Gianluigi Mazzoccoli
- Department of Internal Medicine and Chronobiology Unit, Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo-FG, Italy.
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23
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Attias-Geva Z, Bentov I, Ludwig DL, Fishman A, Bruchim I, Werner H. Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells. Eur J Cancer 2011; 47:1717-26. [PMID: 21450456 DOI: 10.1016/j.ejca.2011.02.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Revised: 02/22/2011] [Accepted: 02/25/2011] [Indexed: 12/20/2022]
Abstract
Specific insulin-like growth factor-I receptor (IGF-IR) targeting emerged in recent years as a promising therapeutic strategy in cancer. Endometrial cancer is the most common gynaecological cancer in the Western world. The aim of this study was to evaluate the potential of cixutumumab (IMC-A12, ImClone Systems), a fully human monoclonal antibody against the IGF-IR, to inhibit IGF-I-mediated biological actions and cell signalling events in four endometrial carcinoma-derived cell lines (ECC-1, Ishikawa, USPC-1 and USPC-2). Our results demonstrate that cixutumumab was able to block the IGF-I-induced autophosphorylation of the IGF-IR. In addition, the PI3K and MAPK downstream signalling pathways were also inactivated by cixutumumab in part of the cell lines. Prolonged (24h and 48h) exposures to cixutumumab reduced IGF-IR expression. Furthermore, confocal microscopy of GFP-tagged receptors shows that cixutumumab treatment led to IGF-IR redistribution from the cell membrane to the cytoplasm. Antiapoptotic effects were evaluated by cleavage of caspase 3 and PARP, and mitogenicity and transformation by proliferation and cell cycle assays. Results obtained showed that cixutumumab abrogated the IGF-I-stimulated increase in proliferation rate, and increased caspase-3 and PARP cleavage, two markers of apoptosis. Of importance, cixutumumab had no effect neither on insulin receptor (IR) expression nor on IGF-I activation of IR. In summary, in a cellular model of endometrial cancer cixutumumab was able to inhibit the IGF-I-induced activation of intracellular cascades, apoptosis and proliferation.
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Affiliation(s)
- Zohar Attias-Geva
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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24
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Luo J, Zhang L, Tu H, Hu J, Li X, Li D, Lei T. Experimental study on treatment of glioma by embryonic neural stem cell transplantation in rats. ACTA ACUST UNITED AC 2010; 27:571-5. [PMID: 18060638 DOI: 10.1007/s11596-007-0524-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Indexed: 10/22/2022]
Abstract
The neural stem cells in Wistar rats were cultured in vitro, purified, and transplanted into C6 glioma model in order to observe their biological characters and provide a basic foundation for treatment of neurological diseases by neural stem cell transplantation. The cells at hippocampal area from gestation 15-day rats were cultured in vitro, and frozen and preserved in liquid nitrogen. C6 tumor-bearing models (n=25) and neural stem cells transplantation models (n=35) were established. When the tumor grew to 3 to 4 weeks, 5 rats in each group were randomly selected for MRI examination. At different intervals, the rats were perfused and sampled for HE staining, GFAP and BrdU immunohistochemical staining. The results showed that after resuscitation of neural stem cells at 1-4 passages, the cell viability was 40%-63% with the difference being not significant. The cells could proliferate, passage, and most cells transplanted into glioma model survived. The mean survival time in neural stem cell transplantation group and control was 4.28 and 3.88 weeks respectively, and the average tumor size in the former was smaller than in the latter. It was concluded that embryonic neural stem cells in rats could proliferate and differentiate, and after resuscitation the biological characteristic and viability of the cells were not influenced. Neural stem cells had inhibitory effects on the growth of glioma cells and could prolong the survival of rat model.
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Affiliation(s)
- Jie Luo
- Department of Neurosurgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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25
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Alexandru O, Dragutescu L, Tataranu L, Ciubotaru V, Sevastre A, Georgescu AM, Purcaru O, Danoiu S, Bäcklund LM, Dricu A. Helianthin induces antiproliferative effect on human glioblastoma cells in vitro. J Neurooncol 2010; 102:9-18. [PMID: 20635119 DOI: 10.1007/s11060-010-0285-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2009] [Accepted: 06/21/2010] [Indexed: 02/07/2023]
Abstract
A major focus of brain cancer research today is to translate understanding of glioma biology into advances in treatment, by exploring the potential of target therapy. Here we investigated the ability of three compounds belonging to the chemical class of azo dyes (methyl red, methyl yellow, and helianthin) to inhibit glioblastoma (GB) cell growth in vitro. Our results showed that helianthin induced cytotoxicity in two GB cell cultures, cell lines 18 and 38, whereas methyl red and methyl yellow were not cytotoxic. The effect of helianthin on EGFR, IGF-1R, and their common intracellular signaling via PI3-K and ERK1/2 was also analyzed. Treatment with helianthin down-regulated EGFR and IGF-1R activity in both cell lines. Helianthin treatment blocked ERK1/2 phosphorylation without affecting PI3K activity in cell line 18 and reduced both PI3K and ERK1/2 in GB 38 cell line. The cell death was accompanied by degradation of PARP without affecting BCL2 expression in both GB cell cultures. Because of the genetic heterogeneity of malignant gliomas, we tested the effect of helianthin on other two primary GB lines (11 and 15) and two early-passage GB cultures (BT1GB and BT2GB), to assess the general nature of the anti-tumor effect of the drug in GB cells. We found that helianthin treatment induced cell death in all the GB cell cultures analyzed. To our knowledge, this is the first report indicating that helianthin can reduce GB cell growth.
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Affiliation(s)
- Oana Alexandru
- University of Medicine and Pharmacy, Petru Rares Street, No 2, 200349 Craiova, Romania
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26
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Melzi R, Antonioli B, Mercalli A, Battaglia M, Valle A, Pluchino S, Galli R, Sordi V, Bosi E, Martino G, Bonifacio E, Doglioni C, Piemonti L. Co-graft of allogeneic immune regulatory neural stem cells (NPC) and pancreatic islets mediates tolerance, while inducing NPC-derived tumors in mice. PLoS One 2010; 5:e10357. [PMID: 20436918 PMCID: PMC2860511 DOI: 10.1371/journal.pone.0010357] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Accepted: 04/01/2010] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Data available on the immunomodulatory properties of neural stem/precursor cells (NPC) support their possible use as modulators for immune-mediated process. The aim of this study was to define whether NPC administered in combination with pancreatic islets prevents rejection in a fully mismatched allograft model. METHODOLOGY/PRINCIPAL FINDING Diabetic Balb/c mice were co-transplanted under the kidney capsule with pancreatic islets and GFP(+) NPC from fully mismatched C57BL/6 mice. The following 4 groups of recipients were used: mice receiving islets alone; mice receiving islets alone and treated with standard immunosuppression (IL-2Ralpha chain mAbs + FK506 + Rapamycin); mice receiving a mixed islet/NPC graft under the same kidney capsule (Co-NPC-Tx); mice receiving the islet graft under the left kidney capsule and the NPC graft under the right kidney capsule (NPC-Tx). Our results demonstrate that only the co-transplantation and co-localization of NPC and islets (Co-NPC-Tx) induce stable long-term graft function in the absence of immunosuppression. This condition is associated with an expansion of CD4(+)CD25(+)FoxP3(+) T regulatory cells in the spleen. Unfortunately, stable graft function was accompanied by constant and reproducible development of NPC-derived cancer mainly sustained by insulin secretion. CONCLUSION These data demonstrate that the use of NPC in combination with islets prevents graft rejection in a fully mismatched model. However, the development of NPC-derived cancer raises serious doubts about the safety of using adult stem cells in combination with insulin-producing cells outside the original microenvironment.
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Affiliation(s)
- Raffaella Melzi
- San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Antonioli
- San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy
| | - Alessia Mercalli
- San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy
| | - Manuela Battaglia
- San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy
| | - Andrea Valle
- San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Pluchino
- CNS Repair Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
| | - Rossella Galli
- Neural Stem Cell Biology Unit, Division of Regenerative Medicine Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
| | - Valeria Sordi
- San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy
| | - Emanuele Bosi
- Diabetes and Endocrinology Unit, Department of Internal Medicine, San Raffaele Scientific Institute, Milan, Italy
| | - Gianvito Martino
- Neuroimmunology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
| | - Ezio Bonifacio
- Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany
| | - Claudio Doglioni
- Pathology Unit, San Raffaele Scientific Institute and Università Vita–Salute, Milan, Italy
| | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy
- * E-mail:
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27
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Trojan J, Ly A, Wei MX, Bierwagen M, Kopinski P, Pan Y, Ardourel MY, Dufour T, Shevelev A, Trojan LA, François JC, Andres C, Popiela T, Chatel M, Kasprzak H, Anthony DD, Duc HT. Antisense anti IGF-I cellular therapy of malignant tumours: immune response in cancer patients. Biomed Pharmacother 2010; 64:576-8. [PMID: 20630696 DOI: 10.1016/j.biopha.2010.01.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Accepted: 01/29/2010] [Indexed: 11/19/2022] Open
Abstract
The treatment of cancer by antisense anti-IGF-I cellular therapy inducing immune response has evoked interest among many promising strategies. Here, we reported some results obtained from patients with cancer, mainly glioblastoma treated by this strategy, which was also extended to patients with colon carcinoma, ovary cystadenocarcinoma and prostate adenocarcinoma. It was shown that, in the phase I of clinical trial, patients vaccinated with their own tumour cells treated by antisense IGF-I presented a slight increase of temperature. Their peripheral blood lymphocytes showed a shift in the percentage of CD8 effector cells as judged by expression of cell surface markers CD8+ CD28+. Particularly, in two treated patients with glioblastoma, the survival time was 19 and 24 months respectively in comparison to the range of 12 to 15 months observed in the case of classical treatment such as surgery, radiation or chemotherapy. These results, although preliminary, gave indication that the reported strategy could deserve consideration owing to its safety. Furthermore, the increase in the percentage of peripheral blood monomorphonucleated cells (PBMNCs) with effector phenotype, i.e., CD8+ CD28+ in vaccinated patients might explain their prolonged survival time.
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Affiliation(s)
- J Trojan
- Inserm U602, Paul-Brousse Hospital, Paris XI University, Villejuif, France
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28
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Barth RF, Kaur B. Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J Neurooncol 2009; 94:299-312. [PMID: 19381449 DOI: 10.1007/s11060-009-9875-7] [Citation(s) in RCA: 306] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2009] [Accepted: 03/16/2009] [Indexed: 02/08/2023]
Abstract
In this review we will describe eight commonly used rat brain tumor models and their application for the development of novel therapeutic and diagnostic modalities. The C6, 9L and T9 gliomas were induced by repeated injections of methylnitrosourea (MNU) to adult rats. The C6 glioma has been used extensively for a variety of studies, but since it arose in an outbred Wistar rat, it is not syngeneic to any inbred strain, and its potential to evoke an alloimmune response is a serious limitation. The 9L gliosarcoma has been used widely and has provided important information relating to brain tumor biology and therapy. The T9 glioma, although not generally recognized, was and probably still is the same as the 9L. Both of these tumors arose in Fischer rats and can be immunogenic in syngeneic hosts, a fact that must be taken into consideration when used in therapy studies, especially if survival is the endpoint. The RG2 and F98 gliomas were both chemically induced by administering ethylnitrosourea (ENU) to pregnant rats, the progeny of which developed brain tumors that subsequently were propagated in vitro and cloned. They are either weakly or non-immunogenic and have an invasive pattern of growth and uniform lethality, which make them particularly attractive models to test new therapeutic modalities. The CNS-1 glioma was induced by administering MNU to a Lewis rat. It has an infiltrative pattern of growth and is weakly immunogenic, which should make it useful in experimental neuro-oncology. Finally, the BT4C glioma was induced by administering ENU to a BD IX rat, following which brain cells were propagated in vitro until a tumorigenic clone was isolated. This tumor has been used for a variety of studies to evaluate new therapeutic modalities. The Avian Sarcoma Virus (ASV) induced tumors, and a continuous cell line derived from one of them designated RT-2, have been useful for studies in which de novo tumor induction is an important requirement. These tumors also are immunogenic and this limits their usefulness for therapy studies. It is essential to recognize the limitations of each of the models that have been described, and depending upon the nature of the study to be conducted, it is important that the appropriate model be selected.
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Affiliation(s)
- Rolf F Barth
- Department of Pathology, The Ohio State University, 165 Hamilton Hall, Columbus, OH 43210, USA.
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Stadler ME, Patel MR, Couch ME, Hayes DN. Molecular biology of head and neck cancer: risks and pathways. Hematol Oncol Clin North Am 2009; 22:1099-124, vii. [PMID: 19010262 DOI: 10.1016/j.hoc.2008.08.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Patients present with a differential baseline risk of cancer based on normal and expected variations in genes associated with cancer. The baseline risk of developing cancer is acted on throughout life as the genome of different cells interacts with the environment in the form of exposures (eg, toxins, infections). As genetic damage is incurred throughout a lifetime (directly to DNA sequences or to the epigenome), events are set in motion to progressively disrupt normal cellular pathways toward tumorigenesis. This article attempts to characterize broad categories of genetic aberrations and pathways in a manner that might be useful for the clinician to understand the risk of developing cancer, the pathways that are disrupted, and the potential for molecular-based diagnostics.
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Affiliation(s)
- Michael E Stadler
- Department of Otolaryngology-Head & Neck Surgery, University of North Carolina at Chapel Hill, CB #7070, Chapel Hill, NC 27599, USA
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Gao Y, Zu T, Low WC, Orr HT, McIvor RS. Antisense RNA sequences modulating the ataxin-1 message: molecular model of gene therapy for spinocerebellar ataxia type 1, a dominant-acting unstable trinucleotide repeat disease. Cell Transplant 2008; 17:723-34. [PMID: 19044200 DOI: 10.3727/096368908786516729] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Spinocerebellar ataxia type 1 (SCA1) is a dominant inherited disease caused by expanded trinucleotide repeats resulting in an increased polyglutamine tract in the gene product. As a potential therapeutic approach for SCA1, we tested antisense RNAs targeting two regions of the ataxin-1 message. Single-stranded regions around the translational initiation site and the intron 8 splice donor site of the ataxin-1 message were identified by computer-assisted RNA secondary structure prediction. Plasmids were generated to contain a 254-bp antisense sequence spanning the translation initiation site (pLasBDini) or a 317-bp sequence spanning the intron 8 splice donor site (pLasBDei) of the ataxin-1 message. These plasmids were transfected into Chinese hamster ovary cells engineered to express either expanded or unexpanded ataxin-1 message and protein. Reduced levels of mutant ataxin-1 message (82 CAG repeats), wild-type ataxin-1 message (30 CAG repeats), and ataxin-1 protein were observed by Northern and Western blot analyses in pLasBDini-transfected clones. pLasBDei-transfected 293 cells exhibited a shift in ataxin-1 message to a size several kilobases longer than that of the natural message. Reverse transcriptase/polymerase chain reaction assays demonstrated the retention of message spanning the intron 8 splice acceptor and the inability to amplify sequences between exons 8 and 9, implying that normal splicing of intron 8 had been interrupted. We conclude that antisense RNAs were effective in reducing or modifying ataxin-1 messages in transfected cells, and may be an effective genetic strategy for therapy of SCA1 and similar dominant-acting neurological disorders.
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Affiliation(s)
- Youxin Gao
- Institute of Human Genetics, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
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Growth factor receptors signaling in glioblastoma cells: therapeutic implications. J Neurooncol 2008; 92:137-47. [PMID: 19043776 DOI: 10.1007/s11060-008-9753-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2008] [Accepted: 11/17/2008] [Indexed: 10/21/2022]
Abstract
In this study, we investigated the protein expression of platelet-derived growth factor receptor (PDGFR), insulin like growth factor-1 receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1/2) in five primary glioblastoma (GB), with a view to their possible use as therapeutic targets. Our results demonstrated that appreciable levels of these proteins could be detected in the analysed GB cell lines, except for a low level of PDGFR and ERK1/2 expression in one GB cell line. The small molecule inhibitors towards IGF-1R, PDGFR, PI3-K and ERK1/2 respectively, have only modest or no anti-tumour activity on GB cells and therefore their combination with other therapy modalities was analysed. The interaction between small inhibitors and radiation was mostly additive or sub-additive; synergistic interaction was found in five of forty analysed combinations. Our results showed that GB cells are in general resistant to treatment and illustrate the difficulties in predicting the treatment response in malignant gliomas.
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Kern MA, Breuhahn K, Schuchmann M, Schirmacher P. [Molecular pathogenesis of hepatocellular carcinoma: new therapeutic approaches and predictive pathology]. DER PATHOLOGE 2008; 28:261-8. [PMID: 17605064 DOI: 10.1007/s00292-007-0890-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma is one of the most prevalent malignancies worldwide and its incidence is increasing. Multimodal strategies directed towards this carcinoma include primary (e.g. immunisation) and secondary (e.g. antiviral therapy) prevention, surgical approaches, novel specific systemic therapies (targeted therapy), and the treatment of comorbidity (cirrhosis). New molecular approaches are currently under development. These tackle several specific targets, with pathology being challenged in many aspects: experimental evaluation, the development of valid tumor-relevant diagnostic tests as well as morphological evaluation in the context of clinical studies, and finally in routine diagnosis.
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Affiliation(s)
- M A Kern
- Pathologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 220/221, 69120, Heidelberg, Deutschland.
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Barami K. Biology of the subventricular zone in relation to gliomagenesis. J Clin Neurosci 2007; 14:1143-9. [DOI: 10.1016/j.jocn.2007.04.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2007] [Revised: 04/02/2007] [Accepted: 04/03/2007] [Indexed: 01/05/2023]
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Insulin-like growth factor type I biology and targeting in malignant gliomas. Neuroscience 2007; 145:795-811. [DOI: 10.1016/j.neuroscience.2007.01.021] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2006] [Revised: 01/04/2007] [Accepted: 01/05/2007] [Indexed: 11/20/2022]
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Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007; 28:20-47. [PMID: 16931767 DOI: 10.1210/er.2006-0001] [Citation(s) in RCA: 730] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IGF-I receptor (IGF-IR) signaling and functions are mediated through the activities of a complex molecular network of positive (e.g., type I IGF) and negative (e.g., the type II IGF receptor, IGF-IIR) effectors. Under normal physiological conditions, the balance between the expression and activities of these molecules is tightly controlled. Changes in this delicate balance (e.g., overexpression of one effector) may trigger a cascade of molecular events that can ultimately lead to malignancy. In recent years, evidence has been mounting that the IGF axis may be involved in human cancer progression and can be targeted for therapeutic intervention. Here we review old and more recent evidence on the role the IGF system in malignancy and highlight experimental and clinical studies that provide novel insights into the complex mechanisms that contribute to its oncogenic potential. Controversies arising from conflicting evidence on the relevance of IGF-IR and its ligands to human cancer are discussed. Our review highlights the importance of viewing the IGF axis as a complex multifactorial system and shows that changes in the expression levels of any one component of the axis, in a given malignancy, should be interpreted with caution and viewed in a wider context that takes into account the expression levels, state of activation, accessibility, and functionality of other interacting components. Because IGF targeting for anticancer therapy is rapidly becoming a clinical reality, an understanding of this complexity is timely because it is likely to have an impact on the design, mode of action, and clinical outcomes of newly developed drugs.
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Affiliation(s)
- Amir Abbas Samani
- Department of Medicine, McGill University Health Center, Royal Victoria Hospital, Room H6.25687, Pine Avenue West, Montreal, Québec, Canada H3A 1A1
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Casellas A, Salavert A, Agudo J, Ayuso E, Jimenez V, Moya M, Muñoz S, Franckhauser S, Bosch F. Expression of IGF-I in pancreatic islets prevents lymphocytic infiltration and protects mice from type 1 diabetes. Diabetes 2006; 55:3246-55. [PMID: 17130467 DOI: 10.2337/db06-0328] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Type 1 diabetic patients are diagnosed when beta-cell destruction is almost complete. Reversal of type 1 diabetes will require beta-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. IGF-I expression in beta-cells of streptozotocin (STZ)-treated transgenic mice regenerates the endocrine pancreas by increasing beta-cell replication and neogenesis. Here, we examined whether IGF-I also protects islets from autoimmune destruction. Expression of interferon (IFN)-beta in beta-cells of transgenic mice led to islet beta(2)-microglobulin and Fas hyperexpression and increased lymphocytic infiltration. Pancreatic islets showed high insulitis, and these mice developed overt diabetes when treated with very-low doses of STZ, which did not affect control mice. IGF-I expression in IFN-beta-expressing beta-cells of double-transgenic mice reduced beta(2)-microglobulin, blocked Fas expression, and counteracted islet infiltration. This was parallel to a decrease in beta-cell death by apoptosis in islets of STZ-treated IGF-I+IFN-beta-expressing mice. These mice were normoglycemic, normoinsulinemic, and showed normal glucose tolerance. They also presented similar pancreatic insulin content and beta-cell mass to healthy mice. Thus, local expression of IGF-I prevented islet infiltration and beta-cell death in mice with increased susceptibility to diabetes. These results indicate that pancreatic expression of IGF-I may regenerate and protect beta-cell mass in type 1 diabetes.
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Affiliation(s)
- Alba Casellas
- Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain
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38
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Trabado S, Nguyen Van Binh P, Martin C, Lafarge-Frayssinet C, Thevenin M, Baudouin F, Warnet JM, Duc HT. Modulated expression of cell surface molecules and in vivo outgrowth of modified melanoma cells. Biomed Pharmacother 2006; 60:693-7. [PMID: 17071049 DOI: 10.1016/j.biopha.2006.09.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2006] [Accepted: 09/18/2006] [Indexed: 10/24/2022] Open
Abstract
Modulation of cell surface molecules involved in immune recognition and cellular interactions (class I major histocompatibility complex or MHC-I, B7.1 or CD80, integrin alpha4 or CD49d, tetraspanins CD9, CD81) was examined in modified B16 melanoma cells displaying either inhibited IGF-I expression or transfected OVA encoding gene. It was shown that inhibiting IGF-I expression or inserting OVA encoding gene did not lead to modification relevant to the presence of MHC-I or B7.1. However downregulation of tetraspanin CD9 was observed in modified IGF-I but not in OVA encoding gene inserted melanoma cells. Expression of tetraspanin CD81 and integrin alpha4/CD49d remained unchanged. Inoculated into syngeneic recipients, the modified melanoma cells exhibited significant delayed outgrowth with a reduction in the percentage of lethal tumors observed essentially in hosts injected with inhibited IGF-I expression cells.
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MESH Headings
- Animals
- Anti-Bacterial Agents/pharmacology
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Surface/genetics
- Antigens, Surface/metabolism
- B7-1 Antigen/genetics
- B7-1 Antigen/metabolism
- Cell Line, Tumor
- Cell Survival/drug effects
- DNA, Antisense/genetics
- Down-Regulation/drug effects
- Electroporation/methods
- Female
- Flow Cytometry
- Gene Expression/drug effects
- Histocompatibility Antigens Class I/genetics
- Histocompatibility Antigens Class I/metabolism
- Hygromycin B/pharmacology
- Immunohistochemistry
- Insulin-Like Growth Factor I/genetics
- Insulin-Like Growth Factor I/metabolism
- Integrin alpha4/genetics
- Integrin alpha4/metabolism
- Melanoma, Experimental/genetics
- Melanoma, Experimental/metabolism
- Melanoma, Experimental/pathology
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/metabolism
- Mice
- Mice, Inbred C57BL
- Ovalbumin/genetics
- Ovalbumin/metabolism
- Tetraspanin 28
- Tetraspanin 29
- Transfection/methods
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Affiliation(s)
- S Trabado
- Laboratoire de Toxicologie, Faculté de Pharmacie, Université René-Descartes Paris-V, Paris, France
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Lam-Himlin D, Espey MG, Perry G, Smith MA, Castellani RJ. Malignant glioma progression and nitric oxide. Neurochem Int 2006; 49:764-8. [PMID: 16971023 DOI: 10.1016/j.neuint.2006.07.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2006] [Revised: 06/29/2006] [Accepted: 07/05/2006] [Indexed: 12/30/2022]
Abstract
Glioblastoma multiforme, the most common of the malignant gliomas, carries a dismal prognosis in spite of the most aggressive therapy and recent advances in molecular pathways of glioma progression. Although it has received relatively little attention in the setting of malignant gliomas, nitric oxide metabolism may be intimately associated with the disease process. Interestingly, nitric oxide has both physiological roles (e.g., neurotransmitter-like activity, stimulation of cyclic GMP), and pathophysiological roles (e.g., neoplastic transformation, tumor neovascularization, induction of apoptosis, free radical damage). Moreover, whether nitric oxide is neuroprotective or neurotoxic in a given disease state, or whether it enhances or diminishes chemotherapeutic efficacy in malignant neoplasia, is unresolved. This review discusses the multifaceted activity of nitric oxide with particular reference to malignant gliomas.
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Affiliation(s)
- Dora Lam-Himlin
- Department of Pathology, University of Maryland, 22 South Greene Street, Baltimore, MD 21201, USA
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40
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Nguyen van Binh P, Duc HT. Analyses and perspectives in cancer immunotherapy. Biomed Pharmacother 2006; 60:621-8. [PMID: 16978826 DOI: 10.1016/j.biopha.2006.07.092] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2006] [Accepted: 07/28/2006] [Indexed: 01/15/2023] Open
Abstract
Since the last two decades, rapid progress has been made in the field of cancer immunotherapy relevant to manipulation of adaptative cytotoxic T lymphocytes (CTLs) and innate immunity natural killer (NK) cells as well as antibodies. Many possibilities are now offered for therapeutic purposes contributing to better approaches in treatment of cancer.
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Affiliation(s)
- P Nguyen van Binh
- Inserm, U602, Micro-environnement et Physiopathologie de la Différenciation, Hôpital Paul-Brousse, 16, avenue Paul-Vaillant-Couturier, 94807 Villejuif cedex, France
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41
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Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006; 25:3787-800. [PMID: 16799620 DOI: 10.1038/sj.onc.1209556] [Citation(s) in RCA: 432] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Dysregulation of pleiotropic growth factors, receptors and their downstream signaling pathway components represent a central protumorigenic principle in human hepatocarcinogenesis. Especially the Insulin-like Growth Factor/IGF-1 receptor (IGF/IGF-1R), Hepatocyte Growth Factor (HGF/MET), Wingless (Wnt/beta-catenin/FZD), Transforming Growth Factor alpha/Epidermal Growth Factor receptor (TGFalpha/EGFR) and Transforming Growth Factor beta (TGFbeta/TbetaR) pathways contribute to proliferation, antiapoptosis and invasive behavior of tumor cells. This review focuses on the relevant alterations in these pathways identified in human human hepatocellular carcinomas (HCCs). Resultant functional effects are modulated by multiple cross-talks between the different signaling pathways and additional tumor-relevant factors, such as cyclooxygenase-2 and p53. Several specific strategies are currently under development such as receptor kinase inhibitors, neutralizing antibodies and antagonistic proteins, which may improve the systemic treatment of human HCCs.
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Affiliation(s)
- K Breuhahn
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
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42
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Szatmári T, Lumniczky K, Désaknai S, Trajcevski S, Hídvégi EJ, Hamada H, Sáfrány G. Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. Cancer Sci 2006; 97:546-53. [PMID: 16734735 PMCID: PMC11159227 DOI: 10.1111/j.1349-7006.2006.00208.x] [Citation(s) in RCA: 252] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Mouse glioma 261 (Gl261) cells are used frequently in experimental glioblastoma therapy; however, no detailed description of the Gl261 tumor model is available. Here we present that Gl261 cells carry point mutations in the K-ras and p53 genes. Basal major histocompatibility complex (MHC)I, but not MHCII, expression was detected in Gl261 cells. The introduction of interferon-gamma-encoding genes increased expression of both MHCI and MHCII. A low amount of B7-1 and B7-2 RNA was detected in wild-type cells, but cytokine production did not change expression levels. Gl261 cells were transduced efficiently by adenoviral vectors; the infectivity of retroviral vectors was limited. Low numbers of transplanted Gl261 cells formed both subcutaneous and intracranial tumors in C57BL/6 mice. The cells were moderately immunogenic: prevaccination of mice with irradiated tumor cells 7 days before intracranial tumor challenge prevented tumor formation in approximately 90% of mice. When vaccination was carried out on the day or 3 days after tumor challenge, no surviving animals could be found. In vitro-growing cells were radiosensitive: less than 2 Gy was required to achieve 50% cell mortality. Local tumor irradiation with 4 Gy X-rays in brain tumor-bearing mice slowed down tumor progression, but none of the mice were cured off the tumor. In conclusion, the Gl261 brain tumor model might be efficiently used to study the antitumor effects of various therapeutic modalities, but the moderate immunogenicity of the cells should be considered.
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Affiliation(s)
- Tünde Szatmári
- Department of Molecular and Tumor Radiobiology, Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Budapest 1221, Hungary
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Schillaci R, Salatino M, Cassataro J, Proietti CJ, Giambartolomei GH, Rivas MA, Carnevale RP, Charreau EH, Elizalde PV. Immunization with murine breast cancer cells treated with antisense oligodeoxynucleotides to type I insulin-like growth factor receptor induced an antitumoral effect mediated by a CD8+ response involving Fas/Fas ligand cytotoxic pathway. THE JOURNAL OF IMMUNOLOGY 2006; 176:3426-37. [PMID: 16517711 DOI: 10.4049/jimmunol.176.6.3426] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
We have demonstrated that in vivo administration of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODNs) to type I insulin-like growth factor receptor (IGF-IR) mRNA resulted in inhibition of C4HD breast cancer growth in BALB/c mice. The present study focused on whether in vivo administration of C4HD tumor cells pretreated with IGF-IR AS[S]ODN and irradiated could provide protection against C4HD wild-type tumor challenge and also on elucidating the mechanism mediating this effect. Our results showed that mice immunized with IGF-IR AS[S]ODN-treated C4HD cells experienced a growth inhibition of 53.4%, 61.6%, and 60.2% when compared with PBS-treated mice, wild-type C4HD cell-injected mice, or phosphorothioate sense oligodeoxynucleotide-treated C4HD cell-injected mice, respectively. The protective effect was C4HD-specific, because no cross-protection was observed against other syngeneic mammary tumor lines. The lack of protection against tumor formation in nude mice indicated that T cells were involved in the antitumoral response. Furthermore, cytotoxicity and splenocyte proliferation assays demonstrated that a cellular CD8(+)-dependent immune response, acting through the Fas/Fas ligand death pathway, could be mediating the antitumor effect induced by immunization with AS[S]ODN-treated cells. Immunization also induced splenocytes to produce Ag-dependent IFN-gamma, indicating the presence of a type 1 response. We demonstrated for the first time that IGF-IR AS[S]ODN treatment of breast cancer cells induced expression of CD86 and heat shock protein 70 molecules, both involved in the induction of the immunogenic phenotype. Immunization with these tumor immunogens imparted protection against parental tumor growth through activation of a specific immune response.
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Affiliation(s)
- Roxana Schillaci
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Vuelta de Obligado 2490, Buenos Aires C1428ADN, Argentina
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Nieder C, Grosu AL, Mehta MP, Andratschke N, Molls M. Treatment of malignant gliomas: radiotherapy, chemotherapy and integration of new targeted agents. Expert Rev Neurother 2006; 4:691-703. [PMID: 15853588 DOI: 10.1586/14737175.4.4.691] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Progress in the biological and molecular characterization of gliomas and studies of factors associated with tumor growth and progression have led to translational research projects and the development of rational new approaches regarding prognostic models, better prediction of response to treatment and innovative therapeutic strategies. This review summarizes the available data on established and emerging prognostic factors and prognostic scores, and discusses their limitations as well as their potential influence on future therapeutic efforts. Recent developments in standard treatment options (i.e., surgery, radiotherapy and chemotherapy) are reviewed. Experimental data indicate that inhibition of several signaling pathways (e.g., epidermal growth factor, transforming growth factor-beta and phosphatidylinositol 3 kinase) may represent a promising therapeutic strategy. Some inhibitory agents (i.e., drugs, antibodies and antisense oligonucleotides) have now entered clinical trials, mainly for recurrent gliomas and a small number are being tested in combination with radiotherapy. Early results of such approaches are presented.
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Affiliation(s)
- Carsten Nieder
- Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
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45
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Pu P, Kang C, Li J, Jiang H, Cheng J. The effects of antisense AKT2 RNA on the inhibition of malignant glioma cell growth in vitro and in vivo. J Neurooncol 2006; 76:1-11. [PMID: 16402276 DOI: 10.1007/s11060-005-3029-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The oncogenic role of AKT2 in the development of malignant gliomas was examined by using antisense approach. AKT2 expression was significantly inhibited in rat C6 glioma cells transfected with antisense AKT2 cDNA construct (LXSN-AS-AKT2). In addition, the transfected cells proliferated at a lowered level and apoptosis was induced. For in vivo studies, parental C6 cells and C6 cells transfected with LXSN-AS-AKT2 were implanted stereotactically into the right caudate nucleus of SD rats (control C6 group and transfected group). The rats bearing well-established C6 gliomas were treated with LXSN-AS-AKT2 DNA or LXSN (empty vector)-lipofectamine complexes intratumorally (treated group and control treated group). The mean survival of the rats of control C6 group and treated control group was 17.8+/-0.92 days and 17.5+/-1.10 days, respectively. The mean survival of the rats of transfected and treated group was significantly prolonged. MR images revealed distinct cerebral tumor foci in all of the control rats, whereas four rats in transfected group did not develop tumors and the tumor foci in five rats of treated group were regressed and disappeared. The expression of AKT2, PCNA, MMP2/9, and cyclin D were inhibited in the tumors of rats in transfected and treated groups while GFAP expression was increased. These results suggest that AKT pathway may play an important role in the development and progression of gliomas. Anti-AKT approach will open a new perspective for a targeted molecular therapy of malignant gliomas.
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Affiliation(s)
- Peiyu Pu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, People's Republic of China,
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Glass R, Synowitz M, Kronenberg G, Walzlein JH, Markovic DS, Wang LP, Gast D, Kiwit J, Kempermann G, Kettenmann H. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 2006; 25:2637-46. [PMID: 15758174 PMCID: PMC6725181 DOI: 10.1523/jneurosci.5118-04.2005] [Citation(s) in RCA: 157] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Neural precursor cells contribute to adult neurogenesis and to limited attempts of brain repair after injury. Here we report that in a murine experimental glioblastoma model, endogenous neural precursors migrate from the subventricular zone toward the tumor and surround it. The association of endogenous precursors with syngenic tumor grafts was observed, after injecting red fluorescent protein-labeled G261 cells into the caudate-putamen of transgenic mice, which express green fluorescent protein under a promoter for nestin (nestin-GFP). Fourteen days after inoculation, the nestin-GFP cells surrounded the tumors in several cell layers and expressed markers of early noncommitted and committed precursors. Nestin-GFP cells were further identified by a characteristic membrane current pattern as recorded in acute brain slices. 5-bromo-2-deoxyuridine labeling and dye tracing experiments revealed that the tumor-associated precursors originated from the subventricular zone. Moreover, in cultured explants from the subventricular zone, the neural precursors showed extensive tropism for glioblastomas. Tumor-induced endogenous precursor cell accumulation decreased with age of the recipient; this correlated with increased tumor size and shorter survival times in aged mice. Coinjection of glioblastoma cells with neural precursors improved the survival time of old mice to a level similar to that in young mice. Coculture experiments showed that neural precursors suppressed the rapid increase in tumor cell number, which is characteristic of glioblastoma, and induced glioblastoma cell apoptosis. Our results indicate that tumor cells attract endogenous precursor cells; the presence of precursor cells is antitumorigenic; and this cellular interaction decreases with aging.
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Affiliation(s)
- Rainer Glass
- Cellular Neuroscience Group, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany
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Nieto-Sampedro M, Doncel-Pérez E, Fernández-Mayoralas A. Natural, synthetic and semisynthetic glycolipid inhibitors of glioma growth. Expert Opin Ther Pat 2005; 14:487-97. [DOI: 10.1517/13543776.14.4.487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Hua Y, Tang LL, Fewel ME, Keep RF, Schallert T, Muraszko KM, Hoff JT, Xi GH. Systemic use of argatroban reduces tumor mass, attenuates neurological deficits and prolongs survival time in rat glioma models. ACTA NEUROCHIRURGICA. SUPPLEMENT 2005; 95:403-6. [PMID: 16463890 DOI: 10.1007/3-211-32318-x_82] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Our previous studies showed that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurological deficits in a C6 glioma model. The present study investigated whether systemic argatroban administration can reduce glioma mass and neurological deficits and extend survival time in C6 and F98 gliomas. Rat C6 or F98 glioma cells were infused into the right caudate of adult male Fischer 344 rats. Osmotic minipump loaded with argatroban (0.3 mg/hour) or vehicle was implanted into abdomen immediately after glioma implantation. Tumor mass was determined at day 9. Over the period of the experiment, the animals underwent behavioral testing (forelimb placing and forelimb use asymmetry). In addition, survival time was tested in the F98 glioma model. In C6 glioma, argatroban reduced glioma mass (p < 0.05) and neurological deficits (p < 0.05) at day 9. In F98 glioma, agratroban prolonged the survival time (p < 0.05) and reduced the body weight loss (84 +/- 15 gram vs. 99 +/- 2 gram in the vehicle group, P < 0.05). In conclusion, systemic use of argatroban reduced tumor mass and neurological deficits, and prolonged survival time. These results suggest that thrombin plays a key role in glioma growth and thrombin inhibition with argatroban may be a novel treatment for gliomas.
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Affiliation(s)
- Y Hua
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109-0532, USA
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De Vleeschouwer S, Van Gool SW, Van Calenbergh F. Immunotherapy for malignant gliomas: emphasis on strategies of active specific immunotherapy using autologous dendritic cells. Childs Nerv Syst 2005; 21:7-18. [PMID: 15452731 DOI: 10.1007/s00381-004-0994-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2004] [Indexed: 12/25/2022]
Abstract
REVIEW In this review, we discuss immunotherapy for malignant gliomas. EMPHASIS The emphasis is on the novel strategy of active specific immunotherapy using dendritic cells as antigen-presenting cells, especially its theoretical concepts and advantages, specific requirements, critical issues, pre-clinical and early clinical experience. Dendritic cell vaccination is situated in the diversity of other immunotherapeutical approaches. FURTHER DISCUSSION Future directions, challenges, and drawbacks will be discussed.
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Affiliation(s)
- Steven De Vleeschouwer
- Department of Neurosurgery, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
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Vince GH, Bendszus M, Schweitzer T, Goldbrunner RH, Hildebrandt S, Tilgner J, Klein R, Solymosi L, Christian Tonn J, Roosen K. Spontaneous regression of experimental gliomas--an immunohistochemical and MRI study of the C6 glioma spheroid implantation model. Exp Neurol 2004; 190:478-85. [PMID: 15530886 DOI: 10.1016/j.expneurol.2004.08.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2004] [Revised: 08/20/2004] [Accepted: 08/23/2004] [Indexed: 10/26/2022]
Abstract
OBJECTIVE The orthotopic C6 glioma spheroid implantation model has been used to examine factors of neoangiogenesis, growth factor release, and protease expression as well the effect of antitumor agents. The present study systematically investigates the long-term course of orthotopically implanted C6 spheroid gliomas. METHODS Reaggregated C6 spheroid tumors were implanted into the forebrain of 48 male Sprague-Dawley rats (32 immunocompetent, 16 thymectomized). The animals were examined by MRI at postoperative day (POD) 7, 14, 21, 28, 32, 45, 60, and 70. The MRI protocol included a T2-w and T1-w SE sequence before and after application of contrast medium and a CISS 3D sequence for volumetry. A total of six animals were selected after each MR exam from both groups and sacrificed for HE light microscopy and CD8+ T-lymphocyte, ED1+ macrophage, CD31+ endothelial cell immunohistochemistry. RESULTS The tumors progressed to reach a maximum volume on day 28: 0.23 +/- 0.05 ml in the thymectomized and 0.16 +/- 0.021 ml in the immunocompetent group. Tumors then consistently regressed to vanish completely by POD 70. The influx of cytotoxic CD8+ T-lymphocytes correlated with tumor progression and the tumors reached a larger size in the thymectomized group. However, the time course of tumor regression was the same for both groups. CONCLUSION The present data suggest that the orthotopic C6 glioma implanted into Sprague-Dawley rats will progress within a time span of approximately 4 weeks and can then retrogress again spontaneously. This finding has to be taken into account when deciding on a study protocol and the appropriate animal model. The C6 glioma model may be suitable to study the cell biological steps involved in the phenomenon of spontaneous tumor regression.
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Affiliation(s)
- Giles H Vince
- Department of Neurosurgery, University of Wuerzburg, Germany.
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