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Dadgar H, Norouzbeigi N, Assadi M, Jafari E, Al-Balooshi B, Al-Ibraheem A, Esmail AA, Marafi F, Haidar M, Al-Alawi HM, Omar Y, Usmani S, Cimini A, Ricci M, Arabi H, Zaidi H. A Prospective Evaluation of Chemokine Receptor-4 (CXCR4) Overexpression in High-grade Glioma Using 68Ga-Pentixafor (Pars-Cixafor™) PET/CT Imaging. Acad Radiol 2025; 32:2247-2256. [PMID: 39690071 DOI: 10.1016/j.acra.2024.11.064] [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: 06/27/2024] [Revised: 11/01/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024]
Abstract
BACKGROUND While magnetic resonance imaging (MRI) remains the gold standard for morphological imaging, its ability to differentiate between tumor tissue and treatment-induced changes on the cellular level is insufficient. Notably, glioma cells, particularly glioblastoma multiforme (GBM), demonstrate overexpression of chemokine receptor-4 (CXCR4). This study aims to evaluate the feasibility of non-invasive 68Ga-Cixafor™ PET/CT as a tool to improve diagnostic accuracy in patients with high-grade glioma. METHODS In this retrospective analysis, a database of histopathology-confirmed glioma patients with MRI findings consistent with high-grade gliomas was utilized. Within 2 weeks of their MRI, these patients underwent 68Ga-Cixafor™ PET/CT scans to assess CXCR4 expression. Both visual scoring based on established criteria and semi-quantitative measures including maximum standardized uptake value (SUVmax) and tumor-to-background ratios (TBR) were calculated to analyze the PET/CT data. RESULTS Our retrospective study enrolled 29 histologically confirmed glioma patients with MRI findings consistent with high-grade gliomas. All patients underwent 68Ga-Cixafor™ PET/CT scans within 2 weeks of their MRI, specifically at one-hour post-injection time point. Visual assessment based on a standardized scoring system identified 27 positive scans out of 29 (93.1%). Median SUVmax was 2.31 (range: 0.49-9.96) and median TBR was 20 (range: 6.12-124.5). Pathological analysis revealed 5 grade III (17.24%) and 24 grade IV (82.75%) lesions among the 29 patients. Notably, the median SUVmax of grade IV lesions (2.85) was significantly higher than grade III lesions (1.27) (P=0.02). Conversely, there was no significant difference in median TBR between grade IV (20) and grade III (22.37). These findings support the correlation between high CXCR4 expression, particularly in high-grade gliomas, and elevated uptake of 68Ga-Pentixafor. While areas with high uptake showed CXCR4 expression, areas with low uptake did not exhibit noticeable expression (data not shown). CONCLUSION This study demonstrated that 68Ga-Cixafor™ PET exhibits a TBR with minimal cortical uptake, significantly enhancing glioma detection compared to conventional imaging methods. This, combined with the potential therapeutic capabilities of CXCR4-targeting radiopharmaceuticals, highlights the promise of 68Ga-Cixafor™ as a valuable tool for not only improved glioma diagnosis but also personalized treatment strategies.
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Affiliation(s)
- Habibollah Dadgar
- Cancer Research Center, RAZAVI Hospital, Imam Reza International University, Mashhad, Iran (H.D., N.N.)
| | - Nasim Norouzbeigi
- Cancer Research Center, RAZAVI Hospital, Imam Reza International University, Mashhad, Iran (H.D., N.N.)
| | - Majid Assadi
- The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Radionuclide Therapy (MIRT), Bushehr Medical University Hospital, Bushehr University of Medical Sciences, Bushehr, Iran (M.A., E.J.)
| | - Esmail Jafari
- The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Radionuclide Therapy (MIRT), Bushehr Medical University Hospital, Bushehr University of Medical Sciences, Bushehr, Iran (M.A., E.J.)
| | - Batool Al-Balooshi
- Dubai Nuclear medicine & Molecular imaging Center, Dubai Academic Health corporation, DAHC, United Arab Emirates (B.A.B.)
| | - Akram Al-Ibraheem
- Department of Nuclear Medicine, King Hussein Cancer Center, Amman, Jordan (A.A.I.); Division of Nuclear Medicine/Department of Radiology and Nuclear Medicine, University of Jordan, Amman, Jordan (A.A.I.)
| | - Abdulredha A Esmail
- Nuclear Medicine Department, Kuwait Cancer Control Center, Kuwait City, Kuwait (A.A.E.)
| | - Fahad Marafi
- Jaber Alahmad Center of Nuclear Medicine and Molecular Imaging, Kuwait City, Kuwait (F.M.)
| | - Mohamad Haidar
- Diagnostic Clinical Radiology Department, American University of Beirut, Beirut, Lebanon (M.H.)
| | - Haider Muhsin Al-Alawi
- Nuclear Medicine department, Amir Al-momineen Specialty Hospital, Al-Najaf Governorate, Iraq (H.M.A.A.); Middle Euphrates Cancer Hospital, Al-Najaf Governorate, Iraq (H.M.A.A.)
| | - Yehia Omar
- PET-CT department at Misr Radiology Center, Heliopolis, Egypt (Y.O.)
| | - Sharjeel Usmani
- Department of Nuclear Medicine Sultan Qaboos Comprehensive Cancer Care and Research Center (SQCCCRC), Seeb, Oman (S.U.)
| | - Andrea Cimini
- Nuclear Medicine Unit, St. Salvatore Hospital, 67100 L'Aquila, Italy (A.C.)
| | - Maria Ricci
- Nuclear Medicine Unit, Cardarelli Hospital, 86100 Campobasso, Italy (M.R.)
| | - Hossein Arabi
- Division of Nuclear Medicine and Molecular Imaging, Department of Medical Imaging, Geneva University Hospital, CH-1211 Geneva 4, Switzerland (H.A., H.Z.)
| | - Habib Zaidi
- Division of Nuclear Medicine and Molecular Imaging, Department of Medical Imaging, Geneva University Hospital, CH-1211 Geneva 4, Switzerland (H.A., H.Z.); Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, Netherlands (H.Z.); Department of Nuclear Medicine, University of Southern Denmark, Odense, Denmark (H.Z.); University Research and Innovation Center, Óbuda University, Budapest, Hungary (H.Z.).
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Lee M, Lee M, Song Y, Kim S, Park N. Recent Advances and Prospects of Nucleic Acid Therapeutics for Anti-Cancer Therapy. Molecules 2024; 29:4737. [PMID: 39407665 PMCID: PMC11477775 DOI: 10.3390/molecules29194737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/03/2024] [Accepted: 10/05/2024] [Indexed: 10/20/2024] Open
Abstract
Nucleic acid therapeutics are promising alternatives to conventional anti-cancer therapy, such as chemotherapy and radiation therapy. While conventional therapies have limitations, such as high side effects, low specificity, and drug resistance, nucleic acid therapeutics work at the gene level to eliminate the cause of the disease. Nucleic acid therapeutics treat diseases in various forms and using different mechanisms, including plasmid DNA (pDNA), small interfering RNA (siRNA), anti-microRNA (anti-miR), microRNA mimics (miRNA mimic), messenger RNA (mRNA), aptamer, catalytic nucleic acid (CNA), and CRISPR cas9 guide RNA (gRNA). In addition, nucleic acids have many advantages as nanomaterials, such as high biocompatibility, design flexibility, low immunogenicity, small size, relatively low price, and easy functionalization. Nucleic acid therapeutics can have a high therapeutic effect by being used in combination with various nucleic acid nanostructures, inorganic nanoparticles, lipid nanoparticles (LNPs), etc. to overcome low physiological stability and cell internalization efficiency. The field of nucleic acid therapeutics has advanced remarkably in recent decades, and as more and more nucleic acid therapeutics have been approved, they have already demonstrated their potential to treat diseases, including cancer. This review paper introduces the current status and recent advances in nucleic acid therapy for anti-cancer treatment and discusses the tasks and prospects ahead.
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Affiliation(s)
- Minhyuk Lee
- Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Minjae Lee
- Department of Chemistry and the Natural Science Research Institute, Myongji University, 116 Myongji-ro, Yongin-si 17058, Republic of Korea
| | - Youngseo Song
- Department of Chemistry and the Natural Science Research Institute, Myongji University, 116 Myongji-ro, Yongin-si 17058, Republic of Korea
| | - Sungjee Kim
- Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Nokyoung Park
- Department of Chemistry and the Natural Science Research Institute, Myongji University, 116 Myongji-ro, Yongin-si 17058, Republic of Korea
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Giordano FA, Layer JP, Leonardelli S, Friker LL, Turiello R, Corvino D, Zeyen T, Schaub C, Müller W, Sperk E, Schmeel LC, Sahm K, Oster C, Kebir S, Hambsch P, Pietsch T, Bisdas S, Platten M, Glas M, Seidel C, Herrlinger U, Hölzel M. L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial. Nat Commun 2024; 15:4210. [PMID: 38806504 PMCID: PMC11133480 DOI: 10.1038/s41467-024-48416-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 04/30/2024] [Indexed: 05/30/2024] Open
Abstract
The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.
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Affiliation(s)
- Frank A Giordano
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
| | - Julian P Layer
- Department of Radiation Oncology, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Sonia Leonardelli
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Lea L Friker
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Neuropathology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Roberta Turiello
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Dillon Corvino
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Thomas Zeyen
- Department of Neurooncology, Center for Neurology, University Hospital Bonn, Bonn, Germany
| | - Christina Schaub
- Department of Neurooncology, Center for Neurology, University Hospital Bonn, Bonn, Germany
| | - Wolf Müller
- Institute of Neuropathology, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
| | - Elena Sperk
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | | | - Katharina Sahm
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany
- DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany
| | - Christoph Oster
- Division of Clinical Neurooncology, Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS) and West German Cancer Center, German Cancer Consortium, Partner Site Essen, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sied Kebir
- Division of Clinical Neurooncology, Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS) and West German Cancer Center, German Cancer Consortium, Partner Site Essen, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Peter Hambsch
- Department of Radiation Oncology, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
| | - Torsten Pietsch
- Institute of Neuropathology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Sotirios Bisdas
- Lysholm Department of Neuroradiology, University College London, London, UK
| | - Michael Platten
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany
- DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany
| | - Martin Glas
- Division of Clinical Neurooncology, Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS) and West German Cancer Center, German Cancer Consortium, Partner Site Essen, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Clemens Seidel
- Department of Radiation Oncology, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
| | - Ulrich Herrlinger
- Department of Neurooncology, Center for Neurology, University Hospital Bonn, Bonn, Germany
| | - Michael Hölzel
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
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Huang JH, Chen Y, Kang YB, Yao ZJ, Song JH. The potential crosstalk genes and molecular mechanisms between glioblastoma and periodontitis. Sci Rep 2024; 14:5970. [PMID: 38472293 DOI: 10.1038/s41598-024-56577-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 03/08/2024] [Indexed: 03/14/2024] Open
Abstract
Despite clinical and epidemiological evidence suggestive of a link between glioblastoma (GBM) and periodontitis (PD), the shared mechanisms of gene regulation remain elusive. In this study, we identify differentially expressed genes (DEGs) that overlap between the GEO datasets GSE4290 [GBM] and GSE10334 [PD]. Functional enrichment analysis was conducted, and key modules were identified using protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA). The expression levels of CXCR4, LY96, and C3 were found to be significantly elevated in both the test dataset and external validation dataset, making them key crosstalk genes. Additionally, immune cell landscape analysis revealed elevated expression levels of multiple immune cells in GBM and PD compared to controls, with the key crosstalk genes negatively associated with Macrophages M2. FLI1 was identified as a potential key transcription factor (TF) regulating the three key crosstalk genes, with increased expression in the full dataset. These findings contribute to our understanding of the immune and inflammatory aspects of the comorbidity mechanism between GBM and PD.
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Affiliation(s)
- Jian-Huang Huang
- Department of Neurosurgery, Affiliated Hospital of Putian University, Putian, Fujian, China.
| | - Yao Chen
- Department of Neurosurgery, Affiliated Hospital of Putian University, Putian, Fujian, China
| | - Yuan-Bao Kang
- Department of Neurosurgery, Affiliated Hospital of Putian University, Putian, Fujian, China
| | - Zheng-Jian Yao
- Department of Neurosurgery, Affiliated Hospital of Putian University, Putian, Fujian, China
| | - Jian-Hua Song
- Department of Neurosurgery, Affiliated Hospital of Putian University, Putian, Fujian, China
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Dai Y, Yu C, Zhou L, Cheng L, Ni H, Liang W. Chemokine receptor CXCR4 interacts with nuclear receptor Nur77 and promote glioma invasion and progression. Brain Res 2024; 1822:148647. [PMID: 37890573 DOI: 10.1016/j.brainres.2023.148647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/15/2023] [Accepted: 10/23/2023] [Indexed: 10/29/2023]
Abstract
BACKGROUND Glioma is the most common primary brain tumor. It is prone to progress and have high rate of mortality regardless of radiation or chemotherapy due to its invasive growth features. Chemokine and its receptor CXCL12 and CXCR4 play important roles in cancer metastasis. METHODS In this study, we investigate the role of CXCR4 in the progression of glioma by various molecular technologies, including qRT-PCR, Western blotting, wound closure assay, transwell assay et al. RESULTS: It was found that CXCR4 was overexpressed in glioma tissues. The expression of CXCR4 was correlated with patients' overall survival. Wound closure assay and transwell invasion assay showed that inhibition of CXCR4 significantly reduced the expression of biomarkers related to the formation of invadopodium, leading to decrease the invasion and migration of glioma tumor cells. Knocking down the nuclear receptor Nur77 remarkably decreased CXCR4 expression and reduced glioma cell invasion and migration. The reduction of glioma cell invasion and migration were observed after Nur77 inhibitor treatment. CONCLUSION Taken together, these results indicated that CXCR4 is critical in promoting glioma migration and invasion. Inhibition of Nur77 reduces CXCR4 related cancer progression.
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Affiliation(s)
- Yuxiang Dai
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, China
| | - Chen Yu
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, China
| | - Lu Zhou
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, China
| | - Longyang Cheng
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, China
| | - Hongbin Ni
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, China
| | - Weibang Liang
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, China.
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Giles B, Nakhjavani M, Wiesa A, Knight T, Shigdar S, Samarasinghe RM. Unravelling the Glioblastoma Tumour Microenvironment: Can Aptamer Targeted Delivery Become Successful in Treating Brain Cancers? Cancers (Basel) 2023; 15:4376. [PMID: 37686652 PMCID: PMC10487158 DOI: 10.3390/cancers15174376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/28/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
The key challenges to treating glioblastoma multiforme (GBM) are the heterogeneous and complex nature of the GBM tumour microenvironment (TME) and difficulty of drug delivery across the blood-brain barrier (BBB). The TME is composed of various neuronal and immune cells, as well as non-cellular components, including metabolic products, cellular interactions, and chemical compositions, all of which play a critical role in GBM development and therapeutic resistance. In this review, we aim to unravel the complexity of the GBM TME, evaluate current therapeutics targeting this microenvironment, and lastly identify potential targets and therapeutic delivery vehicles for the treatment of GBM. Specifically, we explore the potential of aptamer-targeted delivery as a successful approach to treating brain cancers. Aptamers have emerged as promising therapeutic drug delivery vehicles with the potential to cross the BBB and deliver payloads to GBM and brain metastases. By targeting specific ligands within the TME, aptamers could potentially improve treatment outcomes and overcome the challenges associated with larger therapies such as antibodies.
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Affiliation(s)
- Breanna Giles
- School of Medicine, Deakin University, Geelong, VIC 3220, Australia; (B.G.); (S.S.); (R.M.S.)
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia
| | - Maryam Nakhjavani
- School of Medicine, Deakin University, Geelong, VIC 3220, Australia; (B.G.); (S.S.); (R.M.S.)
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia
| | - Andrew Wiesa
- School of Medicine, Deakin University, Geelong, VIC 3220, Australia; (B.G.); (S.S.); (R.M.S.)
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia
| | - Tareeque Knight
- School of Medicine, Deakin University, Geelong, VIC 3220, Australia; (B.G.); (S.S.); (R.M.S.)
| | - Sarah Shigdar
- School of Medicine, Deakin University, Geelong, VIC 3220, Australia; (B.G.); (S.S.); (R.M.S.)
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia
| | - Rasika M. Samarasinghe
- School of Medicine, Deakin University, Geelong, VIC 3220, Australia; (B.G.); (S.S.); (R.M.S.)
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia
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Yang Y, Li J, Lei W, Wang H, Ni Y, Liu Y, Yan H, Tian Y, Wang Z, Yang Z, Yang S, Yang Y, Wang Q. CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications. Int J Biol Sci 2023; 19:3341-3359. [PMID: 37497001 PMCID: PMC10367567 DOI: 10.7150/ijbs.82317] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 05/16/2023] [Indexed: 07/28/2023] Open
Abstract
Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines, including chemokines, exhibit expression changes and disorders in all human cancers. These cytokine abnormalities can disrupt homeostasis and immune function, and make outstanding contributions to various stages of cancer development such as invasion, metastasis, and angiogenesis. Chemokines are a superfamily of small molecule chemoattractive cytokines that mediate a variety of cellular functions. Importantly, the interactions of chemokine members CXCL12 and its receptors CXCR4 and CXCR7 have a broad impact on tumor cell proliferation, survival, angiogenesis, metastasis, and tumor microenvironment, and thus participate in the onset and development of many cancers including leukemia, breast cancer, lung cancer, prostate cancer and multiple myeloma. Therefore, this review aims to summarize the latest research progress and future challenges regarding the role of CXCL12-CXCR4/CXCR7 signaling axis in cancer, and highlights the potential of CXCL12-CXCR4/CXCR7 as a biomarker or therapeutic target for cancer, providing essential strategies for the development of novel targeted cancer therapies.
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Affiliation(s)
- Yaru Yang
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Jiayan Li
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Wangrui Lei
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Haiying Wang
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yunfeng Ni
- Department of Thoracic Surgery, Tangdu Hospital, The Airforce Medical University, Xi'an, China
| | - Yanqing Liu
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Huanle Yan
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yifan Tian
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Zheng Wang
- Department of Cardiothoracic Surgery, Central Theater Command General Hospital of Chinese People's Liberation Army, Wuhan, China
| | - Zhi Yang
- Department of Thoracic Surgery, Tangdu Hospital, The Airforce Medical University, Xi'an, China
| | - Shulin Yang
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yang Yang
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Qiang Wang
- Department of Orthopedics, Shenmu Hospital, Faculty of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
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Wu L, Zhang Z, Bai M, Yan Y, Yu J, Xu Y. Radiation combined with immune checkpoint inhibitors for unresectable locally advanced non-small cell lung cancer: synergistic mechanisms, current state, challenges, and orientations. Cell Commun Signal 2023; 21:119. [PMID: 37221584 PMCID: PMC10207766 DOI: 10.1186/s12964-023-01139-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 04/22/2023] [Indexed: 05/25/2023] Open
Abstract
Until the advent of immune checkpoint inhibitors (ICIs), definitive radiotherapy (RT) concurrently with chemotherapy was recommended for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC). The trimodality paradigm with consolidation ICIs following definitive concurrent chemoradiotherapy has been the standard of care since the PACIFIC trial. Preclinical evidence has demonstrated the role of RT in the cancer-immune cycle and the synergistic effect of RT combined with ICIs (iRT). However, RT exerts a double-edged effect on immunity and the combination strategy still could be optimized in many areas. In the context of LA-NSCLC, optimized RT modality, choice, timing, and duration of ICIs, care for oncogenic addicted tumors, patient selection, and novel combination strategies require further investigation. Targeting these blind spots, novel approaches are being investigated to cross the borders of PACIFIC. We discussed the development history of iRT and summarized the updated rationale for the synergistic effect. We then summarized the available research data on the efficacy and toxicity of iRT in LA-NSCLC for cross-trial comparisons to eliminate barriers. Progression during and after ICIs consolidation therapy has been regarded as a distinct resistance scenario from primary or secondary resistance to ICIs, the subsequent management of which has also been discussed. Finally, based on unmet needs, we probed into the challenges, strategies, and auspicious orientations to optimize iRT in LA-NSCLC. In this review, we focus on the underlying mechanisms and recent advances of iRT with an emphasis on future challenges and directions that warrant further investigation. Taken together, iRT is a proven and potential strategy in LA-NSCLC, with multiple promising approaches to further improve the efficacy. Video Abstract.
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Affiliation(s)
- Leilei Wu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhenshan Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
| | - Menglin Bai
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yujie Yan
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinming Yu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Yaping Xu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
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9
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Eulberg D, Frömming A, Lapid K, Mangasarian A, Barak A. The prospect of tumor microenvironment-modulating therapeutical strategies. Front Oncol 2022; 12:1070243. [PMID: 36568151 PMCID: PMC9772844 DOI: 10.3389/fonc.2022.1070243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/10/2022] [Indexed: 12/13/2022] Open
Abstract
Multiple mechanisms promote tumor prosperity, which does not only depend on cell-autonomous, inherent abnormal characteristics of the malignant cells that facilitate rapid cell division and tumor expansion. The neoplastic tissue is embedded in a supportive and dynamic tumor microenvironment (TME) that nurtures and protects the malignant cells, maintaining and perpetuating malignant cell expansion. The TME consists of different elements, such as atypical vasculature, various innate and adaptive immune cells with immunosuppressive or pro-inflammatory properties, altered extracellular matrix (ECM), activated stromal cells, and a wide range of secreted/stroma-tethered bioactive molecules that contribute to malignancy, directly or indirectly. In this review, we describe the various TME components and provide examples of anti-cancer therapies and novel drugs under development that aim to target these components rather than the intrinsic processes within the malignant cells. Combinatory TME-modulating therapeutic strategies may be required to overcome the resistance to current treatment options and prevent tumor recurrence.
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10
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Patient-Oriented Perspective on Chemokine Receptor Expression and Function in Glioma. Cancers (Basel) 2021; 14:cancers14010130. [PMID: 35008294 PMCID: PMC8749846 DOI: 10.3390/cancers14010130] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Chemokines and their receptors have been pointed out as key actors in a variety of human cancers, playing pivotal roles in multiples processes and pathways. The present study aims at deciphering the functions of several chemokine receptors in gliomas, starting from publicly available patient-derived transcriptomic data with support from the current literature in the field, and sheds light on the clinical relevance of chemokine receptors in targeted therapeutic approaches for glioma patients. Abstract Gliomas are severe brain malignancies, with glioblastoma (GBM) being the most aggressive one. Despite continuous efforts for improvement of existing therapies, overall survival remains poor. Over the last years, the implication of chemokines and their receptors in GBM development and progression has become more evident. Recently, large amounts of clinical data have been made available, prompting us to investigate chemokine receptors in GBM from a still-unexplored patient-oriented perspective. This study aims to highlight and discuss the involvement of chemokine receptors—CCR1, CCR5, CCR6, CCR10, CX3CR1, CXCR2, CXCR4, ACKR1, ACKR2, and ACKR3—most abundantly expressed in glioma patients based on the analysis of publicly available clinical datasets. Given the strong intratumoral heterogeneity characterizing gliomas and especially GBM, receptor expression was investigated by glioma molecular groups, by brain region distribution, emphasizing tissue-specific receptor functions, and by cell type enrichment. Our study constitutes a clinically relevant and patient-oriented guide that recapitulates the expression profile and the complex roles of chemokine receptors within the highly diversified glioma landscape. Additionally, it strengthens the importance of patient-derived material for development and precise amelioration of chemokine receptor-targeting therapies.
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11
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Therapeutic targeting of the hypoxic tumour microenvironment. Nat Rev Clin Oncol 2021; 18:751-772. [PMID: 34326502 DOI: 10.1038/s41571-021-00539-4] [Citation(s) in RCA: 242] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.
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12
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Okikawa S, Higashijima J, Nishi M, Yoshimoto T, Eto S, Takasu C, Kashihara H, Tokunaga T, Yoshikawa K, Shimada M. SDF-1 expression after preoperative chemoradiotherapy is associated with prognosis in patients with advanced lower rectal cancer. THE JOURNAL OF MEDICAL INVESTIGATION 2021; 68:309-314. [PMID: 34759150 DOI: 10.2152/jmi.68.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Stromal cell-derived factor-1 (SDF-1) expression is associated with cancer progression, as a biomarker of prognosis. We clarified the significance of SDF-1 expression on chemoradiotherapy (CRT) resistance and prognosis in advanced lower rectal cancer patients. We evaluated 98 patients with advanced lower rectal cancer who underwent preoperative CRT. All patients received 40 Gy of radiation therapy, with concurrent chemotherapy containing fluorinated pyrimidines, followed by surgical resection. SDF-1 expression in surgical specimens was examined by immunohistochemistry. We divided the patients into SDF-1-positive- (n = 52) and SDF-1-negative groups (n = 46) and compared the clinicopathological factors and survival rates. The SDF-1-positive group was more resistant to CRT than the SDF-1-negative group (non-responder rate, 63.5% vs. 47.8%, respectively ; p = 0.12). Overall survival (OS) in the SDF-1 positive group was significantly poorer vs. the SDF-1-negative group (5-year OS, 73.4% vs. 88.0%, respectively ; p = 0.02), and disease-free survival (DFS) was worse (5-year DFS, 61.0% vs. 74.1%, respectively ; p = 0.07). Multivariate analysis confirmed that SDF-1 expression was a significant independent prognostic predictor of OS (p = 0.04). SDF-1 expression after preoperative CRT is significantly associated with a poor prognosis in advanced lower rectal cancer patients and is a promising biomarker. J. Med. Invest. 68 : 309-314, August, 2021.
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Affiliation(s)
- Shohei Okikawa
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Jun Higashijima
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Masaaki Nishi
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Toshiaki Yoshimoto
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Shohei Eto
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Chie Takasu
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Hideya Kashihara
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Takuya Tokunaga
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Kozo Yoshikawa
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
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13
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Suarez-Carmona M, Williams A, Schreiber J, Hohmann N, Pruefer U, Krauss J, Jäger D, Frömming A, Beyer D, Eulberg D, Jungelius JU, Baumann M, Mangasarian A, Halama N. Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects. J Immunother Cancer 2021; 9:e002505. [PMID: 34607895 PMCID: PMC8491418 DOI: 10.1136/jitc-2021-002505] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Immunotherapy in microsatellite stable colorectal or pancreatic cancer has not shown promising results. It has been hypothesized that targeting immunosuppressive molecules like SDF1-alpha/CXCL12 could contribute to immunotherapy and animal models showed promising results on T cell activation and migration in combination with immune checkpoint inhibition. METHODS Here, we describe the successful application of anti-CXCL12 (NOX-A12) in patients with advanced stage pretreated metastatic colorectal and pancreatic cancer (OPERA trial). The treatment consisted of 2 weeks of anti-CXCL12 monotherapy with NOX-A12 followed by combination therapy with pembrolizumab (n=20 patients) until progression or intolerable toxicity had occurred. RESULTS The treatment was safe and well tolerated with 83.8% grade I/II, 15.5% grade III and 0.7% grade V adverse events. Of note, for a majority of patients, time on trial treatment was prolonged compared with their last standard treatment preceding trial participation. Systematic serial biopsies revealed distinct patterns of modulation. Tissue and clinical responses were associated with Th1-like tissue reactivity upon CXCL12 inhibition. A downregulation of a cytokine cassette of interleukin (IL)-2/IL-16/CXCL-10 was associated with tumor resistance and furthermore linked to a rare, CXCL12-associated CD14+CD15+promonocytic population. T cells showed aggregation and directed movement towards the tumor cells in responding tissues. Serum analyses detected homogeneous immunomodulatory patterns in all patients, regardless of tissue responses. CONCLUSIONS We demonstrate that the combination of CXCL12 inhibition and checkpoint inhibition is safe and grants further exploration of synergistic combinatorial strategies.
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Affiliation(s)
- Meggy Suarez-Carmona
- Department of Translational Immunotherapy, German Cancer Research Centre, Heidelberg, Germany
| | - Anja Williams
- Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Baden-Württemberg, Germany
| | - Jutta Schreiber
- Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Baden-Württemberg, Germany
| | - Nicolas Hohmann
- Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Baden-Württemberg, Germany
| | - Ulrike Pruefer
- Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Baden-Württemberg, Germany
| | - Jürgen Krauss
- Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Baden-Württemberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, National Center of Tumor Diseases, Heidelberg, Baden-Württemberg, Germany
| | | | | | | | | | | | | | - Niels Halama
- Department of Translational Immunotherapy, German Cancer Research Centre, Heidelberg, Germany
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14
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Wang Y, Chen W, Shi Y, Yan C, Kong Z, Wang Y, Wang Y, Ma W. Imposing Phase II and Phase III Clinical Trials of Targeted Drugs for Glioblastoma: Current Status and Progress. Front Oncol 2021; 11:719623. [PMID: 34568049 PMCID: PMC8458950 DOI: 10.3389/fonc.2021.719623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/24/2021] [Indexed: 12/21/2022] Open
Abstract
The most common primary intracranial tumor is glioma, among which glioblastoma (GBM) has the worst prognosis. Because of the high degree of malignancy of GBM and frequent recurrence after surgery, postoperative therapy, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, is particularly important. A wide variety of targeted drugs have undergone phase III clinical trials for patients with GBM, but these drugs do not work for all patients, and few patients in these trials have prolonged overall survival. In this review, some imposing phase III clinical trials of targeted drugs for glioma are introduced, and some prospective phase II clinical trials that have been completed or are in progress are summarized. In addition, the mechanisms of these drugs are briefly introduced, and deficiencies of these clinical trials are analyzed. This review aims to provide a comprehensive overview of current research on targeted drugs for glioma to clarify future research directions.
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Affiliation(s)
- Yaning Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wanqi Chen
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yixin Shi
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengrui Yan
- Department of Neurosurgery, Peking University International Hospital, Beijing, China
| | - Ziren Kong
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuekun Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenbin Ma
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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15
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Schulz M, Sevenich L. TAMs in Brain Metastasis: Molecular Signatures in Mouse and Man. Front Immunol 2021; 12:716504. [PMID: 34539650 PMCID: PMC8447936 DOI: 10.3389/fimmu.2021.716504] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 08/13/2021] [Indexed: 12/29/2022] Open
Abstract
Macrophages not only represent an integral part of innate immunity but also critically contribute to tissue and organ homeostasis. Moreover, disease progression is accompanied by macrophage accumulation in many cancer types and is often associated with poor prognosis and therapy resistance. Given their critical role in modulating tumor immunity in primary and metastatic brain cancers, macrophages are emerging as promising therapeutic targets. Different types of macrophages infiltrate brain cancers, including (i) CNS resident macrophages that comprise microglia (TAM-MG) as well as border-associated macrophages and (ii) monocyte-derived macrophages (TAM-MDM) that are recruited from the periphery. Controversy remained about their disease-associated functions since classical approaches did not reliably distinguish between macrophage subpopulations. Recent conceptual and technological advances, such as large-scale omic approaches, provided new insight into molecular profiles of TAMs based on their cellular origin. In this review, we summarize insight from recent studies highlighting similarities and differences of TAM-MG and TAM-MDM at the molecular level. We will focus on data obtained from RNA sequencing and mass cytometry approaches. Together, this knowledge significantly contributes to our understanding of transcriptional and translational programs that define disease-associated TAM functions. Cross-species meta-analyses will further help to evaluate the translational significance of preclinical findings as part of the effort to identify candidates for macrophage-targeted therapy against brain metastasis.
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Affiliation(s)
- Michael Schulz
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.,Biological Sciences, Faculty 15, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Lisa Sevenich
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt am Main, Germany
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16
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Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma. Cancers (Basel) 2021; 13:cancers13122983. [PMID: 34203660 PMCID: PMC8232256 DOI: 10.3390/cancers13122983] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/02/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023] Open
Abstract
With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.
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17
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Naz S, Leiker AJ, Choudhuri R, Preston O, Sowers AL, Gohain S, Gamson J, Mathias A, Van Waes C, Cook JA, Mitchell JB. Pharmacological Inhibition of HSP90 Radiosensitizes Head and Neck Squamous Cell Carcinoma Xenograft by Inhibition of DNA Damage Repair, Nucleotide Metabolism, and Radiation-Induced Tumor Vasculogenesis. Int J Radiat Oncol Biol Phys 2021; 110:1295-1305. [PMID: 33838214 DOI: 10.1016/j.ijrobp.2021.03.048] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/24/2021] [Accepted: 03/23/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Recent preclinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and head and neck squamous cell carcinoma (HNSCC). These studies emphasized that AT13387 downregulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity. Metabolomic analysis of HSP90 inhibition by AT13387 was conducted to identify metabolic biomarkers of radiosensitization and whether modulations of key proteins were involved in IR-induced tumor vasculogenesis, a process involved in tumor recurrence. METHODS AND MATERIALS HNSCC and non-small cell lung cancer cell lines were used to evaluate the AT13387 radiosensitization effect in vitro and in vivo. Flow cytometry, immunofluorescence, and immunoblot analysis were used to evaluate cell cycle changes and HSP90 client protein's role in DNA damage repair. Metabolic analysis was performed using liquid chromatography-Mass spectrometry. Immunohistochemical examination of resected tumors post-AT13387 and IR treatment were conducted to identify biomarkers of IR-induced tumor vasculogenesis. RESULTS In agreement with recent studies, AT13387 treatment combined with IR resulted in a G2/M cell cycle arrest and inhibited DNA repair. Metabolomic profiling indicated a decrease in key metabolites in glycolysis and tricarboxylic acid cycle by AT13387, a reduction in Adenosine 5'-triphosphate levels, and rate-limiting metabolites in nucleotide metabolism, namely phosphoribosyl diphosphate and aspartate. HNSCC xenografts treated with the combination exhibited increased tumor regrowth delay, decreased tumor infiltration of CD45 and CD11b+ bone marrow-derived cells, and inhibition of HIF-1 and SDF-1 expression, thereby inhibiting IR-induced vasculogenesis. CONCLUSIONS AT13387 treatment resulted in pharmacologic inhibition of cancer cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence postradiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment.
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Affiliation(s)
- Sarwat Naz
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Andrew J Leiker
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Missouri Cancer Associates, Columbia, Missouri
| | - Rajani Choudhuri
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Olivia Preston
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Anastasia L Sowers
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sangeeta Gohain
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Janet Gamson
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Askale Mathias
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Carter Van Waes
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - John A Cook
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - James B Mitchell
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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18
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Yeo ECF, Brown MP, Gargett T, Ebert LM. The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy. Cells 2021; 10:607. [PMID: 33803414 PMCID: PMC8001644 DOI: 10.3390/cells10030607] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/23/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma is the most common form of primary brain tumour in adults. For more than a decade, conventional treatment has produced a relatively modest improvement in the overall survival of glioblastoma patients. The immunosuppressive mechanisms employed by neoplastic and non-neoplastic cells within the tumour can limit treatment efficacy, and this can include the secretion of immunosuppressive cytokines and chemokines. These factors can play a significant role in immune modulation, thus disabling anti-tumour responses and contributing to tumour progression. Here, we review the complex interplay between populations of immune and tumour cells together with defined contributions by key cytokines and chemokines to these intercellular interactions. Understanding how these tumour-derived factors facilitate the crosstalk between cells may identify molecular candidates for potential immunotherapeutic targeting, which may enable better tumour control and improved patient survival.
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Affiliation(s)
- Erica C. F. Yeo
- Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5001, Australia; (E.C.F.Y.); (M.P.B.); (T.G.)
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, Australia
| | - Michael P. Brown
- Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5001, Australia; (E.C.F.Y.); (M.P.B.); (T.G.)
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia
| | - Tessa Gargett
- Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5001, Australia; (E.C.F.Y.); (M.P.B.); (T.G.)
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia
| | - Lisa M. Ebert
- Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5001, Australia; (E.C.F.Y.); (M.P.B.); (T.G.)
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia
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19
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Tran TTT, Delgado A, Jeong S. Organ-on-a-Chip: The Future of Therapeutic Aptamer Research? BIOCHIP JOURNAL 2021. [DOI: 10.1007/s13206-021-00016-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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20
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Yang S, Han G, Chen Q, Yu L, Wang P, Zhang Q, Dong J, Zhang W, Huang J. Au-Pt Nanoparticle Formulation as a Radiosensitizer for Radiotherapy with Dual Effects. Int J Nanomedicine 2021; 16:239-248. [PMID: 33469284 PMCID: PMC7811476 DOI: 10.2147/ijn.s287523] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/18/2020] [Indexed: 12/20/2022] Open
Abstract
Background Radiotherapy occupies an essential position as one of the most significant approaches for the clinical treatment of cancer. However, we cannot overcome the shortcoming of X-rays which is the high value of the oxygen enhancement ratio (OER). Radiosensitizers with the ability to enhance the radiosensitivity of tumor cells provide an alternative to changing X-rays to protons and heavy ion radiotherapy. Materials and Methods We prepared the Au-Pt nanoparticles (Au-Pt NPs) using a one-step method. The characteristics of the Au-Pt NPs were determined using TEM, HAADF-STEM, elemental mapping images, and DLS. The enhanced radiotherapy was demonstrated in vitro using MTT assays, colony formation assays, fluorescence imaging, and flow cytometric analyses of the apoptosis. The biodistribution of the Au-Pt NPs was analyzed using ICP-OES, and thermal images. The enhanced radiotherapy was demonstrated in vitro using immunofluorescence images, tumor volume and weigh, and hematoxylin & eosin (H&E) staining. Results Polyethylene glycol (PEG) functionalized nanoparticles composed of the metallic elements Au and Pt were designed to increase synergistic radiosensitivity. The mechanism demonstrated that heavy metal NPs possess a high X-ray photon capture cross-section and Compton scattering effect which increased DNA damage. Furthermore, the Au-Pt NPs exhibited enzyme-mimicking activities by catalyzing the decomposition of endogenous H2O2 to O2 in the solid tumor microenvironment (TME). Conclusion Our work provides a systematically administered radiosensitizer that can selectively reside in a tumor via the EPR effect and enhances the efficiency of treating cancer with radiotherapy.
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Affiliation(s)
- Song Yang
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China.,Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Gaohua Han
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China.,Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Quan Chen
- Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China.,Department of Thoracic Surgery, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China
| | - Lei Yu
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China.,Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Peng Wang
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China.,Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Qi Zhang
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China.,Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Jiang Dong
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China.,Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Wei Zhang
- Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China.,Department of Infectious Disease, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China
| | - Junxing Huang
- Department of Oncology, Taizhou People's Hospital, Taizhou, Jiangsu, People's Republic of China.,Medical School of Nantong University, Nantong, Jiangsu, People's Republic of China
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21
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Donlon NE, Power R, Hayes C, Reynolds JV, Lysaght J. Radiotherapy, immunotherapy, and the tumour microenvironment: Turning an immunosuppressive milieu into a therapeutic opportunity. Cancer Lett 2021; 502:84-96. [PMID: 33450360 DOI: 10.1016/j.canlet.2020.12.045] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/07/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023]
Abstract
Immune checkpoint blockade (ICB) has revolutionised the treatment of solid tumours, yet most patients do not derive a clinical benefit. Resistance to ICB is often contingent on the tumour microenvironment (TME) and modulating aspects of this immunosuppressive milieu is a goal of combination treatment approaches. Radiation has been used for over a century in the management of cancer with more than half of all cancer patients receiving radiotherapy. Here, we outline the rationale behind combining radiotherapy with ICB, a potential synergy through mutually beneficial remodelling of the TME. We discuss the pleiotropic effects radiation has on the TME including immunogenic cell death, activation of cytosolic DNA sensors, remodelling the stroma and vasculature, and paradoxical infiltration of both anti-tumour and suppressive immune cell populations. These events depend on the radiation dose and fractionation and optimising these parameters will be key to develop safe and effective combination regimens. Finally, we highlight ongoing efforts that combine radiation, immunotherapy and inhibitors of DNA damage response, which can help achieve a favourable equilibrium between the immunogenic and tolerogenic effects of radiation on the immune microenvironment.
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Affiliation(s)
- N E Donlon
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - R Power
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - C Hayes
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - J V Reynolds
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - J Lysaght
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland.
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22
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Chen H, Li M, Guo Y, Zhong Y, He Z, Xu Y, Zou J. Immune response in glioma's microenvironment. Innov Surg Sci 2021; 5:20190001. [PMID: 33511267 PMCID: PMC7810204 DOI: 10.1515/iss-2019-0001] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 10/30/2020] [Indexed: 01/09/2023] Open
Abstract
Objectives Glioma is the most common tumor of the central nervous system. In this review, we outline the immunobiological factors that interact with glioma cells and tumor microenvironment (TME), providing more potential targets for clinical inhibition of glioma development and more directions for glioma treatment. Content Recent studies have shown that glioma cells secrete a variety of immune regulatory factors and interact with immune cells such as microglial cells, peripheral macrophages, myeloid-derived suppressor cells (MDSCs), and T lymphocytes in the TME. In particular, microglia plays a key role in promoting glioma growth. Infiltrating immune cells induce local production of cytokines, chemokines and growth factors. Further leads to immune escape of malignant gliomas. Summary and Outlook The complex interaction of tumor cells with the TME has largely contributed to tumor heterogeneity and poor prognosis. We review the immunobiological factors, immune cells and current immunotherapy of gliomas, provide experimental evidence for future research and treatment of gliomas.
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Affiliation(s)
- Houminji Chen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China.,The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Ming Li
- Department of Neurosurgery, Henan Provical People's Hospital, Zhengzhou, P. R. China
| | - Yanwu Guo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Yongsheng Zhong
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Zhuoyi He
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Yuting Xu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Junjie Zou
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
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23
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Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies. Curr Treat Options Oncol 2021; 22:9. [PMID: 33400014 DOI: 10.1007/s11864-020-00806-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2020] [Indexed: 12/25/2022]
Abstract
OPINION STATEMENT The role of targeted therapy is firmly established for gastrointestinal stromal tumors (GISTs); other modalities for targeting this disease are necessary for recurrent and refractory disease. There are several lines of evidence pointing to an active role of the immune system in GIST. Preclinical and clinical studies revealed that the most common type of immune cell infiltration in GISTs is tumor-associated macrophages (TAMs). The mechanism of how TAMs sculpt the tumor microenvironment in GIST is not clear, but it seems that the presence of immunosuppressive regulatory T cells (Tregs) is correlated with the number of TAMs, thus linking macrophages to immunosuppression. CD3+ T cells and NK infiltrates are found in the GIST microenvironment and carry some prognostic value. In early clinical trials, there is evidence for an active role for immunotherapy in treating GIST patients. Moreover, preclinical evidence has indicated that combining TKIs with checkpoint blockers may be synergistic in murine GIST models. Overall, there is substantial preclinical and clinical evidence to support a role for immunoregulation in GIST and further studies will be important for the development of immunotherapies for GIST.
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24
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Portella L, Bello AM, Scala S. CXCL12 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1302:51-70. [PMID: 34286441 DOI: 10.1007/978-3-030-62658-7_5] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tumor microenvironment (TME) is the local environment of tumor, composed of tumor cells and blood vessels, extracellular matrix (ECM), immune cells, and metabolic and signaling molecules. Chemokines and their receptors play a fundamental role in the crosstalk between tumor cells and TME, regulating tumor-related angiogenesis, specific leukocyte infiltration, and activation of the immune response and directly influencing tumor cell growth, invasion, and cancer progression. The chemokine CXCL12 is a homeostatic chemokine that regulates physiological and pathological process such as inflammation, cell proliferation, and specific migration. CXCL12 activates CXCR4 and CXCR7 chemokine receptors, and the entire axis has been shown to be dysregulated in more than 20 different tumors. CXCL12 binding to CXCR4 triggers multiple signal transduction pathways that regulate intracellular calcium flux, chemotaxis, transcription, and cell survival. CXCR7 binds with high-affinity CXCL12 and with lower-affinity CXCL11, which binds also CXCR3. Although CXCR7 acts as a CXCL12 scavenger through ligand internalization and degradation, it transduces the signal mainly through β-arrestin with a pivotal role in endothelial and neural cells. Recent studies demonstrate that TME rich in CXCL12 leads to resistance to immune checkpoint inhibitors (ICI) therapy and that CXCL12 axis inhibitors sensitize resistant tumors to ICI effect. Thus targeting the CXCL12-mediated axis may control tumor and tumor microenvironment exerting an antitumor dual action. Herein CXCL12 physiology, role in cancer biology and in composite TME, prognostic role, and the relative inhibitors are addressed.
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Affiliation(s)
- Luigi Portella
- Microenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy
| | - Anna Maria Bello
- Microenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy
| | - Stefania Scala
- Microenvironment Molecular Targets, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy.
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25
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Aptamer-Based In Vivo Therapeutic Targeting of Glioblastoma. Molecules 2020; 25:molecules25184267. [PMID: 32957732 PMCID: PMC7570863 DOI: 10.3390/molecules25184267] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/28/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive, infiltrative, and lethal brain tumor in humans. Despite the extensive advancement in the knowledge about tumor progression and treatment over the last few years, the prognosis of GBM is still very poor due to the difficulty of targeting drugs or anticancer molecules to GBM cells. The major challenge in improving GBM treatment implicates the development of a targeted drug delivery system, capable of crossing the blood–brain barrier (BBB) and specifically targeting GBM cells. Aptamers possess many characteristics that make them ideal novel therapeutic agents for the treatment of GBM. They are short single-stranded nucleic acids (RNA or ssDNA) able to bind to a molecular target with high affinity and specificity. Several GBM-targeting aptamers have been developed for imaging, tumor cell isolation from biopsies, and drug/anticancer molecule delivery to the tumor cells. Due to their properties (low immunogenicity, long stability, and toxicity), a large number of aptamers have been selected against GBM biomarkers and tested in GBM cell lines, while only a few of them have also been tested in in vivo models of GBM. Herein, we specifically focus on aptamers tested in GBM in vivo models that can be considered as new diagnostic and/or therapeutic tools for GBM patients’ treatment.
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26
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Rajendiran S, Smith-Berdan S, Kunz L, Risolino M, Selleri L, Schroeder T, Forsberg EC. Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells. Stem Cells 2020; 38:1159-1174. [PMID: 32442338 DOI: 10.1002/stem.3205] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/16/2020] [Indexed: 12/12/2022]
Abstract
C-X-C motif chemokine ligand 12 (CXCL12; aka SDF1α) is a major regulator of a number of cellular systems, including hematopoiesis, where it influences hematopoietic cell trafficking, proliferation, and survival during homeostasis and upon stress and disease. A variety of constitutive, temporal, ubiquitous, and cell-specific loss-of-function models have documented the functional consequences on hematopoiesis upon deletion of Cxcl12. Here, in contrast to loss-of-function experiments, we implemented a gain-of-function approach by generating a doxycycline-inducible transgenic mouse model that enables spatial and temporal overexpression of Cxcl12. We demonstrated that ubiquitous CXCL12 overexpression led to an increase in multipotent progenitors in the bone marrow and spleen. The CXCL12+ mice displayed reduced reconstitution potential as either donors or recipients in transplantation experiments. Additionally, we discovered that Cxcl12 overexpression improved hematopoietic stem and progenitor cell mobilization into the blood, and conferred radioprotection by promoting quiescence. Thus, this new CXCL12+ mouse model provided new insights into major facets of hematopoiesis and serves as a versatile resource for studying CXCL12 function in a variety of contexts.
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Affiliation(s)
- Smrithi Rajendiran
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA
| | - Stephanie Smith-Berdan
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA
| | - Leo Kunz
- Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, Basel, Switzerland
| | - Maurizio Risolino
- Program in Craniofacial Biology, Institute of Human Genetics, Eli and Edyth Broad Center of Regeneration Medicine and Stem Cell Research, Departments of Orofacial Sciences and Anatomy, University of California, San Francisco, California, USA
| | - Licia Selleri
- Program in Craniofacial Biology, Institute of Human Genetics, Eli and Edyth Broad Center of Regeneration Medicine and Stem Cell Research, Departments of Orofacial Sciences and Anatomy, University of California, San Francisco, California, USA
| | - Timm Schroeder
- Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, Basel, Switzerland
| | - E Camilla Forsberg
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA
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27
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Radiation Damage to Tumor Vasculature Initiates a Program That Promotes Tumor Recurrences. Int J Radiat Oncol Biol Phys 2020; 108:734-744. [PMID: 32473180 DOI: 10.1016/j.ijrobp.2020.05.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/07/2020] [Accepted: 05/18/2020] [Indexed: 01/03/2023]
Abstract
This review, mostly of preclinical data, summarizes the evidence that radiation at doses relevant to radiation therapy initiates a pathway that promotes the reconstitution of the tumor vasculature leading to tumor recurrence. The pathway is not specific to tumors; it promotes repair of damaged and ischemic normal tissues by attracting proangiogenic cells from the bone marrow. For irradiated tumors the pathway comprises: (1) loss of endothelial cells and reduced tumor blood perfusion leading to increased tumor hypoxia and increased levels of hypoxia inducible factor-1 (HIF-1). Alternatively, increased HIF-1 levels may arise by reactive oxygen species (ROS) production caused by tumor reoxygenation. (2) Increased HIF-1 levels lead to increased levels in the tumor of the chemokine stromal cell-derived factor-1 (SDF-1, CXCL12), which captures monocytes/macrophages expressing the CXCR4 receptor of CXCL12. (3) The increased levels of tumor-associated macrophages (TAMs) become highly proangiogenic (M2 polarized) and restore the tumor vasculature, thereby promoting tumor recurrence. The relevance of this pathway for radiation therapy is that it can be blocked in a number of different ways including by inhibitors of monocytes/macrophages, of HIF-1, of CXCL12, of CXCR4, and of CSF-1R, the latter of which is responsible for the M2 polarization of the TAMs. All of these inhibitors produce a robust enhancement of the radiation response of a wide variety of preclinical tumor models. Further, the same inhibitors actually provide protection against radiation damage of several normal tissues. Some of these pathway inhibitors are available clinically, and a first-in-human trial of the CXCR4 inhibitor, plerixafor, with radiation therapy of glioblastoma has yielded promising results, including an impressive increase in local tumor control. Further clinical trials are warranted.
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28
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Crijns H, Vanheule V, Proost P. Targeting Chemokine-Glycosaminoglycan Interactions to Inhibit Inflammation. Front Immunol 2020; 11:483. [PMID: 32296423 PMCID: PMC7138053 DOI: 10.3389/fimmu.2020.00483] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
Leukocyte migration into tissues depends on the activity of chemokines that form concentration gradients to guide leukocytes to a specific site. Interaction of chemokines with their specific G protein-coupled receptors (GPCRs) on leukocytes induces leukocyte adhesion to the endothelial cells, followed by extravasation of the leukocytes and subsequent directed migration along the chemotactic gradient. Interaction of chemokines with glycosaminoglycans (GAGs) is crucial for extravasation in vivo. Chemokines need to interact with GAGs on endothelial cells and in the extracellular matrix in tissues in order to be presented on the endothelium of blood vessels and to create a concentration gradient. Local chemokine retention establishes a chemokine gradient and prevents diffusion and degradation. During the last two decades, research aiming at reducing chemokine activity mainly focused on the identification of inhibitors of the interaction between chemokines and their cognate GPCRs. This approach only resulted in limited success. However, an alternative strategy, targeting chemokine-GAG interactions, may be a promising approach to inhibit chemokine activity and inflammation. On this line, proteins derived from viruses and parasites that bind chemokines or GAGs may have the potential to interfere with chemokine-GAG interactions. Alternatively, chemokine mimetics, including truncated chemokines and mutant chemokines, can compete with chemokines for binding to GAGs. Such truncated or mutated chemokines are characterized by a strong binding affinity for GAGs and abrogated binding to their chemokine receptors. Finally, Spiegelmers that mask the GAG-binding site on chemokines, thereby preventing chemokine-GAG interactions, were developed. In this review, the importance of GAGs for chemokine activity in vivo and strategies that could be employed to target chemokine-GAG interactions will be discussed in the context of inflammation.
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Affiliation(s)
- Helena Crijns
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Vincent Vanheule
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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29
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Pombo Antunes AR, Scheyltjens I, Duerinck J, Neyns B, Movahedi K, Van Ginderachter JA. Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. eLife 2020; 9:52176. [PMID: 32014107 PMCID: PMC7000215 DOI: 10.7554/elife.52176] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 01/30/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy by immune checkpoint blockade has proven its great potential by saving the lives of a proportion of late stage patients with immunogenic tumor types. However, even in these sensitive tumor types, the majority of patients do not sufficiently respond to the therapy. Furthermore, other tumor types, including glioblastoma, remain largely refractory. The glioblastoma immune microenvironment is recognized as highly immunosuppressive, posing a major hurdle for inducing immune-mediated destruction of cancer cells. Scattered information is available about the presence and activity of immunosuppressive or immunostimulatory cell types in glioblastoma tumors, including tumor-associated macrophages, tumor-infiltrating dendritic cells and regulatory T cells. These cell types are heterogeneous at the level of ontogeny, spatial distribution and functionality within the tumor immune compartment, providing insight in the complex cellular and molecular interplay that determines the immune refractory state in glioblastoma. This knowledge may also yield next generation molecular targets for therapeutic intervention.
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Affiliation(s)
- Ana Rita Pombo Antunes
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Isabelle Scheyltjens
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Bart Neyns
- Department of Medical Oncology, UZ Brussels, Brussels, Belgium
| | - Kiavash Movahedi
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jo A Van Ginderachter
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.,Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
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30
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Georgieva PB, Mathivet T, Alt S, Giese W, Riva M, Balcer M, Gerhardt H. Long-lived tumor-associated macrophages in glioma. Neurooncol Adv 2020; 2:vdaa127. [PMID: 33205045 PMCID: PMC7649962 DOI: 10.1093/noajnl/vdaa127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The tumor microenvironment plays a major tumor-supportive role in glioma. In particular, tumor-associated macrophages (TAMs), which can make up to one-third of the tumor mass, actively support tumor growth, invasion, and angiogenesis. Predominantly alternatively activated (M2-polarized) TAMs are found in late-stage glioma in both human and mouse tumors, as well as in relapse samples from patients. However, whether tumor-educated M2 TAMs can actively contribute to the emergence and growth of relapse is currently debated. METHODS To investigate whether tumor-educated stromal cells remaining in the brain after surgical removal of the primary tumor can be long-lived and retain their tumor-supporting function, we developed a transplantation mouse model and performed lineage-tracing. RESULTS We discovered that macrophages can survive transplantation and stay present in the tumor much longer than previously suggested, while sustaining an M2-polarized protumorigenic phenotype. Transplanted tumors showed a more aggressive growth and faster polarization of the TAMs toward an M2 phenotype compared with primary tumors, a process dependent on the presence of few cotransplanted macrophages. CONCLUSIONS Overall, we propose a new way for tumor-educated TAMs to contribute to glioma aggressiveness by long survival and stable protumorigenic features. These properties could have a relapse-supporting effect.
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Affiliation(s)
- Petya B Georgieva
- Department: Cardiovascular and metabolic diseases, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Vascular Patterning Laboratory, VIB Center for Cancer Biology, VIB Leuven, Leuven, Belgium
- Vascular Patterning Laboratory, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Thomas Mathivet
- Vascular Patterning Laboratory, VIB Center for Cancer Biology, VIB Leuven, Leuven, Belgium
- Vascular Patterning Laboratory, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Silvanus Alt
- Department: Cardiovascular and metabolic diseases, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Wolfgang Giese
- Department: Cardiovascular and metabolic diseases, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Matteo Riva
- Laboratory of Tumor Immunology and Immunotherapy, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Marly Balcer
- Vascular Patterning Laboratory, VIB Center for Cancer Biology, VIB Leuven, Leuven, Belgium
- Vascular Patterning Laboratory, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Holger Gerhardt
- Department: Cardiovascular and metabolic diseases, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Vascular Patterning Laboratory, VIB Center for Cancer Biology, VIB Leuven, Leuven, Belgium
- Vascular Patterning Laboratory, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- DZHK (German Center for Cardiovascular Research), Partner site Berlin, Berlin, Germany
- Department of Vascular Biomedicine, Berlin Institute of Health (BIH), Berlin, Germany
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31
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Macrophage exclusion after radiation therapy (MERT): A new and effective way to increase the therapeutic ratio of radiotherapy. Radiother Oncol 2019; 144:159-164. [PMID: 31812931 DOI: 10.1016/j.radonc.2019.11.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/17/2019] [Accepted: 11/19/2019] [Indexed: 01/09/2023]
Abstract
Here we review a variety of preclinical studies and a first-in-human clinical trial of newly diagnosed glioblastoma (GBM) patients that have investigated the significance of the influx of tumor associated macrophages (TAMs) into tumors after irradiation. We summarize the effects on the response of the tumors and normal tissues to radiation of various agents that either reduce the influx of TAMs into tumors after radiation or change their M1/M2 polarization. The studies show that following irradiation there is an accumulation of bone marrow derived TAMs in the irradiated tumors. These TAMs stimulate the resumption of blood flow in the irradiated tumors thereby promoting recurrence of the tumors. A key mechanism for this accumulation of TAMs is driven by the SDF-1/CXCR4 chemokine pathway though other pathways could also be involved for some tumors. Blocking this pathway to prevent the TAM accumulation in the tumors both enhances tumor response to radiation and protects irradiated tissues. A clinical trial in which the CXCR4 antagonist plerixafor was added to standard therapy of glioblastoma validated the preclinical findings by demonstrating i) reduced blood flow in the irradiated site, and ii) significantly improved tumor local control compared to GBM patients not treated with plerixafor. We conclude that macrophage exclusion after radiation therapy (MERT) is an effective way both to enhance the tumor response to radiation and to protect the irradiated normal tissues. Further clinical trials are warranted.
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32
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Thomas RP, Nagpal S, Iv M, Soltys SG, Bertrand S, Pelpola JS, Ball R, Yang J, Sundaram V, Lavezo J, Born D, Vogel H, Brown JM, Recht LD. Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma. Clin Cancer Res 2019; 25:6948-6957. [PMID: 31537527 PMCID: PMC6891194 DOI: 10.1158/1078-0432.ccr-19-1421] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/17/2019] [Accepted: 09/11/2019] [Indexed: 01/18/2023]
Abstract
PURPOSE Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma. PATIENTS AND METHODS We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors. RESULTS Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9-NA] with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization. CONCLUSIONS Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
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Affiliation(s)
- Reena P Thomas
- Department of Neurology, Division of Neuro Oncology, Stanford, California.
| | - Seema Nagpal
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Michael Iv
- Department of Radiology, Division of Neuro Radiology, Stanford, California
| | | | - Sophie Bertrand
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Judith S Pelpola
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Robyn Ball
- Department of Medicine, Quantitative Sciences Unit, Stanford, California
| | - Jaden Yang
- Department of Medicine, Quantitative Sciences Unit, Stanford, California
| | - Vandana Sundaram
- Department of Medicine, Quantitative Sciences Unit, Stanford, California
| | - Jonathan Lavezo
- Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California
| | - Donald Born
- Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California
| | - Hannes Vogel
- Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California
| | - J Martin Brown
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Lawrence D Recht
- Department of Neurology, Division of Neuro Oncology, Stanford, California
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33
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Portella L, Scala S. Ionizing radiation effects on the tumor microenvironment. Semin Oncol 2019; 46:254-260. [PMID: 31383368 DOI: 10.1053/j.seminoncol.2019.07.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 07/17/2019] [Indexed: 12/12/2022]
Abstract
The broad use of radiotherapy (RT) in the management of solid human tumors is based on its ability to damage cellular macromolecules, particularly the DNA, effectively inducing growth arrest and cell death locally in irradiated tumor cells. However, bystander effects, such as the transmission of lethal signals between cells via gap junctions or the production of diffusible cytotoxic mediators, can also contribute to the local antineoplastic action of RT. Traditionally, RT has been considered to exert immunosuppressive effects on the host. This idea largely stems from the radiosensitivity of quiescent lymphocytes and on the use of total body irradiation as part of myeloablative conditioning regimens preceding hematopoietic stem cell transplantation. Additionally, the occurrence of the so-called "abscopal effect," where nonirradiated distant lesions display effects of RT response, suggests that RT may also induce tumor immunization. Several RT-induced effects on cancer, immune and stromal cells, contribute to the abscopal effect: (1) induction of "immunogenic cell death", with release of tumor-associated antigens, (2) alterations of cancer cell immunophenotype, and (3) modulation of the tumor microenvironment. Damage and death of cancer cells leads to the surface exposure of immunogenic molecules as well as the release of damage associated molecular patterns such as adenosine triphosphate or High-Mobility-Group-Protein B1, and potentially tumor antigens that activate the innate and adaptive immune systems. Moreover, nuclear release and cytoplasmic sensing of altered nucleic acids via cyclic GMP-AMP Synthase/Stimulator of Interferon Genes is connected to the secretion of cytokines that support innate and adaptive antitumor immunity. As a result of the above, irradiated tumor cells may potentially act as an "in situ vaccine."
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Affiliation(s)
- Luigi Portella
- Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Naples, Italy
| | - Stefania Scala
- Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Naples, Italy.
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34
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Lecavalier-Barsoum M, Chaudary N, Han K, Pintilie M, Hill RP, Milosevic M. Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy. Br J Cancer 2019; 121:249-256. [PMID: 31239542 PMCID: PMC6738100 DOI: 10.1038/s41416-019-0497-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. We previously reported that radiochemotherapy (RTCT) and concurrent administration of the CXCR4 inhibitor plerixafor improved primary tumour response. The aims of this study were to determine optimal sequencing of RTCT and plerixafor, the mechanisms responsible for improved response and the effect of plerixafor on late intestinal toxicity. METHODS Orthotopic cervical cancer xenografts were treated with RTCT (30 Gy in 2 Gy fractions and cisplatin) with or without concurrent, adjuvant or continuous plerixafor. The endpoints were growth delay and molecular and immune cell changes at the end of treatment. Late intestinal toxicity was assessed by histologic examination of the rectum 90 days after a single 20 Gy fraction. RESULTS RTCT increased CXCL12/CXCR4 signalling and the intratumoral accumulation of myeloid cells; the addition of plerixafor mitigated these effects. All of the RTCT and plerixafor arms showed prolonged tumour growth delay compared to RTCT alone, with the adjuvant arm showing the greatest improvement. Plerixafor also reduced late intestinal toxicity. CONCLUSION Adding Plerixafor to RTCT blunts treatment-induced increases in CXCL12/CXCR4 signalling, improves primary tumour response and reduces intestinal side effects. This combination warrants testing in future clinical trials.
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Affiliation(s)
| | - Naz Chaudary
- University Health Network and Princess Margaret Cancer Centre, Toronto, Canada
| | - Kathy Han
- University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Melania Pintilie
- University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Richard P Hill
- University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Michael Milosevic
- University Health Network and Princess Margaret Cancer Centre, Toronto, Canada. .,Department of Radiation Oncology, University of Toronto, Toronto, Canada. .,Institute of Medical Science, University of Toronto, Toronto, Canada.
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35
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Giordano FA, Link B, Glas M, Herrlinger U, Wenz F, Umansky V, Brown JM, Herskind C. Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12. Cancers (Basel) 2019; 11:cancers11030272. [PMID: 30813533 PMCID: PMC6468743 DOI: 10.3390/cancers11030272] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/14/2019] [Accepted: 02/20/2019] [Indexed: 01/05/2023] Open
Abstract
Radiotherapy is a mainstay in glioblastoma therapy as it not only directly targets tumor cells but also depletes the tumor microvasculature. The resulting intra-tumoral hypoxia initiates a chain of events that ultimately leads to re-vascularization, immunosuppression and, ultimately, tumor-regrowth. The key component of this cascade is overexpression of the CXC-motive chemokine ligand 12 (CXCL12), formerly known as stromal-cell derived factor 1 (SDF-1). We here review the role of CXCL12 in recruitment of pro-vasculogenic and immunosuppressive cells and give an overview on future and current drugs that target this axis.
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Affiliation(s)
- Frank A Giordano
- Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
| | - Barbara Link
- Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
| | - Martin Glas
- Division of Clinical Neurooncology, Department of Neurology and West German Cancer Center (WTZ), University Hospital Essen and German Cancer Consortium, Partner Site University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
| | - Ulrich Herrlinger
- Division of Clinical Neurooncology, Department of Neurology, University of Bonn Medical Center, 53105 Bonn, Germany.
| | - Frederik Wenz
- CEO, University Medical Center Freiburg, 79110 Freiburg, Germany.
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany.
| | - J Martin Brown
- Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Carsten Herskind
- Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
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36
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Jeong H, Kim S, Hong BJ, Lee CJ, Kim YE, Bok S, Oh JM, Gwak SH, Yoo MY, Lee MS, Chung SJ, Defrêne J, Tessier P, Pelletier M, Jeon H, Roh TY, Kim B, Kim KH, Ju JH, Kim S, Lee YJ, Kim DW, Kim IH, Kim HJ, Park JW, Lee YS, Lee JS, Cheon GJ, Weissman IL, Chung DH, Jeon YK, Ahn GO. Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis. Cancer Res 2019; 79:795-806. [PMID: 30610087 DOI: 10.1158/0008-5472.can-18-2545] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 12/03/2018] [Accepted: 12/27/2018] [Indexed: 12/15/2022]
Abstract
Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.
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Affiliation(s)
- Hoibin Jeong
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea
| | - Sehui Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Beom-Ju Hong
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea
| | - Chan-Ju Lee
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea
| | - Young-Eun Kim
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea
| | - Seoyeon Bok
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea
| | - Jung-Min Oh
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea
| | - Seung-Hee Gwak
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea
| | - Min Young Yoo
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Min Sun Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Seock-Jin Chung
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Joan Defrêne
- Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Ville de Québec, Québec, Canada
| | - Philippe Tessier
- Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Ville de Québec, Québec, Canada
| | - Martin Pelletier
- Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Ville de Québec, Québec, Canada
| | - Hyeongrin Jeon
- Department of Life Sciences, POSTECH, Pohang, Gyeongbuk, Korea
| | - Tae-Young Roh
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea.,Department of Life Sciences, POSTECH, Pohang, Gyeongbuk, Korea
| | - Bumju Kim
- Department of Mechanical Engineering, POSTECH, Pohang, Gyeongbuk, Korea
| | - Ki Hean Kim
- Department of Mechanical Engineering, POSTECH, Pohang, Gyeongbuk, Korea
| | - Ji Hyeon Ju
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Korea
| | - Sungjee Kim
- Department of Chemistry, POSTECH, Pohang, Gyeongbuk, Korea
| | - Yoon-Jin Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Dong-Wan Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Il Han Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hak Jae Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jong-Wan Park
- Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea
| | - Yun-Sang Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Gi Jeong Cheon
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Irving L Weissman
- Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California
| | - Doo Hyun Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
| | - G-One Ahn
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea. .,Department of Life Sciences, POSTECH, Pohang, Gyeongbuk, Korea
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37
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Eckert F, Schilbach K, Klumpp L, Bardoscia L, Sezgin EC, Schwab M, Zips D, Huber SM. Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer. Front Immunol 2018; 9:3018. [PMID: 30622535 PMCID: PMC6308162 DOI: 10.3389/fimmu.2018.03018] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/06/2018] [Indexed: 12/28/2022] Open
Abstract
Cancer immunotherapy has been established as standard of care in different tumor entities. After the first reports on synergistic effects with radiotherapy and the induction of abscopal effects-tumor shrinkage outside the irradiated volume attributed to immunological effects of radiotherapy-several treatment combinations have been evaluated. Different immunotherapy strategies (e.g., immune checkpoint inhibition, vaccination, cytokine based therapies) have been combined with local tumor irradiation in preclinical models. Clinical trials are ongoing in different cancer entities with a broad range of immunotherapeutics and radiation schedules. SDF-1 (CXCL12)/CXCR4 signaling has been described to play a major role in tumor biology, especially in hypoxia adaptation, metastasis and migration. Local tumor irradiation is a known inducer of SDF-1 expression and release. CXCR4 also plays a major role in immunological processes. CXCR4 antagonists have been approved for the use of hematopoietic stem cell mobilization from the bone marrow. In addition, several groups reported an influence of the SDF-1/CXCR4 axis on intratumoral immune cell subsets and anti-tumor immune response. The aim of this review is to merge the knowledge on the role of SDF-1/CXCR4 in tumor biology, radiotherapy and immunotherapy of cancer and in combinatorial approaches.
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Affiliation(s)
- Franziska Eckert
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Karin Schilbach
- Department of General Pediatrics/Pediatric Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Lukas Klumpp
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany.,Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
| | - Lilia Bardoscia
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany.,Department of Radiation Oncology, University of Brescia, Brescia, Italy
| | - Efe Cumhur Sezgin
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.,Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University Hospital and University Tuebingen, Tuebingen, Germany
| | - Daniel Zips
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Stephan M Huber
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
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38
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Matias D, Balça-Silva J, da Graça GC, Wanjiru CM, Macharia LW, Nascimento CP, Roque NR, Coelho-Aguiar JM, Pereira CM, Dos Santos MF, Pessoa LS, Lima FRS, Schanaider A, Ferrer VP, Moura-Neto V. Microglia/Astrocytes-Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors. Front Cell Neurosci 2018; 12:235. [PMID: 30123112 PMCID: PMC6086063 DOI: 10.3389/fncel.2018.00235] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 07/16/2018] [Indexed: 12/11/2022] Open
Abstract
In recent years, the functions of glial cells, namely, astrocytes and microglia, have gained prominence in several diseases of the central nervous system, especially in glioblastoma (GB), the most malignant primary brain tumor that leads to poor clinical outcomes. Studies showed that microglial cells or astrocytes play a critical role in promoting GB growth. Based on the recent findings, the complex network of the interaction between microglial/astrocytes cells and GB may constitute a potential therapeutic target to overcome tumor malignancy. In the present review, we summarize the most important mechanisms and functions of the molecular factors involved in the microglia or astrocytes-GB interactions, which is particularly the alterations that occur in the cell's extracellular matrix and the cytoskeleton. We overview the cytokines, chemokines, neurotrophic, morphogenic, metabolic factors, and non-coding RNAs actions crucial to these interactions. We have also discussed the most recent studies regarding the mechanisms of transportation and communication between microglial/astrocytes - GB cells, namely through the ABC transporters or by extracellular vesicles. Lastly, we highlight the therapeutic challenges and improvements regarding the crosstalk between these glial cells and GB.
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Affiliation(s)
- Diana Matias
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.,Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Joana Balça-Silva
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.,Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences Consortium, University of Coimbra, Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Grazielle C da Graça
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | - Caroline M Wanjiru
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.,Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lucy W Macharia
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.,Programa de Pós-Graduação em Anatomia Patológica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carla Pires Nascimento
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.,Programa de Pós-Graduação em Anatomia Patológica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Natalia R Roque
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | - Juliana M Coelho-Aguiar
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | | | - Marcos F Dos Santos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luciana S Pessoa
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | - Flavia R S Lima
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alberto Schanaider
- Centro de Cirurgia Experimental do Departamento de Cirurgia da Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Valéria P Ferrer
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | | | - Vivaldo Moura-Neto
- Instituto Estadual do Cérebro Paulo Niemeyer - Secretaria de Estado de Saúde, Rio de Janeiro, Brazil.,Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Universidade do Grande Rio (Unigranrio), Duque de Caxias, Brazil
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39
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Wang C, Chen W, Shen J. CXCR7 Targeting and Its Major Disease Relevance. Front Pharmacol 2018; 9:641. [PMID: 29977203 PMCID: PMC6021539 DOI: 10.3389/fphar.2018.00641] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/29/2018] [Indexed: 12/25/2022] Open
Abstract
Chemokine receptors are the target of small peptide chemokines. They play various important roles in physiological and pathological processes. CXCR7, later renamed ACKR3, is a non-classical seven transmembrane-spanning receptor whose function as a signaling or non-signaling scavenger/decoy receptor is currently under debate. Even for cell signaling mechanisms, there has been inconsistency on whether CXCR7 couples to G-proteins or β-arrestins. Several reasons may contribute to this uncertainty or controversy. In one hand, it has been neglected that CXCR7 has more than five natural ligands and unfortunately, most of the prior research only studied SDF-1 (CXCL12) and/or I-TAC (CXCL11); on the other hand, there are mounting evidence supporting ligand and tissue bias for receptor signaling, but limited such information is available for CXCR7. In this review we focus on summarizing the endogenous and exogenous ligands of CXCR7, the main diseases related to CXCR7 and the biased signaling events happening on CXCR7. These three aspects of CXCR7 pharmacologic properties may explain why the contradicting opinions of whether CXCR7 is a signaling or non-signaling receptor exist. Further, potential new direction and perspective for the study of CXCR7 biology and pharmacology are highlighted.
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Affiliation(s)
- Chuan Wang
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
| | - Weilin Chen
- Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Jianzhong Shen
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
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40
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Morita Y, Leslie M, Kameyama H, Volk DE, Tanaka T. Aptamer Therapeutics in Cancer: Current and Future. Cancers (Basel) 2018; 10:cancers10030080. [PMID: 29562664 PMCID: PMC5876655 DOI: 10.3390/cancers10030080] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 03/13/2018] [Accepted: 03/15/2018] [Indexed: 12/14/2022] Open
Abstract
Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth that of monoclonal antibodies—their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesized and modified. In addition, aptamers’ long storage period and low immunogenicity are favorable properties for clinical utility. Due to their flexibility of chemical modification, aptamers are conjugated to other chemical entities including chemotherapeutic agents, siRNA, nanoparticles, and solid phase surfaces for therapeutic and diagnostic applications. However, as relatively small sized oligonucleotides, aptamers present several challenges for successful clinical translation. Their short plasma half-lives due to nuclease degradation and rapid renal excretion necessitate further structural modification of aptamers for clinical application. Since the US Food and Drug Administration (FDA) approval of the first aptamer drug, Macugen® (pegaptanib), which treats wet-age-related macular degeneration, several aptamer therapeutics for oncology have followed and shown promise in pre-clinical models as well as clinical trials. This review discusses the advantages and challenges of aptamers and introduces therapeutic aptamers under investigation and in clinical trials for cancer treatments.
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Affiliation(s)
- Yoshihiro Morita
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE 10th, BRC-W, Rm 1415, Oklahoma City, OK 73104, USA.
| | - Macall Leslie
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE 10th, BRC-W, Rm 1415, Oklahoma City, OK 73104, USA.
| | - Hiroyasu Kameyama
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE 10th, BRC-W, Rm 1415, Oklahoma City, OK 73104, USA.
| | - David E Volk
- McGovern Medical School, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, TX 77030, USA.
| | - Takemi Tanaka
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE 10th, BRC-W, Rm 1415, Oklahoma City, OK 73104, USA.
- Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, 940 SL Young Blvd, Oklahoma City, OK 73104, USA.
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41
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Lecavalier-Barsoum M, Chaudary N, Han K, Koritzinsky M, Hill R, Milosevic M. Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer. Int J Cancer 2018; 143:1017-1028. [PMID: 29417588 DOI: 10.1002/ijc.31297] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/10/2018] [Accepted: 02/01/2018] [Indexed: 12/17/2022]
Abstract
Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide. Approximately half of cervical cancer patients present with locally advanced disease, for which surgery is not an option. These cases are nonetheless potentially curable with radiotherapy and cisplatin chemotherapy. Unfortunately, some tumours are resistant to treatment, and lymph node and distant recurrences are major problems in patients with advanced disease at diagnosis. New targeted treatments that can overcome treatment resistance and reduce metastases are urgently needed. The CXCL12/CXCR4 chemokine pathway is ubiquitously expressed in many normal tissues and cancers, including cervical cancer. Emerging evidence indicates that it plays a central role in cervical cancer pathogenesis, malignant progression, the development of metastases and radiation treatment response. Pre-clinical studies of standard-of-care fractionated radiotherapy and concurrent weekly cisplatin plus the CXCR4 inhibitor Plerixafor (AMD3100) in patient-derived orthotopic cervical cancer xenografts have shown improved primary tumour response and reduced lymph node metastases with no increase in early or late side effects. These studies have pointed the way forward to future clinical trials of radiotherapy/cisplatin plus Plerixafor or other newly emerging CXCL12 or CXCR4 inhibitors in women with cervical cancer.
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Affiliation(s)
- Magali Lecavalier-Barsoum
- Department of Oncology, Segal Cancer Centre, Jewish General Hospital, McGill University, Montréal, Canada
| | - Naz Chaudary
- Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Canada
| | - Kathy Han
- Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Marianne Koritzinsky
- Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Richard Hill
- Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Canada.,Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Michael Milosevic
- Radiation Medicine Program, University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
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CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study. Oncotarget 2018; 7:83701-83719. [PMID: 27863376 PMCID: PMC5341257 DOI: 10.18632/oncotarget.13295] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 10/17/2016] [Indexed: 01/19/2023] Open
Abstract
Glioblastoma (GBM) is a highly invasive brain tumor. Perivascular invasion, autovascularization and vascular co-option occur throughout the disease and lead to tumor invasion and progression. The molecular basis for perivascular invasion, i.e., the interaction of glioma tumor cells with endothelial cells is not well characterized. Recent studies indicate that glioma cells have increased expression of CXCR4. We investigated the in-vivo role of CXCR4 in perivascular invasion of glioma cells using shRNA-mediated knock down of CXCR4. We show that primary cultures of human glioma stem cells HF2303 and mouse glioma GL26-Cit cells exhibit significant migration towards human (HBMVE) and mouse (MBVE) brain microvascular endothelial cells. Blocking CXCR4 on tumor cells with AMD3100 in-vitro, inhibits migration of GL26-Cit and HF2303 toward MBVE and HBMVE cells. Additionally, genetic down regulation of CXCR4 in mouse glioma GL26-Cit cells inhibits their in-vitro migration towards MBVE cells; in an in-vivo intracranial mouse model, these cells display reduced tumor growth and perivascular invasion, leading to increased survival. Quantitative analysis of brain sections showed that CXCR4 knockdown tumors are less invasive. Lastly, we tested the effects of radiation on CXCR4 knock down GL26-Cit cells in an orthotopic brain tumor model. Radiation treatment increased apoptosis of CXCR4 downregulated tumor cells and prolonged median survival. In summary, our data suggest that CXCR4 signaling is critical for perivascular invasion of GBM cells and targeting this receptor makes tumors less invasive and more sensitive to radiation therapy. Combination of CXCR4 knock down and radiation treatment might improve the efficacy of GBM therapy.
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Shi X, Shiao SL. The role of macrophage phenotype in regulating the response to radiation therapy. Transl Res 2018; 191:64-80. [PMID: 29175267 PMCID: PMC6018060 DOI: 10.1016/j.trsl.2017.11.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 10/23/2017] [Accepted: 11/11/2017] [Indexed: 12/14/2022]
Abstract
Increasing experimental and clinical evidence has revealed a critical role for myeloid cells in the development and progression of cancer. The ability of monocytes and macrophages to regulate inflammation allows them to manipulate the tumor microenvironment to support the growth and development of malignant cells. Recent studies have shown that macrophages can exist in several functional states depending on the microenvironment they encounter in the tissue. These functional phenotypes influence not only the genesis and propagation of tumors, but also the efficacy of cancer therapies, particularly radiation. Early classification of the macrophage phenotypes, or "polarization states," identified 2 major states, M1 and M2, that have cytotoxic and wound repair capacity, respectively. In the context of tumors, classically activated or M1 macrophages driven by interferon-gamma support antitumor immunity while alternatively activated or M2 macrophages generated in part from interleukin-4 exposure hinder antitumor immunity by suppressing cytotoxic responses against a tumor. In this review, we discuss the role that the functional phenotype of a macrophage population plays in tumor development. We will then focus specifically on how macrophages and myeloid cells regulate the tumor response to radiation therapy.
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Affiliation(s)
- Xiaoshan Shi
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Stephen L Shiao
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA.
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Inhibition of SDF-1-induced migration of oncogene-driven myeloid leukemia by the L-RNA aptamer (Spiegelmer), NOX-A12, and potentiation of tyrosine kinase inhibition. Oncotarget 2017; 8:109973-109984. [PMID: 29299123 PMCID: PMC5746358 DOI: 10.18632/oncotarget.22409] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 10/25/2017] [Indexed: 01/06/2023] Open
Abstract
Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells. NOX-A12 was sufficient to suppress SDF-1-induced migration in vitro. The combination of NOX-A12 with TKIs reduced cell migration in the same in vitro model of SDF-1-induced chemotaxis to a greater extent than either drug alone, suggesting positive cooperativity as a result of the SDF-1 blocking function of NOX-A12 and cytotoxicity resulting from targeted oncogenic kinase inhibition. These results are consistent with our in vivo findings using a functional pre-clinical mouse model of chronic myeloid leukemia (CML), whereby we demonstrated the ability of NOX-A12, combined with the ABL kinase inhibitor, nilotinib, to reduce the leukemia burden in mice to a greater extent than either agent alone. Overall, the data support the idea of using SDF-1 inhibition in combination with targeted kinase inhibition to override drug resistance in oncogene-driven leukemia to significantly diminish or eradicate residual leukemic disease.
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Zboralski D, Hoehlig K, Eulberg D, Frömming A, Vater A. Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade. Cancer Immunol Res 2017; 5:950-956. [PMID: 28963140 DOI: 10.1158/2326-6066.cir-16-0303] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 07/14/2017] [Accepted: 09/22/2017] [Indexed: 12/23/2022]
Abstract
Immune checkpoint inhibitors promote T cell-mediated killing of cancer cells; however, only a subset of patients benefit from the treatment. A possible reason for this limitation may be that the tumor microenvironment (TME) is immune privileged, which may exclude cytotoxic T cells from the vicinity of cancer cells. The chemokine CXCL12 is key to the TME-driven immune suppression. In this study, we investigated the potential of CXCL12 inhibition by use of the clinical-stage l-RNA-aptamer NOX-A12 (olaptesed pegol) to increase the number of tumor-infiltrating lymphocytes. We used heterotypic tumor-stroma spheroids that mimic a solid tumor with a CXCL12-abundant TME. NOX-A12 enhanced the infiltration of T and NK cells in a dose-dependent manner. NOX-A12 and PD-1 checkpoint inhibition synergistically activated T cells in the spheroids, indicating that the agents complement each other. The findings were validated in vivo in a syngeneic murine model of colorectal cancer in which the addition of NOX-A12 improved anti-PD-1 therapy. Taken together, our work shows that CXCL12 inhibition can break the immune-privileged status of the TME by paving the way for immune effector cells to enter into the tumor, thereby broadening the applicability of checkpoint inhibitors in cancer patients. Cancer Immunol Res; 5(11); 950-6. ©2017 AACR.
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46
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Leblond MM, Pérès EA, Helaine C, Gérault AN, Moulin D, Anfray C, Divoux D, Petit E, Bernaudin M, Valable S. M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma. Oncotarget 2017; 8:72597-72612. [PMID: 29069812 PMCID: PMC5641155 DOI: 10.18632/oncotarget.19994] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 07/23/2017] [Indexed: 01/07/2023] Open
Abstract
In some highly inflammatory tumors, such as glioblastoma (GB), macrophages (MΦ) represent the most abundant population of reactive cells. MΦ, initially denoted as M0 MΦ, can be polarized into two further phenotypes: the antitumor M1 MΦ, and the protumor M2 MΦ. The three phenotypes can reside simultaneously in the tumor mass and various external factors may influence MΦ polarization. Radiotherapy is a common modality of cancer treatment aiming to target tumor cells. However, the specific effects of X-ray radiation on the inflammatory cells are, so far, controversial and not fully understood. In the present investigation, we have first analyzed, in vivo, the effect of X-ray radiation on MΦ present in GB tumors. We have observed a decrease in MΦ number paralleled by an increase in the proportion of M2 MΦ. To understand this phenomenon, we then evaluated, in vitro, the effects of X-rays on the MΦ phenotypes and survival. We have found that X-ray radiation failed to modify the phenotype of the different MΦ. However, M1 MΦ were more sensitive to ionizing radiation than M2 MΦ, both in normoxia and in hypoxia, which could explain the in vivo observations. To conclude, M2 MΦ are more radioresistant than M0 and M1 MΦ and the present study allows us to propose that X-ray radiotherapy could contribute, along with other phenomena, to the increased density in the protumor M2 MΦ in GB.
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Affiliation(s)
- Marine M. Leblond
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Elodie A. Pérès
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Charly Helaine
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Aurélie N. Gérault
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Damien Moulin
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Clément Anfray
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Didier Divoux
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Edwige Petit
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Myriam Bernaudin
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
| | - Samuel Valable
- Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000 Caen, France
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Gagner JP, Sarfraz Y, Ortenzi V, Alotaibi FM, Chiriboga LA, Tayyib AT, Douglas GJ, Chevalier E, Romagnoli B, Tuffin G, Schmitt M, Lemercier G, Dembowsky K, Zagzag D. Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with Anti-Vascular Endothelial Growth Factor Therapy-Induced Glioma Dissemination. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2080-2094. [PMID: 28734730 PMCID: PMC5809520 DOI: 10.1016/j.ajpath.2017.04.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 04/05/2017] [Indexed: 01/31/2023]
Abstract
Resistance to antiangiogenic therapy in glioblastoma (GBM) patients may involve hypoxia-induced expression of C-X-C motif chemokine receptor 4 (CXCR4) on invading tumor cells, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with POL5551 disrupts anti-vascular endothelial growth factor (VEGF) therapy-induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti-VEGF antibody B20-4.1.1. Brain tissue was analyzed for tumor volume, invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and MGCs. Glioma cells were evaluated for CXCR4 expression and polymorphism and POL5551's effects on CXCR4 ligand binding, cell viability, and migration. No CXCR4 mutations were identified. POL5551 inhibited CXCR4 binding to its ligand, stromal cell-derived factor-1α, and reduced hypoxia- and stromal cell-derived factor-1α-mediated migration dose-dependently but minimally affected cell viability. In vivo, B20-4.1.1 increased hypoxic foci and invasiveness, as seen in GBM patients receiving anti-VEGF therapy. Combination of POL5551 and B20-4.1.1 reduced both glioma invasiveness by 16% to 39% and vascular density compared to B20-4.1.1 alone in both glioma models. Reduced populations of GSCs and MGCs were also seen in CT-2A tumors. POL5551 concentrations, evaluated by mass spectrometry, were higher in tumors than in neighboring brain tissues, likely accounting for the results. Inhibition of CXCR4-regulated tumoral, stem cell, and immune mechanisms by adjunctive CXCR4 antagonists may help overcome antiangiogenic therapy resistance, benefiting GBM patients.
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Affiliation(s)
- Jean-Pierre Gagner
- Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York
| | - Yasmeen Sarfraz
- Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York
| | - Valerio Ortenzi
- Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York
| | - Fawaz M Alotaibi
- Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York
| | - Luis A Chiriboga
- Department of Pathology, New York University Langone Medical Center, New York, New York
| | - Awab T Tayyib
- Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York
| | | | | | | | | | | | | | | | - David Zagzag
- Microvascular and Molecular Neuro-Oncology Laboratory, New York University Langone Medical Center, New York, New York; Department of Pathology, New York University Langone Medical Center, New York, New York; Division of Neuropathology, New York University Langone Medical Center, New York, New York; Department of Neurosurgery, New York University Langone Medical Center, New York, New York; New York University Langone Laura and Isaac Perlmutter Cancer Center, New York, New York.
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Abstract
Aptamers are nucleic acids referred to as chemical antibodies as they bind to their specific targets with high affinity and selectivity. They are selected via an iterative process known as ‘selective evolution of ligands by exponential enrichment’ (SELEX). Aptamers have been developed against numerous cancer targets and among them, many tumor cell-membrane protein biomarkers. The identification of aptamers targeting cell-surface proteins has mainly been performed by two different strategies: protein- and cell-based SELEX, when the targets used for selection were proteins and cells, respectively. This review aims to update the literature on aptamers targeting tumor cell surface protein biomarkers, highlighting potentials, pitfalls of protein- and cell-based selection processes and applications of such selected molecules. Aptamers as promising agents for diagnosis and therapeutic approaches in oncology are documented, as well as aptamers in clinical development.
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Brown JM, Recht L, Strober S. The Promise of Targeting Macrophages in Cancer Therapy. Clin Cancer Res 2017; 23:3241-3250. [PMID: 28341752 DOI: 10.1158/1078-0432.ccr-16-3122] [Citation(s) in RCA: 248] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/17/2017] [Accepted: 03/17/2017] [Indexed: 12/14/2022]
Abstract
Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy. Clin Cancer Res; 23(13); 3241-50. ©2017 AACR.
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Affiliation(s)
- J Martin Brown
- Department of Radiation Oncology, Stanford University, Stanford, California.
| | - Lawrence Recht
- Department of Neurology, Stanford University, Stanford, California
| | - Samuel Strober
- Department of Medicine, Stanford University, Stanford, California
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Abstract
Nucleic acid aptamers, often termed 'chemical antibodies', are functionally comparable to traditional antibodies, but offer several advantages, including their relatively small physical size, flexible structure, quick chemical production, versatile chemical modification, high stability and lack of immunogenicity. In addition, many aptamers are internalized upon binding to cellular receptors, making them useful targeted delivery agents for small interfering RNAs (siRNAs), microRNAs and conventional drugs. However, several crucial factors have delayed the clinical translation of therapeutic aptamers, such as their inherent physicochemical characteristics and lack of safety data. This Review discusses these challenges, highlighting recent clinical developments and technological advances that have revived the impetus for this promising class of therapeutics.
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Affiliation(s)
- Jiehua Zhou
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA
| | - John Rossi
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA
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