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1
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Mao C, Poimenidou M, Craig BT. Current Knowledge and Perspectives of Immunotherapies for Neuroblastoma. Cancers (Basel) 2024; 16:2865. [PMID: 39199637 PMCID: PMC11353182 DOI: 10.3390/cancers16162865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/02/2024] [Accepted: 08/12/2024] [Indexed: 09/01/2024] Open
Abstract
Neuroblastoma (NBL) cells highly express disialoganglioside GD2, which is restricted and weakly expressed in selected healthy cells, making it a desirable target of immunotherapy. Over the past two decades, application of dinutuximab, an anti-GD2 monoclonal antibody (mAb), has been one of the few new therapies to substantially improve outcomes to current levels. Given the persistent challenge of relapse and therapeutic resistance, there is an urgent need for new effective and tolerable treatment options for high-risk NBL. Recent breakthroughs in immune checkpoint inhibitor (ICI) therapeutics have not translated into high-risk NBL, like many other major pediatric solid tumors. Given the suppressed tumor microenvironment (TME), single ICIs like anti-CTLA4 and anti-PD1 have not demonstrated significant antitumor response rates. Meanwhile, emerging studies are reporting novel advancements in GD2-based therapies, targeted therapies, nanomedicines, and other immunotherapies such as adoptive transfer of natural killer (NK) cells and chimeric antigen receptors (CARs), and these hold interesting promise for the future of high-risk NBL patient care. Herein, we summarize the current state of the art in NBL therapeutic options and highlight the unique challenges posed by NBL that have limited the successful adoption of immune-modifying therapies. Through this review, we aim to direct the field's attention to opportunities that may benefit from a combination immunotherapy strategy.
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Affiliation(s)
- Chenkai Mao
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Center for Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - Maria Poimenidou
- Center for Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - Brian T. Craig
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Center for Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
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2
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Majnooni MB, Fakhri S, Ghanadian SM, Bahrami G, Mansouri K, Iranpanah A, Farzaei MH, Mojarrab M. Inhibiting Angiogenesis by Anti-Cancer Saponins: From Phytochemistry to Cellular Signaling Pathways. Metabolites 2023; 13:metabo13030323. [PMID: 36984763 PMCID: PMC10052344 DOI: 10.3390/metabo13030323] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/06/2023] [Accepted: 02/16/2023] [Indexed: 02/25/2023] Open
Abstract
Saponins are one of the broadest classes of high-molecular-weight natural compounds, consisting mainly of a non-polar moiety with 27 to 30 carbons and a polar moiety containing sugars attached to the sapogenin structure. Saponins are found in more than 100 plant families as well as found in marine organisms. Saponins have several therapeutic effects, including their administration in the treatment of various cancers. These compounds also reveal noteworthy anti-angiogenesis effects as one of the critical strategies for inhibiting cancer growth and metastasis. In this study, a comprehensive review is performed on electronic databases, including PubMed, Scopus, ScienceDirect, and ProQuest. Accordingly, the structural characteristics of triterpenoid/steroid saponins and their anti-cancer effects were highlighted, focusing on their anti-angiogenic effects and related mechanisms. Consequently, the anti-angiogenic effects of saponins, inhibiting the expression of genes related to vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) are two main anti-angiogenic mechanisms of triterpenoid and steroidal saponins. The inhibition of inflammatory signaling pathways that stimulate angiogenesis, such as pro-inflammatory cytokines, mitogen-activated protein kinase (MAPKs), and phosphoinositide 3-kinases/protein kinase B (PI3K/Akt), are other anti-angiogenic mechanisms of saponins. Furthermore, the anti-angiogenic and anti-cancer activity of saponins was closely related to the binding site of the sugar moiety, the type and number of their monosaccharide units, as well as the presence of some functional groups in their aglycone structure. Therefore, saponins are suitable candidates for cancer treatment by inhibiting angiogenesis, for which extensive pre-clinical and comprehensive clinical trial studies are recommended.
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Affiliation(s)
- Mohammad Bagher Majnooni
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6714415153, Iran
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Syed Mustafa Ghanadian
- Department of Pharmacognosy, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran
| | - Gholamreza Bahrami
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran
| | - Amin Iranpanah
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
- Correspondence: or (M.H.F.); (M.M.); Tel.: +98-08334266780 (M.M.)
| | - Mahdi Mojarrab
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
- Correspondence: or (M.H.F.); (M.M.); Tel.: +98-08334266780 (M.M.)
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Bartolucci D, Montemurro L, Raieli S, Lampis S, Pession A, Hrelia P, Tonelli R. MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment. Cancers (Basel) 2022; 14:4421. [PMID: 36139583 PMCID: PMC9496712 DOI: 10.3390/cancers14184421] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
Among childhood cancers, neuroblastoma is the most diffuse solid tumor and the deadliest in children. While to date, the pathology has become progressively manageable with a significant increase in 5-year survival for its less aggressive form, high-risk neuroblastoma (HR-NB) remains a major issue with poor outcome and little survivability of patients. The staging system has also been improved to better fit patient needs and to administer therapies in a more focused manner in consideration of pathology features. New and improved therapies have been developed; nevertheless, low efficacy and high toxicity remain a staple feature of current high-risk neuroblastoma treatment. For this reason, more specific procedures are required, and new therapeutic targets are also needed for a precise medicine approach. In this scenario, MYCN is certainly one of the most interesting targets. Indeed, MYCN is one of the most relevant hallmarks of HR-NB, and many studies has been carried out in recent years to discover potent and specific inhibitors to block its activities and any related oncogenic function. N-Myc protein has been considered an undruggable target for a long time. Thus, many new indirect and direct approaches have been discovered and preclinically evaluated for the interaction with MYCN and its pathways; a few of the most promising approaches are nearing clinical application for the investigation in HR-NB.
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Affiliation(s)
| | - Luca Montemurro
- Pediatric Oncology and Hematology Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | | | | | - Andrea Pession
- Pediatric Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Roberto Tonelli
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
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4
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Frosch J, Leontari I, Anderson J. Combined Effects of Myeloid Cells in the Neuroblastoma Tumor Microenvironment. Cancers (Basel) 2021; 13:1743. [PMID: 33917501 PMCID: PMC8038814 DOI: 10.3390/cancers13071743] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/02/2021] [Accepted: 04/02/2021] [Indexed: 12/13/2022] Open
Abstract
Despite multimodal treatment, survival chances for high-risk neuroblastoma patients remain poor. Immunotherapeutic approaches focusing on the activation and/or modification of host immunity for eliminating tumor cells, such as chimeric antigen receptor (CAR) T cells, are currently in development, however clinical trials have failed to reproduce the preclinical results. The tumor microenvironment is emerging as a major contributor to immune suppression and tumor evasion in solid cancers and thus has to be overcome for therapies relying on a functional immune response. Among the cellular components of the neuroblastoma tumor microenvironment, suppressive myeloid cells have been described as key players in inhibition of antitumor immune responses and have been shown to positively correlate with more aggressive disease, resistance to treatments, and overall poor prognosis. This review article summarizes how neuroblastoma-driven inflammation induces suppressive myeloid cells in the tumor microenvironment and how they in turn sustain the tumor niche through suppressor functions, such as nutrient depletion and generation of oxidative stress. Numerous preclinical studies have suggested a range of drug and cellular therapy approaches to overcome myeloid-derived suppression in neuroblastoma that warrant evaluation in future clinical studies.
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Affiliation(s)
| | | | - John Anderson
- UCL Institute of Child Health, Developmental Biology and Cancer Section, University College London, London WC1N 1EH, UK; (J.F.); (I.L.)
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5
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Liu KX, Joshi S. "Re-educating" Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma. Front Immunol 2020; 11:1947. [PMID: 32983125 PMCID: PMC7493646 DOI: 10.3389/fimmu.2020.01947] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/20/2020] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma is the most common extracranial pediatric tumor and often presents with metastatic disease, and patients with high-risk neuroblastoma have survival rates of ~50%. Neuroblastoma tumorigenesis is associated with the infiltration of various types of immune cells, including myeloid derived suppressor cells, tumor associated macrophages (TAMs), and regulatory T cells, which foster tumor growth and harbor immunosuppressive functions. In particular, TAMs predict poor clinical outcomes in neuroblastoma, and among these immune cells, TAMs with an M2 phenotype comprise an immune cell population that promotes tumor metastasis, contributes to immunosuppression, and leads to failure of radiation or checkpoint inhibitor therapy. This review article summarizes the role of macrophages in tumor angiogenesis, metastasis, and immunosuppression in neuroblastoma and discusses the recent advances in "macrophage-targeting strategies" in neuroblastoma with a focus on three aspects: (1) inhibition of macrophage recruitment, (2) targeting macrophage survival, and (3) reprogramming of macrophages into an immunostimulatory phenotype.
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Affiliation(s)
- Kevin X. Liu
- Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Shweta Joshi
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, UCSD Rady's Children's Hospital, University of California, San Diego, La Jolla, CA, United States
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6
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Joshi S. Targeting the Tumor Microenvironment in Neuroblastoma: Recent Advances and Future Directions. Cancers (Basel) 2020; 12:E2057. [PMID: 32722460 PMCID: PMC7465822 DOI: 10.3390/cancers12082057] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 12/30/2022] Open
Abstract
Neuroblastoma (NB) is the most common pediatric tumor malignancy that originates from the neural crest and accounts for more than 15% of all the childhood deaths from cancer. The neuroblastoma cancer research has long been focused on the role of MYCN oncogene amplification and the contribution of other genetic alterations in the progression of this malignancy. However, it is now widely accepted that, not only tumor cells, but the components of tumor microenvironment (TME), including extracellular matrix, stromal cells and immune cells, also contribute to tumor progression in neuroblastoma. The complexity of different components of tumor stroma and their resemblance with surrounding normal tissues pose huge challenges for therapies targeting tumor microenvironment in NB. Hence, the detailed understanding of the composition of the TME of NB is crucial to improve existing and future potential immunotherapeutic approaches against this childhood cancer. In this review article, I will discuss different components of the TME of NB and the recent advances in the strategies, which are used to target the tumor microenvironment in neuroblastoma.
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Affiliation(s)
- Shweta Joshi
- Department of Pediatrics, Division of Pediatric Hematology-Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0815, USA
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7
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VEGF expression correlates with neuronal differentiation and predicts a favorable prognosis in patients with neuroblastoma. Sci Rep 2017; 7:11212. [PMID: 28894229 PMCID: PMC5593816 DOI: 10.1038/s41598-017-11637-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 08/29/2017] [Indexed: 01/25/2023] Open
Abstract
Neuroblastoma (NB) is a childhood cancer with a low survival rate and great metastatic potential. Vascular endothelial growth factor (VEGF), an angiogenesis factor, has been found to be involved in CRT-related neuronal differentiation of NB cells. In this study, we further confirmed the role VEGF in NB through mouse xenograft model and clinical analysis from NB patients. In xenograft experiments, CRT overexpression effectively inhibited the tumor growth. In addition, the mRNA and protein levels of VEGF and differentiation marker GAP-43 were upregulated by induced CRT expression. However, no significant correlation between the expression level of VEGF and microvessel density was observed in human NB tumors, suggesting a novel mechanism of VEGF participating in NB tumorigenesis through an angiogenesis-independent pathway. In NB patients' samples, mRNA expression levels of CRT and VEGF were positively correlated. Furthermore, positive VEGF expression by immunostaining of NB tumors was found to correlate well with histological grade of differentiation and predicted a favorable prognosis. In conclusion, our findings suggest that VEGF is a favorable prognostic factor of NB and might affect NB tumor behavior through CRT-driven neuronal differentiation rather than angiogenesis that might shed light on a novel therapeutic strategy to improve the outcome of NB.
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8
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Erdreich-Epstein A, Singh AR, Joshi S, Vega FM, Guo P, Xu J, Groshen S, Ye W, Millard M, Campan M, Morales G, Garlich JR, Laird PW, Seeger RC, Shimada H, Durden DL. Association of high microvessel α vβ 3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126. Oncotarget 2016; 8:52193-52210. [PMID: 28881723 PMCID: PMC5581022 DOI: 10.18632/oncotarget.13386] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 10/26/2016] [Indexed: 11/25/2022] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αvβ3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αvβ3 was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in αvβ3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry). Integrin αvβ3 was expressed on 60% of tumor microvessels when PTEN was negative or focal, as compared to 32% of microvessels in tumors with diffuse PTEN expression (p < 0.001). In a MYCN transgenic mouse model, loss of one allele of PTEN promoted tumor growth, illustrating the potential role of PTEN in neuroblastoma pathogenesis. Interestingly, we report the novel dual PI-3K/BRD4 activity of SF1126 (originally developed as an RGD-conjugated pan PI3K inhibitor). SF1126 inhibits BRD4 bromodomain binding to acetylated lysine residues with histone H3 as well as PI3K activity in the MYCN amplified neuroblastoma cell line IMR-32. Moreover, SF1126 suppressed MYCN expression and MYCN associated transcriptional activity in IMR-32 and CHLA136, resulting in overall decrease in neuroblastoma cell viability. Finally, treatment of neuroblastoma tumors with SF1126 inhibited neuroblastoma growth in vivo. These data suggest integrin αvβ3, MYCN/BRD4 and PTEN/PI3K/AKT signaling as biomarkers and hence therapeutic targets in neuroblastoma and support testing of the RGD integrin αvβ3-targeted PI-3K/BRD4 inhibitor, SF1126 as a therapeutic strategy in this specific subgroup of high risk neuroblastoma.
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Affiliation(s)
- Anat Erdreich-Epstein
- Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA.,Department of Pathology, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Alok R Singh
- Department of Pediatrics, Moores Cancer Center, University of California San Diego, California, USA
| | - Shweta Joshi
- Department of Pediatrics, Moores Cancer Center, University of California San Diego, California, USA
| | - Francisco M Vega
- Department of Pediatrics, Moores Cancer Center, University of California San Diego, California, USA.,Instituto de Biomedicina de Sevilla, IBiS/HUVR/CSIC/Universidad de Sevilla and Department of Medical Physiology and Biophysics, Universidad de Sevilla, Spain
| | - Pinzheng Guo
- Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Jingying Xu
- Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Susan Groshen
- Department of Preventive Medicine, Keck School of Medicine, Los Angeles, California, USA
| | - Wei Ye
- Department of Preventive Medicine, Keck School of Medicine, Los Angeles, California, USA
| | - Melissa Millard
- Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Mihaela Campan
- Department of Surgery University of Southern California, Keck School of Medicine, Los Angeles, California, USA
| | | | | | - Peter W Laird
- Department of Surgery University of Southern California, Keck School of Medicine, Los Angeles, California, USA.,USC Epigenome Center, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.,Current Address: Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - Robert C Seeger
- Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Hiroyuki Shimada
- Department of Pathology, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Donald L Durden
- Department of Pediatrics, Moores Cancer Center, University of California San Diego, California, USA.,SignalRx Pharmaceuticals, San Diego, California, USA.,Department of Pediatrics, UCSD School of Medicine and Rady Children's Hospital San Diego, California, USA
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9
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PlGF and VEGF-A Regulate Growth of High-Risk MYCN-Single Copy Neuroblastoma Xenografts via Different Mechanisms. Int J Mol Sci 2016; 17:ijms17101613. [PMID: 27669225 PMCID: PMC5085646 DOI: 10.3390/ijms17101613] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 09/06/2016] [Accepted: 09/13/2016] [Indexed: 01/05/2023] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and is a rapidly growing, highly-vascularized cancer. NBs frequently express angiogenic factors and high tumor angiogenesis has been associated with poor outcomes. Placental growth factor (PlGF) is an angiogenic protein belonging to the vascular endothelial growth factor (VEGF) family and is up-regulated mainly in pathologic conditions. Recently, PlGF was identified as a member of a gene expression signature characterizing highly malignant NB stem cells drawing attention as a potential therapeutic target in NB. In the present study, we sought to investigate the expression of PlGF in NB patients and the effect of PlGF inhibition on high-risk MYCN-non-amplified SK-N-AS NB xenografts. Human SK-N-AS cells, which are poorly differentiated and express PlGF and VEGF-A, were implanted subcutaneously in athymic nude mice. Treatment was done by intratumoral injection of replication-incompetent adenoviruses (Ad) expressing PlGF- or VEGF-specific short hairpin (sh)RNA, or soluble (s)VEGF receptor 2 (VEGFR2). The effect on tumor growth and angiogenesis was analyzed. High PlGF expression levels were observed in human advanced-stage NBs. Down-regulating PlGF significantly reduced NB growth in established NB xenografts by reducing cancer cell proliferation but did not suppress angiogenesis. In contrast, blocking VEGF by administration of Ad(sh)VEGF and Ad(s)VEGFR2 reduced tumor growth associated with decreased tumor vasculature. These findings suggest that PlGF and VEGF-A modulate MYCN-non-amplified NB tumors by different mechanisms and support a role for PlGF in NB biology.
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Qiao D, Wei C, Ke C, Zeng X. Effects of Hyriopsis cumingii polysaccharides on angiogenesis, macrophage chemotaxis, proliferation and phagocytosis. Food Funct 2015; 6:869-77. [PMID: 25620195 DOI: 10.1039/c4fo01121j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hyriopsis cumingii polysaccharides (HCPS) showed anti-angiogenic activity and promoting effects on the chemotaxis, proliferation and phagocytosis of peritoneal macrophage.
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Affiliation(s)
- Deliang Qiao
- College of Biological and Pharmaceutical Engineering
- West Anhui University
- Lu'an 237012
- China
- College of Food Science and Technology
| | - Chuanbao Wei
- College of Biological and Pharmaceutical Engineering
- West Anhui University
- Lu'an 237012
- China
| | - Chunlin Ke
- College of Food Science and Technology
- Nanjing Agricultural University
- Nanjing 210095
- China
| | - Xiaoxiong Zeng
- College of Food Science and Technology
- Nanjing Agricultural University
- Nanjing 210095
- China
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11
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Weng WC, Lin KH, Wu PY, Lu YC, Weng YC, Wang BJ, Liao YF, Hsu WM, Lee WT, Lee H. Calreticulin Regulates VEGF-A in Neuroblastoma Cells. Mol Neurobiol 2014; 52:758-70. [PMID: 25288151 DOI: 10.1007/s12035-014-8901-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 09/24/2014] [Indexed: 01/06/2023]
Abstract
Calreticulin (CRT) has been previously correlated with the differentiation of neuroblastoma (NB), implying a favorable prognostic factor. Vascular endothelial growth factor (VEGF) has been reported to participate in the behavior of NB. This study investigated the association of CRT and VEGF-A in NB cells. The expressions of VEGF-A and HIF-1α, with overexpression or knockdown of CRT, were measured in three NB cells (SH-SY5Y, SK-N-DZ, and stNB-V1). An inducible CRT NB cell line and knockdown CRT stable cell lines were also established. The impacts of CRT overexpression on NB cell apoptosis, proliferation, and differentiation were also evaluated. We further examined the role of VEGF-A in the NB cell differentiation via VEGF receptor blockade. Constitutive overexpression of CRT led to NB cell differentiation without proliferation. Thus, an inducible CRT stNB-V1 cell line was generated by a tetracycline-regulated gene system. CRT overexpression increased VEGF-A and HIF-1α messenger RNA (mRNA) expressions in SH-SY5Y, SK-N-DZ, and stNB-V1 cells. CRT overexpression also enhanced VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. Knockdown of CRT decreased VEGF-A and HIF-1α mRNA expressions and lowered VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. We further demonstrated that NB cell apoptosis was not affected by CRT overexpression in stNB-V1 cells. Nevertheless, overexpression of CRT suppressed cell proliferation and enhanced cell differentiation in stNB-V1 cells, whereas blockage of VEGFR-1 markedly suppressed the expression of neuron-specific markers including GAP43, NSE2, and NFH, as well as TrkA, a molecular marker indicative of NB cell differentiation. Our findings suggest that VEGF-A is involved in CRT-related neuronal differentiation in NB. Our work may provide important information for developing a new therapeutic strategy to improve the outcome of NB patients.
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Affiliation(s)
- Wen-Chin Weng
- Department of Pediatrics, College of Medicine, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan
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12
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Dorstyn L, Puccini J, Nikolic A, Shalini S, Wilson CH, Norris MD, Haber M, Kumar S. An unexpected role for caspase-2 in neuroblastoma. Cell Death Dis 2014; 5:e1383. [PMID: 25144718 PMCID: PMC4454317 DOI: 10.1038/cddis.2014.342] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 07/11/2014] [Indexed: 12/12/2022]
Abstract
Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene-mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the Eμ-Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH-MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2−/− mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2+/+ counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2−/− tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis.
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Affiliation(s)
- L Dorstyn
- 1] Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia [2] Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia
| | - J Puccini
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia
| | - A Nikolic
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia
| | - S Shalini
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia
| | - C H Wilson
- Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia
| | - M D Norris
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
| | - M Haber
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
| | - S Kumar
- 1] Centre for Cancer Biology, University of South Australia, Adelaide, SA 5001, Australia [2] Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia
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Dimethyl phenyl piperazine iodide (DMPP) induces glioma regression by inhibiting angiogenesis. Exp Cell Res 2013; 320:354-64. [PMID: 24162003 DOI: 10.1016/j.yexcr.2013.10.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 10/04/2013] [Accepted: 10/09/2013] [Indexed: 01/09/2023]
Abstract
1,1-Dimethyl-4-phenyl piperazine iodide (DMPP) is a synthetic nicotinic acetylcholine receptor (nAChR) agonist that could reduce airway inflammation. In this study, we demonstrated that DMPP could dramatically inhibit glioma size maintained on the chick embryonic chorioallantoic membrane (CAM). We first performed MTT and BrdU incorporation experiments on U87 glioma cells in vitro to understand the mechanism involved. We established that DMPP did not significantly affect U87 cell proliferation and survival. We speculated that DMPP directly caused the tumor to regress by affecting the vasculature in and around the implanted tumor on our chick CAM model. Hence, we conducted detailed analysis of DMPP's inhibitory effects on angiogenesis. Three vasculogenesis and angiogenesis in vivo models were used in the study which included (1) early chick blood islands formation, (2) chick yolk-sac membrane (YSW) and (3) CAM models. The results revealed that DMPP directly suppressed all developmental stages involved in vasculogenesis and angiogenesis - possibly by acting through Ang-1 and HIF-2α signaling. In sum, our results show that DMPP could induce glioma regression grown on CAM by inhibiting vasculogenesis and angiogenesis.
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Ward NL, Lamanna JC. The neurovascular unit and its growth factors: coordinated response in the vascular and nervous systems. Neurol Res 2013; 26:870-83. [PMID: 15727271 DOI: 10.1179/016164104x3798] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The nervous and vascular systems contain many common organizational features and develop similarly in terms of anatomical patterning. During embryogenesis and in regions of the brain undergoing postnatal neurogenesis, neural stem cells and endothelial cells are found in close proximity, or within a so-called vascular niche. The similarities in patterning and proximity may reflect coordinated development based on responsiveness to similar growth factors such as vascular endothelial growth factor, semaphorin, and ephrins/Ephs: molecules involved in the development and maintenance of both the nervous and vascular systems. Despite the blatant similarities between the vascular and nervous systems, little is still known about the co-dependence and/or interactions between the two systems during development and following alterations in metabolic demand as seen during aging, exercise, and disease processes. The interactions between the two systems involving common growth factors suggest these two systems have evolved in an interconnected way.
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Affiliation(s)
- Nicole L Ward
- Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
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15
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Waheed Roomi M, Kalinovsky T, Roomi NW, Niedzwiecki A, Rath M. Inhibition of the SK-N-MC human neuroblastoma cell line in vivo and in vitro by a novel nutrient mixture. Oncol Rep 2013; 29:1714-20. [PMID: 23446555 PMCID: PMC3658814 DOI: 10.3892/or.2013.2307] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 01/29/2013] [Indexed: 01/12/2023] Open
Abstract
Neuroblastoma, a peripheral nervous system cancer that can be highly invasive and metastatic, accounts for 8–10% of all solid childhood tumors in children under the age of 15 years. Despite multiple clinical efforts, prognosis remains poor for this enigmatic disease. A nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract has shown significant antitumor effects. Using the nude mouse xenograft model, we investigated the efficacy of NM. We also tested the effect of NM in vitro, evaluating cell viability, secretion of the matrix metalloproteinases (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 secretion, Matrigel invasion and cellular apoptosis and morphology. Athymic nude mice 5–6 weeks of age were inoculated with 3×106 SK-N-MC neuroblastoma cells subcutaneously and randomly divided into two groups. Group A was fed a regular diet and group B a regular diet supplemented with 0.5% NM. Four weeks later, the mice were sacrificed and their tumors were excised, weighed and processed for histology. We also tested the effect of NM in vitro. NM inhibited the growth of xenograft tumors by 22% (P=0.04); and, in vitro, NM induced dose-dependent inhibition of cell proliferation with a decrease of 27% (P=0.001) and 36% (P=0.002) at 500 and 1000 μg/ml NM compared to the control, respectively. Zymography revealed MMP-2 secretion in normal cells and PMA (100 ng/ml)-induced MMP-9 secretion. NM inhibited the secretion of both MMPs with total blockage at a concentration of 100 μg/ml. Reverse zymography demonstrated a dose-dependent increase in TIMP-2 expression by NM. Notable, SK-N-MC human neuroblastoma cells were not invasive through Matrigel. NM induced dose-dependent apoptosis of SK-N-MC cells. The results suggest that NM may have therapeutic potential in treating neuroblastoma.
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Affiliation(s)
- M Waheed Roomi
- Dr Rath Research Institute, Oncology Division, Santa Clara, CA, USA
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16
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Pistoia V, Bianchi G, Borgonovo G, Raffaghello L. Cytokines in neuroblastoma: from pathogenesis to treatment. Immunotherapy 2012; 3:895-907. [PMID: 21751957 DOI: 10.2217/imt.11.80] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Cytokines released by cancer cells or by cells of the tumor microenvironment stimulate angiogenesis, act as autocrine or paracrine growth factors for malignant cells, promote tumor cell migration and metastasis or create an immunosuppressive microenvironment. These tumor-promoting effects of cytokines also apply to neuroblastoma (NB), a pediatric neuroectodermal malignancy with frequent metastatic presentation at diagnosis and poor prognosis. IL-6 and VEGF are the best characterized cytokines that stimulated tumor growth and metastasis, while others such as IFN-γ can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis. On the other hand, cytokines are part of the anti-NB therapeutic armamentarium, as exemplified by IL-2 and granulocyte-macrophage colony stimulating factor that potentiate the activity of anti-NB antibodies. These recent results raise hope for more efficacious treatment of this ominous pediatric malignancy.
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Affiliation(s)
- Vito Pistoia
- Laboratory of Oncology, G Gaslini Institute, Largo G Gaslini 5, 16148 Genova, Italy.
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17
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Wang R, Gu Y, Zhang WD, Yan XN, Jin L, Wang XJ. Inhibition of tumor-induced angiogenesis and its mechanism by ardipusilloside I purified from Ardisia pusilla. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2012; 14:55-63. [PMID: 22263594 DOI: 10.1080/10286020.2011.631182] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
The aim of this study was to evaluate the effects of ardipusilloside I isolated from Ardisia pusilla on tumor angiogenesis and its mechanism of action. The anti-angiogenic effect in vivo was evaluated on xenograft in the athymic mice model and the chicken chorioallantoic membrane (CAM) neovascularization model, the inhibition of growth in vitro was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the mechanism was demonstrated through detecting microvessel density (MVD), vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2) and P-VEGFR2 protein expressions, as well as mRNA expressions of VEGF and VEGFR2. The results showed that ardipusilloside I had a good inhibitory effect on A549 xenografted tumor growth, angiogenesis of CAM, and A549 cell growth. Compared to the negative control, MVD protein and mRNA expressions of VEGF and VEGFR were significantly inhibited by ardipusilloside I in a dose-dependent manner. These findings suggested that ardipusilloside I might be a promising candidate as angiogenesis inhibitors.
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Affiliation(s)
- Rong Wang
- Department of Pharmaceutical Preparation, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China
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18
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Zhen Z, Sun X, He Y, Cai Y, Wang J, Guan Z. The sequence of drug administration influences the antitumor effects of bevacizumab and cyclophosphamide in a neuroblastoma model. Med Oncol 2010; 28 Suppl 1:S619-25. [PMID: 20844988 DOI: 10.1007/s12032-010-9664-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2010] [Accepted: 08/17/2010] [Indexed: 10/19/2022]
Abstract
Currently, the prognosis of neuroblastoma is poor, and new therapeutic strategies are needed. This study aimed at evaluating whether the administration sequence of bevacizumab and cyclophosphamide influenced the antitumor effects in a neuroblastoma model. Bevacizumab was administered at 5 mg/kg body weight weekly, alone or combined with cyclophosphamide, to treat a neuroblastoma xenograft in nude mice, and the tumor inhibition rates were compared. The functions of tumor vessels at different time points after bevacizumab administration were detected by Hoechst 33342 labeling. The antitumor effects of cyclophosphamide, administered concomitantly with bevacizumab or when vessel function was most improved post-bevacizumab administration, were compared. The tumor inhibition rates of the neuroblastoma xenograft treated with bevacizumab, cyclophosphamide, or both were 38.1, 44.0, and 56.0%, respectively (P < 0.05). Bevacizumab reduced 64% of angiogenesis. Tumor vessel function was most improved 6 days after bevacizumab administration. The tumor inhibition rates in mice treated with cyclophosphamide, concomitantly with bevacizumab or 6 days after bevacizumab administration, were 55.9 and 66.8%, respectively (P < 0.05). Bevacizumab can reduce neuroblastoma growth and has a synergistic effect when combined with cyclophosphamide in vivo. This synergistic effect is further enhanced when cyclophosphamide is administered after bevacizumab, when tumor vessel function is most improved.
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Affiliation(s)
- Zijun Zhen
- Department of Pediatric Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
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19
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Pastorino F, Loi M, Sapra P, Becherini P, Cilli M, Emionite L, Ribatti D, Greenberger LM, Horak ID, Ponzoni M. Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor. Clin Cancer Res 2010; 16:4809-21. [DOI: 10.1158/1078-0432.ccr-10-1354] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Nyalendo C, Sartelet H, Barrette S, Ohta S, Gingras D, Béliveau R. Identification of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation in association with neuroblastoma progression. BMC Cancer 2009; 9:422. [PMID: 19961596 PMCID: PMC2796679 DOI: 10.1186/1471-2407-9-422] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2009] [Accepted: 12/04/2009] [Indexed: 01/23/2023] Open
Abstract
Background Neuroblastoma is a pediatric tumor of neural crest cells that is clinically characterized by its variable evolution, from spontaneous regression to malignancy. Despite many advances in neuroblastoma research, 60% of neuroblastoma, which are essentially metastatic cases, are associated with poor clinical outcome due to the lack of effectiveness of current therapeutic strategies. Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), an enzyme involved in several steps in tumor progression, has previously been shown to be associated with poor clinical outcome for neuroblastoma. Based on our recent demonstration that MT1-MMP phosphorylation is involved in the growth of fibrosarcoma tumors, we examined the potential role of phosphorylated MT1-MMP in neuroblastoma progression. Methods Tyrosine phosphorylated MT1-MMP was immunostained on tissue microarray samples from 55 patients with neuroblastoma detected by mass screening (known to be predominantly associated with favourable outcome), and from 234 patients with standard diagnosed neuroblastoma. In addition, the effects of a non phosphorylable version of MT1-MMP on neuroblastoma cell migration and proliferation were investigated within three-dimensional collagen matrices. Results Although there is no correlation between the extent of tyrosine phosphorylation of MT1-MMP (pMT1-MMP) and MYCN amplification or clinical stage, we observed greater phosphorylation of pMT1-MMP in standard neuroblastoma, while it is less evident in neuroblastoma from mass screening samples (P = 0.0006) or in neuroblastoma samples from patients younger than one year (P = 0.0002). In vitro experiments showed that overexpression of a non-phosphorylable version of MT1-MMP reduced MT1-MMP-mediated neuroblastoma cell migration and proliferation within a three-dimensional type I collagen matrix, suggesting a role for the phosphorylated enzyme in the invasive properties of neuroblastoma cells. Conclusion Overall, these results suggest that tyrosine phosphorylated MT1-MMP plays an important role in neuroblastoma progression and that its expression is preferentially observed in tumor specimens from neuroblastoma patients showing poor clinical outcome.
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Affiliation(s)
- Carine Nyalendo
- Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, C,P, 8888, Succ, Centreville, Montréal, Québec H3C 3P8, Canada.
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21
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Jakovljević G, Culić S, Stepan J, Bonevski A, Seiwerth S. Vascular endothelial growth factor in children with neuroblastoma: a retrospective analysis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2009; 28:143. [PMID: 19895696 PMCID: PMC2779806 DOI: 10.1186/1756-9966-28-143] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Accepted: 11/06/2009] [Indexed: 11/18/2022]
Abstract
Background Despite aggressive therapy, advanced stage neuroblastoma patients have poor survival rates. Although angiogenesis correlates with advanced tumour stage and plays an important role in determining the tumour response to treatment in general, clinical data are still insufficient, and more clinical evaluations are needed to draw conclusions. The aim of this study was to evaluate vascular endothelial growth factor (VEGF) expression in patients with neuroblastoma, determine whether it correlates with other prognostic factors and/or therapeutic response, and to assess should VEGF be considered in a routine diagnostic workup. Materials and methods VEGF expression was determined by immunohistochemistry using anti-VEGF antibody in paraffin embedded primary tumour tissue from 56 neuroblastoma patients. Semiquantitative expression of VEGF was estimated and compared with gender, age, histology, disease stage, therapy, and survival. Statistical analyses, including multivariate analysis, were performed. Results VEGF expression correlated with disease stage and survival in neuroblastoma patients. Combination of VEGF expression and disease stage as a single prognostic value for survival (P-value = 0.0034; odds ratio (OR) (95%CI) = 26.17 (2.97-230.27) exhibited greater correlation with survival than individually. Hematopoietic stem cell transplantation significantly improved survival of the advanced stage patients with high VEGF expression. Conclusion VEGF expression should be considered in a routine diagnostic workup of children with neuroblastoma, especially in those more than 18 months old and with advanced disease stage. High VEGF expression at the time of disease diagnosis is a bad risk prognostic factor, and can be used to characterize subsets of patients with an unfavourable outcome.
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Affiliation(s)
- Gordana Jakovljević
- Department of Hematology and Oncology, Pediatric Clinic, Children's Clinical Hospital Zagreb, Zagreb, Croatia.
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22
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Xiong C, Wu H, Wei P, Pan M, Tuo Y, Kusakabe I, Du Y. Potent angiogenic inhibition effects of deacetylated chitohexaose separated from chitooligosaccharides and its mechanism of action in vitro. Carbohydr Res 2009; 344:1975-83. [DOI: 10.1016/j.carres.2009.06.036] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2009] [Revised: 06/03/2009] [Accepted: 06/18/2009] [Indexed: 11/30/2022]
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Taylor M, Geoerger B, Lagodny J, Farace F, Vassal G, Rössler J. [Potential role of antiangiogenic treatment in neuroblastoma]. Arch Pediatr 2009; 16:457-67. [PMID: 19299115 DOI: 10.1016/j.arcped.2009.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2008] [Revised: 09/17/2008] [Accepted: 02/01/2009] [Indexed: 10/21/2022]
Abstract
Focus on new drug development over the last few years has yielded new agents that differ from unspecific classical chemotherapeutics and ionizing radiation, while still targeting the cancer cell itself. Antiangiogenesis is a totally distinct approach targeting the tumor's blood vessels. This concept has now found its eligibility for the treatment of several adult solid tumors: the human antivascular endothelial growth factor (VEGF) antibody bevacizumab, as well as the VEGF receptor tyrosine kinase inhibitors, sunitinib and sorafinib, have recently been licensed by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of colorectal, renal, and lung cancer. Other antiangiogenic drugs are under preclinical and early clinical evaluation. However, what do we know of the use of these drugs in pediatric solid tumors, such as sarcomas and embryonal and neuronal tumors? For some time now, neuroblastoma has been shown to be dependent on angiogenesis. However, the first preclinical data on antiangiogenic drugs in neuroblastoma have not been published until recently, and clinical trials with antiangiogenic agents in neuroblastoma treatment protocols are scarce. This review adresses current knowledge on the important role and mechanisms of angiogenesis in neuroblastoma and summarizes available preclinical and clinical results of antiangiogenic agents used to treat neuroblastoma. Our review clearly demonstrates that clinical trials are urgently needed to bring forward promising antiangiogenesis concepts in neuroblastoma therapy.
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Affiliation(s)
- M Taylor
- Institut Gustave-Roussy, UPRES EA3535 Pharmacologie et nouveaux traitements dans le cancer, université Paris-Sud, 63, rue Gabriel-Péri, 94276 Le Kremlin-Bicêtre, France
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24
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Angiogenesis as a target in neuroblastoma. Eur J Cancer 2008; 44:1645-56. [DOI: 10.1016/j.ejca.2008.05.015] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2008] [Revised: 05/16/2008] [Accepted: 05/21/2008] [Indexed: 11/17/2022]
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Zhang Y, He L, Meng L, Luo W, Xu X. Suppression of tumor-induced angiogenesis by taspine isolated from Radix et Rhizoma Leonticis and its mechanism of action in vitro. Cancer Lett 2008; 262:103-13. [DOI: 10.1016/j.canlet.2007.11.035] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Revised: 08/30/2007] [Accepted: 11/26/2007] [Indexed: 01/31/2023]
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Qiao J, Kang JH, Cree J, Evers BM, Chung DH. Ets1 transcription factor mediates gastrin-releasing peptide-induced IL-8 regulation in neuroblastoma cells. Neoplasia 2007; 9:184-91. [PMID: 17401458 PMCID: PMC1838576 DOI: 10.1593/neo.06841] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2006] [Revised: 01/29/2007] [Accepted: 01/31/2007] [Indexed: 01/01/2023] Open
Abstract
Angiogenesis plays a critical role in tumor progression in various cancers, including neuroblastoma. We have previously shown that gastrin-releasing peptide (GRP) stimulates neuroblastoma growth and that its cell surface receptors, gastrin-releasing peptide receptors (GRP-R), are overexpressed in advanced-stage human neuroblastomas; however, the effects of GRP on angiogenesis are not clearly elucidated. Interleukin (IL) 8, a proinflammatory chemokine, plays an important role during tumor angiogenesis. Ets transcription factors, such as oncoproteins, cause tumor development and are also known to induce IL-8 expression. In the present study, we found an increased expression of Ets1 in more undifferentiated human neuroblastomas. Stable transfection of SK-N-SH human neuroblastoma cells with Ets1 plasmid resulted in increased IL-8 luciferase activity and IL-8 secretion into cell culture media. Conversely, silencing of Ets1 resulted in a significant decrease in IL-8 secretion in SK-N-SH cells. Moreover, exogenous GRP treatment increased Ets1 (T38) phosphorylation and Ets1 nuclear accumulation, and enhanced Ets1 binding to its DNA consensus sequence, resulting in the stimulation of IL-8 mRNA expression and protein secretion. Our findings demonstrate that GRP upregulates proangiogenic IL-8 expression in an Ets1-dependent manner, suggesting a critical role of this process during GRP-induced neuroblastoma angiogenesis and metastasis.
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Affiliation(s)
- Jingbo Qiao
- Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353, USA
| | - Jung-Hee Kang
- Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353, USA
| | - Jeremy Cree
- Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353, USA
| | - B Mark Evers
- Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353, USA
- Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353, USA
| | - Dai H. Chung
- Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353, USA
- Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353, USA
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Brignole C, Marimpietri D, Pastorino F, Nico B, Di Paolo D, Cioni M, Piccardi F, Cilli M, Pezzolo A, Corrias MV, Pistoia V, Ribatti D, Pagnan G, Ponzoni M. Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. J Natl Cancer Inst 2006; 98:1142-57. [PMID: 16912267 DOI: 10.1093/jnci/djj309] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Bortezomib is a selective and reversible inhibitor of the 26S proteasome that shows potent antitumor activity in vitro and in vivo against several human cancers of adulthood. No data are available on bortezomib activity against human pediatric neuroblastoma. METHODS Ten neuroblastoma cell lines and suspensions of primary neuroblastoma cells from three patients were tested for sensitivity to bortezomib. Colony formation, cell proliferation, cell cycle progression, and apoptosis were evaluated by a clonogenic assay and by measuring 3H-thymidine incorporation, bromodeoxyuridine uptake, DNA fragmentation, and phosphatidylserine exposure and propidium iodide staining, respectively. Angiogenesis was assessed by the chick embryo chorioallantoic membrane (CAM) assay. Two mouse xenograft models that mimic the growth and spread of neuroblastoma in humans were used to examine in vivo sensitivity of neuroblastoma to bortezomib. All statistical tests were two-sided. RESULTS Bortezomib inhibited proliferation and colony formation of neuroblastoma cell lines in a time- and dose-dependent manner. The mean bortezomib concentration that caused 50% inhibition of growth was 6.1 nM (95% confidence interval [CI] = 0.9 to 11.3 nM) at 72 hours. Bortezomib-treated neuroblastoma cells were arrested at G2/M and underwent apoptosis (mean percentage of apoptotic cells in four neuroblastoma cell lines treated with 20 nM bortezomib for 24 hours ranged from 20% to 35%, and caspases were activated by two- to fivefold with respect to untreated cells). Similar results were obtained for primary neuroblastoma cells exposed to bortezomib. Bortezomib inhibited angiogenesis in CAMs stimulated by conditioned medium from neuroblastoma cell lines, by neuroblastoma xenografts, and by primary neuroblastoma biopsy specimens (microvessel area: 2.9 x 10(-2) mm2, 95% CI = 1.8 x 10(-2) to 3.8 x 10(-2) mm2 in CAMs treated with biopsy specimens alone and 1.3 x 10(-2) mm2, 95% CI = 1 x 10(-2) to 1.5 x 10(-2) mm2 in CAMs treated with biopsy specimens plus bortezomib, P = .024). In both mouse models, mice treated with bortezomib lived statistically significantly longer than control mice (mean survival time in the pseudometastatic model: 74.2 versus 50.3 days, P<.001; mean survival time in the orthotopic model: 72.3 versus 50.6 days, P<.001). CONCLUSIONS Bortezomib is an effective inhibitor of neuroblastoma cell growth and angiogenesis. These findings provide the rationale for further clinical investigation of bortezomib in pediatric neuroblastoma.
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Affiliation(s)
- Chiara Brignole
- Laboratory of Oncology, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16147 Genoa, Italy
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Abstract
Neuroblastoma is a neuroectodermal tumor of childhood with poor prognosis and low survival in patients with advanced-stage disease who respond to conventional therapies but unfortunately, often present relapse. Therefore, the search for novel therapeutic strategies is warranted and represents the objective of many investigators. Among the new, innovative approaches, immunotherapy has attracted much interest. However, until recently, little information was available about the immunogenicity of human neuroblastoma.
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Affiliation(s)
- Lizzia Raffaghello
- Laboratory of Oncology, G Gaslini Institute, Largo Gerolamo Gaslini 5, 16147 Genova, Italy.
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Kalkunte S, Brard L, Granai CO, Swamy N. Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf. Angiogenesis 2006; 8:349-60. [PMID: 16400520 DOI: 10.1007/s10456-005-9024-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2005] [Accepted: 11/04/2005] [Indexed: 11/24/2022]
Abstract
Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with participation of intracellular signaling pathways. Regulation of angiogenesis carries tremendous potential for cancer therapy. Our earlier studies showed that vitamin D-binding protein-macrophage activating factor (DBP-maf) acts as a potent anti-angiogenic factor and inhibits tumor growth in vivo. The goal of this investigation was to understand the effect of DBP-maf on human endothelial cell (HEC) and the mechanism of angiogenesis inhibition. DBP-maf inhibited human endothelial cell (HEC) proliferation by inhibiting DNA synthesis (IC(50) = 7.8 +/- 0.15 microg/ml). DBP-maf significantly induced S- and G0/G1-phase arrest in HEC in 72 h. DBP-maf potently blocked VEGF-induced migration, tube-formation of HEC in a dose dependent manner. In addition, DBP-maf inhibited growth factor-induced microvessel sprouting in rat aortic ring assay. Moreover, DBP-maf inhibited VEGF signaling by decreasing VEGF-mediated phosphorylation of VEGFR-2 and ERK1/2, a downstream target of VEGF signaling cascade. However, Akt activation was not affected. These studies collectively demonstrate that DBP-maf inhibits angiogenesis by blocking critical steps such as HEC proliferation, migration, tube formation and microvessel sprouting. DBP-maf exerts its effect by inhibiting VEGR-2 and ERK1/2 signaling cascades. Understanding the cellular and molecular mechanisms of anti-endothelial activity of DBP-maf will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy.
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Affiliation(s)
- Satyan Kalkunte
- Department of Pediatrics and Program in Women's Oncology, Women and Infants' Hospital, Brown University, Providence, RI 02905, USA
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30
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Abstract
Formation of embryonic blood and lymph vessels is mediated by different steps of vasculogenesis and angiogenesis. The vascular endothelial growth factor family (VEGF) as well as the VEGF-receptors on the surface of blood endothelial cells and lymph endothelial cells are responsible for both processes. In addition to the embryonic development of the vessel systems, the interactions of angiogenesis factors and receptors are also present in solid tumors. Embryonic tumors in children offer an interesting target for new substances developed for anti-angiogenesis. Some data on the role of blood vessels and anti-blood-angiogenesis are available on embryonic tumors. However, studies of lymph-angiogenesis are not found and anti-lymph-angiogenesis is not at all examined in embryonic tumors. This review gives an overview of the challenging field of angiogenesis and anti-angiogenesis of both blood and lymph vessels with a focus on embryonic tumors.
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Affiliation(s)
- Jochen Rössler
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Mathildenstr. 1, 79106 Freiburg, Germany.
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Marimpietri D, Nico B, Vacca A, Mangieri D, Catarsi P, Ponzoni M, Ribatti D. Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin. Oncogene 2005; 24:6785-95. [PMID: 16007159 DOI: 10.1038/sj.onc.1208829] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The aim of this study was to evaluate the synergistic antiangiogenic effect of low dose of vinblastine (VBL) and rapamycin (RAP) in neuroblastoma (NB). Both in vitro (endothelial cells proliferation assay; TUNEL assay; phosphatidylserine exposure and cell cycle analysis) and in vivo (chick embryo chorioallantoic membrane, CAM) assays were used. Each compound alone was able to induce a significant dose- and time-response inhibition of in vitro endothelial cells (EC) growth. Interaction index evaluation indicates that a synergistic effect was found when both drugs were combined at very low doses. Comparable effects were obtained when EC were preincubated with conditioned medium (CM) derived from the human NB cell line HTLA-230. Morphological changes were induced by each drug, and their combination resulted in a clear and stronger effect. Apoptosis was demonstrated by the TUNEL assay and confirmed by Annexin V-FITC staining of EC treated with VBL, showing an increase in the percentage of cells with a G2-M and sub-G1 DNA content, whereas in those treated with RAP a block in the G1 cell fraction and inhibition of progression to the S phase were observed. Here too, the combination resulted in a synergistic cell cycle arrest and induction of apoptosis. Similar results were obtained in vivo with the CAM assay. The angiogenic responses induced by HTLA-230-derived CM, NB tumor xenografts, and human NB biopsy specimens were inhibited by each drug and more significantly by their combination. The observation that these well-known drugs display synergistic effects as antiangiogenics when administered frequently at very low dose may be of significance in the designing of new ways of treating NB.
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Affiliation(s)
- Danilo Marimpietri
- Differentiation Therapy Unit Laboratory of Oncology, G Gaslini Childrens' Hospital, Genoa 16148, and Department of Human Anatomy and Histology, University of Bari Medical School, Italy
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Abstract
Research in the past 15 years has shown that the mammalian cell cycle is controlled by the action of cyclin-dependent kinases (CDKs). A crucial substrate of the CDKs in G1-phase is the retinoblastoma tumor suppressor (pRB), which restrains proliferation largely by repressing the activity of the E2F transcription factors. More recent work has shown that the cell cycle is also a tale of two classes of ubiquitin ligases, referred to as SCF and APC/C ligases. CDKs, E2F and ubiquitin ligases reciprocally regulate each other, resulting in complex feedback loops. Perturbation of this network of molecular machines is associated with proliferative diseases, including cancer.
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Affiliation(s)
- Lili Yamasaki
- Biological Sciences, Columbia University, New York, USA.
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Abstract
Promising new antiangiogenic strategies are emerging for the treatment of cancer and the inhibition of angiogenesis could represent a powerful adjunct to traditional therapy of malignant tumors. Over the last ten years several reports have been published concerning the relationship between tumor progression and angiogenesis in neuroblastoma in experimental models in vitro and in vivo. Moreover, a high vascular index in neuroblastoma correlates with poor prognosis, suggesting dependence of aggressive tumor growth on active angiogenesis. Here, we present an overview of recent advances in antiangiogenesis in neuroblastoma and describe the most important active substances, preclinical and clinical data, as well as future perspectives.
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Affiliation(s)
- Domenico Ribatti
- Department of Human Anatomy and Histology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare, 11, I-70124 Bari, Italy.
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Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW, Sonenberg N. eIF4E--from translation to transformation. Oncogene 2004; 23:3172-9. [PMID: 15094766 DOI: 10.1038/sj.onc.1207549] [Citation(s) in RCA: 361] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Over the years, studies have focused on the transcriptional regulation of oncogenesis. More recently, a growing emphasis has been placed on translational control. The Ras and Akt signal transduction pathways play a critical role in regulating mRNA translation and cellular transformation. The question arises: How might the Ras and Akt signaling pathways affect translation and mediate transformation? These pathways converge on a crucial effector of translation, the initiation factor eIF4E, which binds the 5'cap of mRNAs. This review focuses on the role of eIF4E in oncogenesis. eIF4E controls the translation of various malignancy-associated mRNAs which are involved in polyamine synthesis, cell cycle progression, activation of proto-oncogenes, angiogenesis, autocrine growth stimulation, cell survival, invasion and communication with the extracellular environment. eIF4E-mediated translational modulation of these mRNAs plays a pivotal role in both tumor formation and metastasis. Interestingly, eIF4E activity is implicated in mitosis, embryogenesis and in apoptosis. Finally, the finding that eIF4E is overexpressed in several human cancers makes it a prime target for anticancer therapies.
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Affiliation(s)
- Yaël Mamane
- Department of Biochemistry, McGill Cancer Centre, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec, Canada, H3G 1Y6
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Joseph JM, Bouquet C, Opolon P, Morizet J, Aubert G, Rössler J, Gross N, Griscelli F, Perricaudet M, Vassal G. High level of stabilized angiostatin mediated by adenovirus delivery does not impair the growth of human neuroblastoma xenografts. Cancer Gene Ther 2003; 10:859-66. [PMID: 14605672 DOI: 10.1038/sj.cgt.7700639] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Human neuroblastoma (NB) is a highly heterogeneous childhood cancer secreting a high level of vascular endothelial growth factor (VEGF). Its vascularization has been clearly correlated with metastatic progression and poor outcome. Thus, molecules that target the vascular endothelium are regarded as new therapeutics of clinical interest. Angiostatin, an internal fragment of plasminogen containing the first four kringle structures, has been described as a powerful angiogenic inhibitor. We used a recombinant adenovirus encoding the human angiostatin kringle 1-3 directly fused to human serum albumin HSA (AdK3-HSA). Coupling to HSA has been previously shown to increase the in vivo half-life of this angiostatic factor, and to lead to tumor growth inhibition in the MDA-MB-231 carcinoma model. For the assessment of antiangiogenic gene therapy in the human NB IGR-N835 tumor model, 5 x 10(9) PFU of AdK3-HSA were intravenously injected in tumor-bearing athymic mice presenting either of the following experimental settings: early stage, established, and minimal residual tumors. No delay in tumor growth was observed in animals treated with AdK3-HSA as compared to those treated with the empty virus AdCO1. In early-stage tumors, kinetics of tumor occurrence and tumor growth were similar in AdK3-HSA- and AdCO1-treated animals. K3-HSA was found to be expressed at high levels (the mean value for the three experiments being 19.4+/-15.9 microg/ml) in the circulation of all animals up to 21-35 days after virus injection. In addition, IGR-N835 tumors were found to be highly vascularized and to release high amounts of angiogenic factors, in particular VEGF (665+/-370 pg/mg total protein). Thus, in spite of high circulating levels, K3-HSA may be unable to displace the NB proangiogenic switch. In this regard, a more promising target to inhibit NB angiogenesis seems to be the VEGF/VEGFR system.
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Affiliation(s)
- Jean-Marc Joseph
- UPRES EA3535, Department of Pediatric Oncology, Institut Gustave Roussy, 94805 Villejuif, France
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Davies G, Mason MD, Martin TA, Parr C, Watkins G, Lane J, Matsumoto K, Nakamura T, Jiang WG. The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo. Int J Cancer 2003; 106:348-54. [PMID: 12845672 DOI: 10.1002/ijc.11220] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Our study examined the in vitro and in vivo responses of a newly discovered HGF/SF antagonist, NK4, on HGF/SF-promoted growth of human prostate cancer cells (PC-3). Nude mice were s.c. injected with either PC-3- and/or HGF/SF-producing fibroblasts (MRC5), and tumor size was measured over a 4-week period. rh-HGF/SF and/or NK4 were introduced by osmotic minipumps. An in vitro study found that NK4 significantly suppressed HGF/SF-induced invasion (HGF/SF; p < 0.01 vs. HGF/SF+NK4) and migration (HGF/SF; p < 0.05 vs. HGF/SF+NK4). Similarly, NK4 also suppressed the invasion (MRC5; p < 0.01 vs. MRC5+NK4) and migration (MRC5; p < 0.05 vs. MRC5+NK4) induced by MRC5 cells. NK4 also suppressed HGF/SF- and MRC5-induced tyrosine phosphorylation of the HGF/SF receptor Met as assessed by immunoprecipitation. Using a nude mouse model, prostate tumor volume (mm(3)) was significantly increased in both HGF/SF- (HGF/SF; p < 0.05 vs. control) and MRC5- (MRC5; p < 0.01 vs. control) treated groups compared to the control. In contrast, NK4 alone significantly reduced the growth of prostate tumors (NK4; p < 0.01 vs. control). In addition, NK4 also suppressed both HGF/SF- (HGF/SF; p < 0.01 vs. HGF/SF+NK4) and MRC5- (MRC5; p < 0.05 vs. MRC5+NK4) induced tumor growth in vivo by significantly reducing (p < 0.05) the degree of tumor angiogenesis using a recently discovered family of tumor endothelial markers (TEMs) by Q-RT-PCR analysis. In conclusion, NK4 suppresses both HGF/SF- and MRC5-induced invasion/migration of PC-3 cells in vitro. Furthermore, the HGF/SF antagonist NK4 significantly reduces prostate tumor growth in vivo by inhibiting the degree of tumor angiogenesis as determined by TEM-1 and TEM-8. Finally, our study provides evidence of the therapeutic potential of NK4 in prostate cancer development by antagonising HGF/SF-mediated events.
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Affiliation(s)
- Gaynor Davies
- Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Cardiff CF14 4XN, Wales, UK.
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Bestagno M, Occhino M, Corrias MV, Burrone O, Pistoia V. Recombinant antibodies in the immunotherapy of neuroblastoma: perspectives of new developments. Cancer Lett 2003; 197:193-8. [PMID: 12880981 DOI: 10.1016/s0304-3835(03)00109-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The impact of monoclonal antibodies (mAbs) in the treatment of human tumors has greatly increased in recent years. mAb engineering has allowed reducing the immunogenicity of therapeutic antibodies as well as improving their biodistribution. Furthermore, engineered mAbs have been used to vehiculate toxins, drugs and other anti-neoplastic agents to the tumor site. In the case of neuroblastoma (NB), a pediatric malignancy originating from the neural crest, both murine and chimeric antibodies against the tumor associated antigen GD2 have been tested in clinical trials, either alone or in combination with cytokines. A novel promising approach to mAb engineering is the small immuno-protein (SIP) technique, whereby the variable regions of heavy and light chains of a mAb with a given specificity are connected to the dimerizing CH(3) domain of an immunoglobulin molecule. The current status of mAb therapy for NB is discussed together with our preliminary results on the generation of novel anti-GD2 molecules using the SIP technique.
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Affiliation(s)
- Marco Bestagno
- International Centre for Genetic Engineering and Biotechnology, AREA Science Park, Padriciano 99, 34012 Trieste, Italy.
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Huang ZH, Fan YF, Xia H, Feng HM, Tang FX. Effects of TNP-470 on proliferation and apoptosis in human colon cancer xenografts in nude mice. World J Gastroenterol 2003; 9:281-3. [PMID: 12532448 PMCID: PMC4611328 DOI: 10.3748/wjg.v9.i2.281] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of TNP-470 on cell growth, proliferation and apoptosis in human colon cancer xenografts in nude mice.
METHODS: Human colon cancer xenografts were transplanted into 20 nude mice. Mice were randomly divided into two groups. TNP-470 treated group received TNP-470 (30 mg/kg, s.c) every other day and the control group received a sham injection of same volume saline solution. They were sacrificed after 4 wk and their tumors were processed for histological examination. The expression of proliferating cell nuclear antigen (PCNA) in tumors was detected using immunohistochemical method with image analysis, and apoptosis in tumor cells was measured by TdT-mediated biotinyated-dUTP nick end labeling (TUNEL) staining.
RESULTS: Comparing with controls, tumor growth was significantly inhibited in TNP-470 treated group, the inhibitory rate being 54.4%. Expression of PCNA in tumors of TNP-470 treated group (PI 54.32 ± 11.47) was significantly lower than that of control group (PI 88.54 ± 12.36), P < 0.01. Apoptosis index (AI) of TNP-470 treated group (18.95 ± 1.71) was significantly higher than that of control group (7.26 ± 1.44), P < 0.001, typical morphological change of apoptosis in tumor cells was observed in TNP-470 treated group.
CONCLUSION: Besides the anti-angiogenic effects, TNP-470 can inhibit tumor growth by inhibiting the proliferation and inducing apoptosis of tumor cells.
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Affiliation(s)
- Zong-Hai Huang
- Department of Surgery, Zhujiang Hospital, First Military Medical University, Guangzhou 510282, Guangdong Province, China.
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Abstract
There is reason to believe that the unfolding revolution in molecular biology and translational research will allow selective targeting of tumor cells, and radically change the way general practitioners and pediatric oncologists treat and follow children with cancer. This article highlights some of the most promising approaches being tested in the field. By learning about the underlying biology, the remaining hurdles, the projected timeline, and the possible impact of new therapies on the practice of pediatric oncology, health care professionals and patients should be better prepared for the future of pediatric oncology.
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Affiliation(s)
- Robert J Arceci
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 2M51, Baltimore, Maryland 21231, USA.
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Ribatti D, Raffaghello L, Pastorino F, Nico B, Brignole C, Vacca A, Ponzoni M. In vivo angiogenic activity of neuroblastoma correlates with MYCN oncogene overexpression. Int J Cancer 2002; 102:351-4. [PMID: 12402304 DOI: 10.1002/ijc.10742] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Neuroblastoma (NB) is the most common malignant solid tumor in early childhood. Amplification of the MYCN oncogene is associated with a more malignant course of disease and poor outcome. The role that MYCN plays in the regulation of angiogenesis in NB remains unclear. To better elucidate this matter, fresh biopsy samples from 21 patients, 10 with MYCN-amplified tumors (defined as having >10 copies of the oncogene) and 11 with nonamplified tumors, were tested for their angiogenic capacity using the chick embryo chorioallantoic membrane assay, a useful model for such investigation. Moreover, using the same experimental model, conditioned media obtained from 5 different human NB cell lines MYCN-amplified (HTLA-230, LAN-5 and GI-LI-N) or nonamplified (ACN and SH-SY5Y) and biopsy fragments obtained from xenografts derived from 4 NB cell lines (HTLA-230, GI-LI-N, ACN and SH-SY5Y) injected in nude mice were assayed for angiogenic potential. Our results clearly demonstrated that MYCN amplification parallels angiogenesis in NB. When fresh biopsy samples from patients, CM derived from NB cell lines and biopsy fragments derived from xenografts of the same cell lines injected in nude mice were tested, the response was univocal: the angiogenic response, evaluated both macroscopically and microscopically, was significantly higher in the MYCN-amplified specimens compared to the nonamplified ones.
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Affiliation(s)
- Domenico Ribatti
- Department of Human Anatomy and Histology, University of Bari, Policlinico, Bari, Italy.
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