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Tukimin SN, Karman SB, Wan Kamarul Zaman WS, Mohd Yunos NB, Syed Nor SN, Ahmad MY. The angle of polarized light (AOP) property for optical classification of the crosslinked polymer. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 330:125503. [PMID: 39842129 DOI: 10.1016/j.saa.2024.125503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 10/12/2024] [Accepted: 11/25/2024] [Indexed: 01/24/2025]
Abstract
Light-matter interaction has been profoundly studied for sample material classification. However, the optical classification of the sample through the polarized light-matter interaction remains underexplored. It is limited to the measurement of intensity instead of the angle of polarized light (AOP) for its degree of polarization. Measurement of the degree of polarization within a material or a medium becomes easier with a simple, low-cost and direct measurement without the need of any probing or labelling agent. Thus, this investigation was conducted mainly to determine the angle of polarized light (AOP) property of the crosslinked polymer using our proposed polarization measurement technique as an alternative approach of the material classification. The angle of polarized light (AOP) of each polymer was determined in combination property of polarization by absorption, transmission, and scattering. Our proposed scattered angle (ס=90°, 100°, 110°, and 120°) successfully measured the AOP of each polymer that can be classified into two groups. Group 1 represents the AOP value ( [Formula: see text] ) for a test sample of t1 = 3.1 %, 3.2, and 3.3 % with comparison to the normal sample (n = 3.0 %) and Group 2 represents the AOP value ( [Formula: see text] ) for the test sample oft2 = 3.4 %, 3.6 % and 3.7 % with comparison to the normal sample (n = 3.0 %). Our study proved a direct, easy, and simple method of determining the degree of polarization of the polymers without the need of complex formulation and labelling protocol. Therefore, this work may enhance the investigation of the optical properties of the agarose-based tissue-mimicking phantom (AGTMP) for modeling or simulation of the real biological sample in the future. Our polarization measures are worthy of further explored and implemented in current optical imaging techniques or sensing platform for optical classification of the biomaterials.
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Affiliation(s)
- Siti Nurainie Tukimin
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Federal Territory of Kuala Lumpur, Kuala Lumpur 50603 Malaysia.
| | - Salmah Binti Karman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Federal Territory of Kuala Lumpur, Kuala Lumpur 50603 Malaysia.
| | - Wan Safwani Wan Kamarul Zaman
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Federal Territory of Kuala Lumpur, Kuala Lumpur 50603 Malaysia
| | - Nuranisha Binti Mohd Yunos
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Federal Territory of Kuala Lumpur, Kuala Lumpur 50603 Malaysia
| | - Sharifah Norsyahindah Syed Nor
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Federal Territory of Kuala Lumpur, Kuala Lumpur 50603 Malaysia
| | - Mohd Yazed Ahmad
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Federal Territory of Kuala Lumpur, Kuala Lumpur 50603 Malaysia
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Naldi L, Peri A, Fibbi B. Apelin/APJ: Another Player in the Cancer Biology Network. Int J Mol Sci 2025; 26:2986. [PMID: 40243599 PMCID: PMC11988549 DOI: 10.3390/ijms26072986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
The apelinergic system exerts multiple biological activities in human pathologies, including cancer. Overactivation of apelin/APJ, which has been detected in many malignant tumors, and the strong correlation with progression-free and overall survival, suggested the role of an oncogene for the apelin gene. Emerging evidence sheds new light on the effects of apelin on cellular functions and homeostasis in cancer cells and supports a direct role for this pathway on different hallmarks of cancer: "sustaining proliferative signaling", "resisting cell death", "activating invasion and metastasis", "inducing/accessing vasculature", "reprogramming cellular metabolism", "avoiding immune destruction" and "tumor-promoting inflammation", and "enabling replicative immortality". This article reviews the currently available literature on the intracellular processes regulated by apelin/APJ, focusing on those pathways correlated with tumor development and progression. Furthermore, the association between the activity of the apelinergic axis and the resistance of cancer cells to oncologic treatments (chemotherapy, immunotherapy, radiation) suggests apelin/APJ as a possible target to potentiate traditional therapies, as well as to develop diagnostic and prognostic applications. This issue will be also covered in the review.
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Affiliation(s)
- Laura Naldi
- “Pituitary Diseases and Sodium Alterations” Unit, AOU Careggi, 50139 Florence, Italy; (L.N.); (B.F.)
- Endocrinology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy
| | - Alessandro Peri
- “Pituitary Diseases and Sodium Alterations” Unit, AOU Careggi, 50139 Florence, Italy; (L.N.); (B.F.)
- Endocrinology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy
| | - Benedetta Fibbi
- “Pituitary Diseases and Sodium Alterations” Unit, AOU Careggi, 50139 Florence, Italy; (L.N.); (B.F.)
- Endocrinology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy
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3
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Burban A, Tessier C, Larroquette M, Guyon J, Lubiato C, Pinglaut M, Toujas M, Galvis J, Dartigues B, Georget E, Luchman HA, Weiss S, Cappellen D, Nicot N, Klink B, Nikolski M, Brisson L, Mathivet T, Bikfalvi A, Daubon T, Sharanek A. Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile. EMBO Mol Med 2025; 17:469-503. [PMID: 39901019 PMCID: PMC11903783 DOI: 10.1038/s44321-025-00195-6] [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: 03/15/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 02/05/2025] Open
Abstract
Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delays glioblastoma progression and extends animal survival. Moreover, combining mubritinib with radiotherapy or chemotherapy offers survival advantage to animals. Notably, we showed that mubritinib alleviates hypoxia, thereby enhancing ROS generation, DNA damage, and apoptosis in tumours when combined with radiotherapy. Encouragingly, toxicological and behavioural studies revealed that mubritinib is well tolerated and spares normal cells. Our findings underscore the promising therapeutic potential of mubritinib, warranting its further exploration in clinic for glioblastoma therapy.
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Affiliation(s)
- Audrey Burban
- University of Bordeaux, CNRS, IBGC, UMR5095, Bordeaux, France
| | - Cloe Tessier
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France
| | | | - Joris Guyon
- CHU of Bordeaux, Service de Pharmacologie Médicale, Bordeaux, France
- University of Bordeaux, INSERM, BPH, U1219, Bordeaux, France
| | - Cloe Lubiato
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France
| | - Mathis Pinglaut
- University of Bordeaux, CNRS, IBGC, UMR5095, Bordeaux, France
| | - Maxime Toujas
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France
| | - Johanna Galvis
- University of Bordeaux, CNRS, IBGC, UMR5095, Bordeaux, France
| | - Benjamin Dartigues
- Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France
| | - Emmanuelle Georget
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France
| | - H Artee Luchman
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada
- Arnie Charbonneau Cancer Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Samuel Weiss
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada
- Arnie Charbonneau Cancer Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - David Cappellen
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France
| | - Nathalie Nicot
- LuxGen Genome Center, Luxembourg Institute of Health, Laboratoire national de santé, Dudelange, Luxembourg
| | - Barbara Klink
- LuxGen Genome Center, Luxembourg Institute of Health, Laboratoire national de santé, Dudelange, Luxembourg
- National Center of Genetics (NCG), Laboratoire National de Santé (LNS), Dudelange, Luxembourg
- Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, 1526, Luxembourg
- Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Macha Nikolski
- University of Bordeaux, CNRS, IBGC, UMR5095, Bordeaux, France
- Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France
| | - Lucie Brisson
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France
| | - Thomas Mathivet
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France
| | - Andreas Bikfalvi
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France.
| | - Thomas Daubon
- University of Bordeaux, CNRS, IBGC, UMR5095, Bordeaux, France.
| | - Ahmad Sharanek
- University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France.
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4
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Harris AL, Kerr DJ, Pezzella F, Ribatti D. Accessing the vasculature in cancer: revising an old hallmark. Trends Cancer 2024; 10:1038-1051. [PMID: 39358088 DOI: 10.1016/j.trecan.2024.08.003] [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: 10/03/2022] [Revised: 08/12/2024] [Accepted: 08/12/2024] [Indexed: 10/04/2024]
Abstract
The classic cancer hallmark, inducing angiogenesis, was born out of the long-held notion that tumours could grow only if new vessels were formed. The attempts, based on this premise, to therapeutically restrain angiogenesis in hopes of controlling tumour growth have been less effective than expected. This is partly because primary and metastatic tumours can grow without angiogenesis. The discovery of nonangiogenic cancers and the mechanisms they use to exploit normal vessels, called 'vessel co-option,' has opened a new field in cancer biology. Consequently, the cancer hallmark, 'inducing angiogenesis,' has been modified to 'inducing or accessing vasculature.'
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Affiliation(s)
| | - David J Kerr
- Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Science, University of Oxford, Oxford, UK
| | - Francesco Pezzella
- Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Science, University of Oxford, Oxford, UK.
| | - Domenico Ribatti
- Dipartimento di Biomedicina Traslazionale e Neuroscienze, Università degli Studi di Bari, Bari, Italy
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5
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Zhao C, Zeng Y, Kang N, Liu Y. A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies. Drug Dev Res 2024; 85:e22257. [PMID: 39245913 DOI: 10.1002/ddr.22257] [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: 02/19/2024] [Revised: 07/20/2024] [Accepted: 08/26/2024] [Indexed: 09/10/2024]
Abstract
Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to "starve" the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance.
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Affiliation(s)
- Chen Zhao
- Department of Pharmacy, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Yuan Zeng
- Department of Clinical Pharmacology and Bioanalytics, Pfizer (China) Research and Development Co., Ltd., Shanghai, People's Republic of China
| | - Nannan Kang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yu Liu
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, People's Republic of China
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6
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Dembitskaya Y, Boyce AKJ, Idziak A, Pourkhalili Langeroudi A, Arizono M, Girard J, Le Bourdellès G, Ducros M, Sato-Fitoussi M, Ochoa de Amezaga A, Oizel K, Bancelin S, Mercier L, Pfeiffer T, Thompson RJ, Kim SK, Bikfalvi A, Nägerl UV. Shadow imaging for panoptical visualization of brain tissue in vivo. Nat Commun 2023; 14:6411. [PMID: 37828018 PMCID: PMC10570379 DOI: 10.1038/s41467-023-42055-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 09/25/2023] [Indexed: 10/14/2023] Open
Abstract
Progress in neuroscience research hinges on technical advances in visualizing living brain tissue with high fidelity and facility. Current neuroanatomical imaging approaches either require tissue fixation (electron microscopy), do not have cellular resolution (magnetic resonance imaging) or only give a fragmented view (fluorescence microscopy). Here, we show how regular light microscopy together with fluorescence labeling of the interstitial fluid in the extracellular space provide comprehensive optical access in real-time to the anatomical complexity and dynamics of living brain tissue at submicron scale. Using several common fluorescence microscopy modalities (confocal, light-sheet and 2-photon microscopy) in mouse organotypic and acute brain slices and the intact mouse brain in vivo, we demonstrate the value of this straightforward 'shadow imaging' approach by revealing neurons, microglia, tumor cells and blood capillaries together with their complete anatomical tissue contexts. In addition, we provide quantifications of perivascular spaces and the volume fraction of the extracellular space of brain tissue in vivo.
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Affiliation(s)
- Yulia Dembitskaya
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Andrew K J Boyce
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
- Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Agata Idziak
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | | | - Misa Arizono
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
- Department of Pharmacology, Kyoto University Graduate School of Medicine/The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan
| | - Jordan Girard
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Guillaume Le Bourdellès
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Mathieu Ducros
- Université de Bordeaux, CNRS, INSERM, Bordeaux Imaging Center (BIC), UAR 3420, US 4, F-33000, Bordeaux, France
| | - Marie Sato-Fitoussi
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Amaia Ochoa de Amezaga
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Kristell Oizel
- Université de Bordeaux, INSERM, Bordeaux Institute of Oncology (BRIC), U1312, Bat B2, Allée Geoffroy St Hilaire, 33615, Pessac, France
| | - Stephane Bancelin
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Luc Mercier
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Thomas Pfeiffer
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
| | - Roger J Thompson
- Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Sun Kwang Kim
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Korea
| | - Andreas Bikfalvi
- Université de Bordeaux, INSERM, Bordeaux Institute of Oncology (BRIC), U1312, Bat B2, Allée Geoffroy St Hilaire, 33615, Pessac, France
| | - U Valentin Nägerl
- Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 and University of Bordeaux, F-33000, Bordeaux, France.
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7
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McDonald B, Barth K, Schmidt MHH. The origin of brain malignancies at the blood-brain barrier. Cell Mol Life Sci 2023; 80:282. [PMID: 37688612 PMCID: PMC10492883 DOI: 10.1007/s00018-023-04934-1] [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: 05/17/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/11/2023]
Abstract
Despite improvements in extracranial therapy, survival rate for patients suffering from brain metastases remains very poor. This is coupled with the incidence of brain metastases continuing to rise. In this review, we focus on core contributions of the blood-brain barrier to the origin of brain metastases. We first provide an overview of the structure and function of the blood-brain barrier under physiological conditions. Next, we discuss the emerging idea of a pre-metastatic niche, namely that secreted factors and extracellular vesicles from a primary tumor site are able to travel through the circulation and prime the neurovasculature for metastatic invasion. We then consider the neurotropic mechanisms that circulating tumor cells possess or develop that facilitate disruption of the blood-brain barrier and survival in the brain's parenchyma. Finally, we compare and contrast brain metastases at the blood-brain barrier to the primary brain tumor, glioma, examining the process of vessel co-option that favors the survival and outgrowth of brain malignancies.
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Affiliation(s)
- Brennan McDonald
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, Dresden, Germany.
| | - Kathrin Barth
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, Dresden, Germany
| | - Mirko H H Schmidt
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, Dresden, Germany
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8
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An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid. Cancers (Basel) 2022; 14:cancers14174244. [PMID: 36077783 PMCID: PMC9454704 DOI: 10.3390/cancers14174244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/22/2022] [Accepted: 08/27/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. Before surgery, oral administration of 5-aminolevulinic acid leads to the accumulation of fluorescent protoporphyrin IX, preferentially in the cancer cells rather than in the normal brain. This property is used to optimize the resection of the tumor under fluorescent light. Protoporphyrin IX may also carry radiosensitization activity. To test this hypothesis, we designed a robust murine preclinical model of glioblastoma with tumors implanted into the brain of mice treated by fractionated radiotherapy, as for humans. Despite the specific accumulation of porphyrins in glioblastoma, there was no radiosensitization. We confirmed these results in in vitro 3D patient-derived spheroids. Radiosensitization by molecules such as porphyrins needs more exploration for application in glioblastoma treatment. Abstract Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. The 5-aminolevulinic acid (5-ALA) is metabolized by the heme biosynthesis pathway. 5-ALA overload leads to the accumulation of the intermediate fluorescent metabolite protoporphyrin IX (PpIX) with a radiosensitization potential, never tested in a relevant model of glioblastoma. We used a patient-derived tumor cell line grafted orthotopically to create a brain tumor model. We evaluated tumor growth and tumor burden after different regimens of encephalic multifractionated radiation therapy with or without 5-ALA. A fractionation scheme of 5 × 2 Gy three times a week resulted in intermediate survival [48–62 days] compared to 0 Gy (15–24 days), 3 × 2 Gy (41–47 days) and, 5 × 3 Gy (73–83 days). Survival was correlated to tumor growth. Tumor growth and survival were similar after 5 × 2 Gy irradiations, regardless of 5-ALA treatment (RT group (53–67 days), RT+5-ALA group (40–74 days), HR = 1.57, p = 0.24). Spheroid growth and survival were diminished by radiotherapy in vitro, unchanged by 5-ALA pre-treatment, confirming the in vivo results. The analysis of two additional stem-like patient-derived cell lines confirmed the absence of radiosensitization by 5-ALA. Our study shows for the first time that in a preclinical tumor model relevant to human glioblastoma, treated as in clinical routine, 5-ALA administration, although leading to important accumulation of PpIX, does not potentiate radiotherapy.
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9
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Akindona FA, Frederico SC, Hancock JC, Gilbert MR. Exploring the origin of the cancer stem cell niche and its role in anti-angiogenic treatment for glioblastoma. Front Oncol 2022; 12:947634. [PMID: 36091174 PMCID: PMC9454306 DOI: 10.3389/fonc.2022.947634] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/08/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer stem cells are thought to be the main drivers of tumorigenesis for malignancies such as glioblastoma (GBM). They are maintained through a close relationship with the tumor vasculature. Previous literature has well-characterized the components and signaling pathways for maintenance of this stem cell niche, but details on how the niche initially forms are limited. This review discusses development of the nonmalignant neural and hematopoietic stem cell niches in order to draw important parallels to the malignant environment. We then discuss what is known about the cancer stem cell niche, its relationship with angiogenesis, and provide a hypothesis for its development in GBM. A better understanding of the mechanisms of development of the tumor stem cell niche may provide new insights to potentially therapeutically exploit.
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Affiliation(s)
- Funto A. Akindona
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
| | - Stephen C. Frederico
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - John C. Hancock
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Mark R. Gilbert
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Mark R. Gilbert,
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10
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Kong BT, Fan QS, Wang XM, Zhang Q, Zhang GL. Clinical implications and mechanism of histopathological growth pattern in colorectal cancer liver metastases. World J Gastroenterol 2022; 28:3101-3115. [PMID: 36051338 PMCID: PMC9331533 DOI: 10.3748/wjg.v28.i26.3101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/21/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Liver is the most common site of metastases of colorectal cancer, and liver metastases present with distinct histopathological growth patterns (HGPs), including desmoplastic, pushing and replacement HGPs and two rare HGPs. HGP is a miniature of tumor-host reaction and reflects tumor biology and pathological features as well as host immune dynamics. Many studies have revealed the association of HGPs with carcinogenesis, angiogenesis, and clinical outcomes and indicates HGP functions as bond between microscopic characteristics and clinical implications. These findings make HGP a candidate marker in risk stratification and guiding treatment decision-making, and a target of imaging observation for patient screening. Of note, it is crucial to determine the underlying mechanism shaping HGP, for instance, immune infiltration and extracellular matrix remodeling in desmoplastic HGP, and aggressive characteristics and special vascularization in replacement HGP (rHGP). We highlight the importance of aggressive features, vascularization, host immune and organ structure in formation of HGP, hence propose a novel "advance under camouflage" hypothesis to explain the formation of rHGP.
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Affiliation(s)
- Bing-Tan Kong
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
- School of Graduates, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Qing-Sheng Fan
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Xiao-Min Wang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Qing Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Gan-Lin Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
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APLN/APLNR Signaling Controls Key Pathological Parameters of Glioblastoma. Cancers (Basel) 2021; 13:cancers13153899. [PMID: 34359800 PMCID: PMC8345670 DOI: 10.3390/cancers13153899] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/30/2021] [Accepted: 07/30/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary The neurovascular peptide Apelin and its receptor APLNR are upregulated during glioblastoma pathology. Here we summarize their role in the brain tumor microenvironment composed of neurons, astrocytes, and the vascular and immune systems. Targeting APLN/APLNR signaling promises to unfold multimodal actions in future GBM therapy, acting as an anti-angiogenic and an anti-invasive treatment, and offering the possibility to reduce neurological symptoms and increase overall survival simultaneously. Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM-expansion depends on a dense vascular network and, coherently, GBMs are highly angiogenic. However, new intratumoral blood vessels are often aberrant with consequences for blood-flow and vascular barrier function. Hence, the delivery of chemotherapeutics into GBM can be compromised. Furthermore, leaky vessels support edema-formation, which can result in severe neurological deficits. The secreted signaling peptide Apelin (APLN) plays an important role in the formation of GBM blood vessels. Both APLN and the Apelin receptor (APLNR) are upregulated in GBM cells and control tumor cell invasiveness. Here we summarize the current evidence on the role of APLN/APLNR signaling during brain tumor pathology. We show that targeting APLN/APLNR can induce anti-angiogenic effects in GBM and simultaneously blunt GBM cell infiltration. In addition, we discuss how manipulation of APLN/APLNR signaling in GBM leads to the normalization of tumor vessels and thereby supports chemotherapy, reduces edema, and improves anti-tumorigenic immune reactions. Hence, therapeutic targeting of APLN/APLNR signaling offers an interesting option to address different pathological hallmarks of GBM.
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12
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Teuwen LA, De Rooij LPMH, Cuypers A, Rohlenova K, Dumas SJ, García-Caballero M, Meta E, Amersfoort J, Taverna F, Becker LM, Veiga N, Cantelmo AR, Geldhof V, Conchinha NV, Kalucka J, Treps L, Conradi LC, Khan S, Karakach TK, Soenen S, Vinckier S, Schoonjans L, Eelen G, Van Laere S, Dewerchin M, Dirix L, Mazzone M, Luo Y, Vermeulen P, Carmeliet P. Tumor vessel co-option probed by single-cell analysis. Cell Rep 2021; 35:109253. [PMID: 34133923 DOI: 10.1016/j.celrep.2021.109253] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 05/16/2021] [Accepted: 05/25/2021] [Indexed: 12/15/2022] Open
Abstract
Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer and myeloid cells in tumors growing via vessel co-option, has not been investigated at the single-cell level. Here, we use a murine AAT-resistant lung tumor model, in which VEGF-targeting induces vessel co-option for continued growth. Single-cell RNA sequencing (scRNA-seq) of 31,964 cells reveals, unexpectedly, a largely similar transcriptome of co-opted tumor ECs (TECs) and pericytes as their healthy counterparts. Notably, we identify cell types that might contribute to vessel co-option, i.e., an invasive cancer-cell subtype, possibly assisted by a matrix-remodeling macrophage population, and another M1-like macrophage subtype, possibly involved in keeping or rendering vascular cells quiescent.
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Affiliation(s)
- Laure-Anne Teuwen
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp 2610, Belgium; Center for Oncological Research, University of Antwerp, Antwerp 2000, Belgium
| | - Laura P M H De Rooij
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Anne Cuypers
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Katerina Rohlenova
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Sébastien J Dumas
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Melissa García-Caballero
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Elda Meta
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Jacob Amersfoort
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Federico Taverna
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Lisa M Becker
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Nuphar Veiga
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Anna Rita Cantelmo
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Vincent Geldhof
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Nadine V Conchinha
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Joanna Kalucka
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Lucas Treps
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Lena-Christin Conradi
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Shawez Khan
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Tobias K Karakach
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Stefaan Soenen
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium
| | - Stefan Vinckier
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Luc Schoonjans
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 510275, Guangzhou, Guangdong, P.R. China
| | - Guy Eelen
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Steven Van Laere
- Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp 2610, Belgium; Center for Oncological Research, University of Antwerp, Antwerp 2000, Belgium
| | - Mieke Dewerchin
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Luc Dirix
- Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp 2610, Belgium; Center for Oncological Research, University of Antwerp, Antwerp 2000, Belgium
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Yonglun Luo
- Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, P.R. China; BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, P.R. China.
| | - Peter Vermeulen
- Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp 2610, Belgium; Center for Oncological Research, University of Antwerp, Antwerp 2000, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 510275, Guangzhou, Guangdong, P.R. China; Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.
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13
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Park JE, Kim HS, Kim N, Kim YH, Kim JH, Kim E, Hwang J, Katscher U. Low conductivity on electrical properties tomography demonstrates unique tumor habitats indicating progression in glioblastoma. Eur Radiol 2021; 31:6655-6665. [PMID: 33880619 DOI: 10.1007/s00330-021-07976-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 02/24/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Tissue conductivity measurements made with electrical properties tomography (EPT) can be used to define temporal changes in tissue habitats on longitudinal multiparametric MRI. We aimed to demonstrate the added insights for identifying tumor habitats obtained by including EPT with diffusion- and perfusion-weighted MRI, and to evaluate the use of these tumor habitats for determining tumor treatment response in post-treatment glioblastoma. METHODS Tumor habitats were developed from EPT, diffusion-weighted, and perfusion-weighted MRI in 60 patients with glioblastoma who underwent concurrent chemoradiotherapy. Voxels from EPT, apparent diffusion coefficient (ADC), and cerebral blood volume (CBV) maps were clustered into habitats, and each habitat was serially examined to assess its temporal change. The usefulness of temporal changes in tumor habitats for diagnosing tumor progression and treatment-related change was investigated using logistic regression. The performance of significant predictors was measured using the area under the curve (AUC) from receiver-operating-characteristics analysis with 1000-fold bootstrapping. RESULTS Five tumor habitats were identified, and of these, the hypervascular cellular habitat (odds ratio [OR] 5.45; 95% CI, 1.75-31.42; p = .02), hypovascular low conductivity habitat (OR 2.00; 95% CI, 1.45-3.05; p < .001), and hypovascular intermediate habitat (OR 1.57; 95% CI, 1.18-2.30; p = .006) were predictive of tumor progression. Low EPT and low CBV reflected a unique hypovascular low conductivity habitat that showed the highest diagnostic performance (AUC 0.86; 95% CI, 0.76-0.96). The combined habitats showed high performance (AUC 0.90; 95% CI, 0.82-0.98) in the differentiation of tumor progression from treatment-related change. CONCLUSION EPT reveals low conductivity habitats that can improve the diagnosis of tumor progression in post-treatment glioblastoma. KEY POINTS • Electrical properties tomography (EPT) demonstrated lower conductivity in tumor progression than in treatment-related change. • EPT allowed identification of a unique hypovascular low conductivity habitat when combined with cerebral blood volume mapping. • Tumor habitats with a hypovascular low conductivity habitat, hypervascular cellular habitat, and hypovascular intermediate habitat yielded high diagnostic performance for diagnosing tumor progression.
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Affiliation(s)
- Ji Eun Park
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 43 Olympic-ro 88, Songpa-Gu, Seoul, 05505, South Korea
| | - Ho Sung Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 43 Olympic-ro 88, Songpa-Gu, Seoul, 05505, South Korea.
| | | | - Young-Hoon Kim
- Deparment of Neurosurgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, South Korea
| | - Jeong Hoon Kim
- Deparment of Neurosurgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, South Korea
| | - Eunju Kim
- Philips Healthcare, Seoul, South Korea
| | | | - Ulrich Katscher
- Department of Tomographic Imaging, Philips Research Laboratories, Hamburg, Germany
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14
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Xia H, Huang Z, Liu S, Zhao X, He R, Wang Z, Shi W, Chen W, Li Z, Yu L, Huang P, Kang P, Su Z, Xu Y, Yam JWP, Cui Y. Exosomal Non-Coding RNAs: Regulatory and Therapeutic Target of Hepatocellular Carcinoma. Front Oncol 2021; 11:653846. [PMID: 33869059 PMCID: PMC8044750 DOI: 10.3389/fonc.2021.653846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
Exosomes are small extracellular vesicles secreted by most somatic cells, which can carry a variety of biologically active substances to participate in intercellular communication and regulate the pathophysiological process of recipient cells. Recent studies have confirmed that non-coding RNAs (ncRNAs) carried by tumor cell/non-tumor cell-derived exosomes have the function of regulating the cancerous derivation of target cells and remodeling the tumor microenvironment (TME). In addition, due to the unique low immunogenicity and high stability, exosomes can be used as natural vehicles for the delivery of therapeutic ncRNAs in vivo. This article aims to review the potential regulatory mechanism and the therapeutic value of exosomal ncRNAs in hepatocellular carcinoma (HCC), in order to provide promising targets for early diagnosis and precise therapy of HCC.
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Affiliation(s)
- Haoming Xia
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuqiang Liu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xudong Zhao
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Risheng He
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongrui Wang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenguang Shi
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wangming Chen
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhizhou Li
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liang Yu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Peng Huang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Pengcheng Kang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhilei Su
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
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15
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Nguyen HM, Guz-Montgomery K, Lowe DB, Saha D. Pathogenetic Features and Current Management of Glioblastoma. Cancers (Basel) 2021; 13:cancers13040856. [PMID: 33670551 PMCID: PMC7922739 DOI: 10.3390/cancers13040856] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/09/2021] [Accepted: 02/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common form of primary malignant brain tumor with a devastatingly poor prognosis. The disease does not discriminate, affecting adults and children of both sexes, and has an average overall survival of 12-15 months, despite advances in diagnosis and rigorous treatment with chemotherapy, radiation therapy, and surgical resection. In addition, most survivors will eventually experience tumor recurrence that only imparts survival of a few months. GBM is highly heterogenous, invasive, vascularized, and almost always inaccessible for treatment. Based on all these outstanding obstacles, there have been tremendous efforts to develop alternative treatment options that allow for more efficient targeting of the tumor including small molecule drugs and immunotherapies. A number of other strategies in development include therapies based on nanoparticles, light, extracellular vesicles, and micro-RNA, and vessel co-option. Advances in these potential approaches shed a promising outlook on the future of GBM treatment. In this review, we briefly discuss the current understanding of adult GBM's pathogenetic features that promote treatment resistance. We also outline novel and promising targeted agents currently under development for GBM patients during the last few years with their current clinical status.
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16
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Spatiotemporal habitats from multiparametric physiologic MRI distinguish tumor progression from treatment-related change in post-treatment glioblastoma. Eur Radiol 2021; 31:6374-6383. [PMID: 33569615 DOI: 10.1007/s00330-021-07718-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/14/2020] [Accepted: 01/26/2021] [Indexed: 10/22/2022]
Abstract
OBJECTIVES We aimed to develop multiparametric physiologic MRI-based spatial habitats and to evaluate whether temporal changes in these habitats help to distinguish tumor progression from treatment-related change in post-treatment glioblastoma. METHODS This retrospective, single-institution study included patients with glioblastoma treated by concurrent chemoradiotherapy who had newly developed or enlarging, measurable contrast-enhancing mass. Contrast-enhancing mass was divided into three spatial habitats by K-means clustering of voxel-wise ADC and CBV values. Temporal changes of these habitats between two consecutive examinations prior to the diagnosis of tumor progression or treatment-related change were assessed. Predictors were selected using logistic regression and the performance was measured with an area under the receiver operating characteristics curve (AUC). Spatiotemporal habitats were further analyzed for correlation with the site of tumor progression. RESULTS There were 75 patients (mean, 58 years; range, 26-81 years; 43 men) with 48 cases of tumor progression and 39 cases of treatment-related change including 12 patient overlaps at different time points. Three spatial habitats of hypervascular cellular, hypovascular cellular, and nonviable tissue were identified. Increase in the hypervascular cellular (OR 4.55, p = .002) and hypovascular cellular habitat (OR 1.22, p < .001) was predictive of tumor progression. Combination of spatiotemporal habitats yielded a high diagnostic performance with an AUC of 0.89 (95% CI, 0.87-0.92). An increase in hypovascular cellular habitat predicted the site of tumor progression in 84% [21/25] of cases with tumor progression. CONCLUSIONS Temporal changes in spatial habitats derived from multiparametric physiologic MRI provided diagnostic value in distinguishing tumor progression from treatment-related change and predicted site of tumor progression in post-treatment glioblastoma. KEY POINTS • In post-treatment glioblastoma, three spatial habitats of hypervascular cellular, hypovascular cellular, and nonviable tissue were identified, and an increase in the hypervascular cellular (OR 4.55, p = .002) and hypovascular cellular habitat (OR 1.22, p < .001) was predictive of tumor progression. • Combination of spatiotemporal habitats yielded a high diagnostic performance with an AUC of 0.89 (95% CI, 0.87-0.92). • An increase in hypovascular cellular habitat predicted the site of tumor progression in 84% (21/25) of cases with tumor progression.
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17
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Abstract
Cancer treatment remains a challenge due to a high level of intra- and intertumoral heterogeneity and the rapid development of chemoresistance. In the brain, this is further hampered by the blood-brain barrier that reduces passive diffusion of drugs to a minimum. Tumors grow invasively and form new blood vessels, also in brain tissue where remodeling of pre-existing vasculature is substantial. The cancer-associated vessels in the brain are considered leaky and thus could facilitate the transport of chemotherapeutic agents. Yet, brain tumors are extremely difficult to treat, and, in this review, we will address how different aspects of the vasculature in brain tumors contribute to this.
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Affiliation(s)
- Casper Hempel
- Dept of Health Technology, Technical University of Denmark, 2800, Kgs Lyngby, Denmark.
| | - Kasper B Johnsen
- Dept of Health Technology, Technical University of Denmark, 2800, Kgs Lyngby, Denmark
| | - Serhii Kostrikov
- Dept of Health Technology, Technical University of Denmark, 2800, Kgs Lyngby, Denmark
| | - Petra Hamerlik
- Brain Tumor Biology, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
| | - Thomas L Andresen
- Dept of Health Technology, Technical University of Denmark, 2800, Kgs Lyngby, Denmark.
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18
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Nagaraja TN, deCarvalho AC, Brown SL, Griffith B, Farmer K, Irtenkauf S, Hasselbach L, Mukherjee A, Bartlett S, Valadie OG, Cabral G, Knight RA, Lee IY, Divine GW, Ewing JR. The impact of initial tumor microenvironment on imaging phenotype. Cancer Treat Res Commun 2021; 27:100315. [PMID: 33571801 PMCID: PMC8127413 DOI: 10.1016/j.ctarc.2021.100315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 11/13/2022]
Abstract
Models of human cancer, to be useful, must replicate human disease with high fidelity. Our focus in this study is rat xenograft brain tumors as a model of human embedded cerebral tumors. A distinguishing signature of such tumors in humans, that of contrast-enhancement on imaging, is often not present when the human cells grow in rodents, despite the xenografts having nearly identical DNA signatures to the original tumor specimen. Although contrast enhancement was uniformly evident in all the human tumors from which the xenografts’ cells were derived, we show that long-term contrast enhancement in the model tumors may be determined conditionally by the tumor microenvironment at the time of cell implantation. We demonstrate this phenomenon in one of two patient-derived orthotopic xenograft (PDOX) models using cancer stem-like cell (CSC)-enriched neurospheres from human tumor resection specimens, transplanted to groups of immune-compromised rats in the presence or absence of a collagen/fibrin scaffolding matrix, Matrigel. The rats were imaged by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and their brains were examined by histopathology. Targeted proteomics of the PDOX tumor specimens grown from CSC implanted with and without Matrigel showed that while the levels of the majority of proteins and post-translational modifications were comparable between contrast-enhancing and non-enhancing tumors, phosphorylation of Fox038 showed a differential expression. The results suggest key proteins determine contrast enhancement and suggest a path toward the development of better animal models of human glioma. Future work is needed to elucidate fully the molecular determinants of contrast-enhancement.
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Affiliation(s)
| | | | - Stephen L Brown
- Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, United States; Department of Public Health, Henry Ford Hospital, Detroit, MI, United States
| | - Brent Griffith
- Department of Radiology, Henry Ford Hospital, Detroit, MI, United States
| | - Katelynn Farmer
- Department of Biomedical Engineering, Wayne State University, Detroit, MI, United States
| | - Susan Irtenkauf
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI
| | | | - Abir Mukherjee
- Department of Pathology, Henry Ford Hospital, Detroit, MI, United States
| | - Seamus Bartlett
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI; School of Medicine, Wayne State University, Detroit, MI, United States
| | - O Grahm Valadie
- Department of Radiation Oncology, Wayne State University, Detroit, MI, United States
| | - Glauber Cabral
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Robert A Knight
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States; Department of Physics, Oakland University, Rochester, MI, United States
| | - Ian Y Lee
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI
| | - George W Divine
- Department of Public Health, Henry Ford Hospital, Detroit, MI, United States
| | - James R Ewing
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI; Department of Neurology, Henry Ford Hospital, Detroit, MI, United States; Department of Physics, Oakland University, Rochester, MI, United States; Department of Neurology, Wayne State University, Detroit, MI, United States
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19
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Klein E, Hau AC, Oudin A, Golebiewska A, Niclou SP. Glioblastoma Organoids: Pre-Clinical Applications and Challenges in the Context of Immunotherapy. Front Oncol 2020; 10:604121. [PMID: 33364198 PMCID: PMC7753120 DOI: 10.3389/fonc.2020.604121] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/09/2020] [Indexed: 12/13/2022] Open
Abstract
Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due to inappropriate preclinical model systems, which do not reflect the complexity of patient tumors. Furthermore, clinically relevant patient-derived models recapitulating the immune compartment are lacking, which represents a bottleneck for adequate immunotherapy testing. Emerging 3D organoid cultures offer innovative possibilities for cancer modeling. Here, we review available GBM organoid models amenable to a large variety of pre-clinical applications including functional bioassays such as proliferation and invasion, drug screening, and the generation of patient-derived orthotopic xenografts (PDOX) for validation of biological responses in vivo. We emphasize advantages and technical challenges in establishing immunocompetent ex vivo models based on co-cultures of GBM organoids and human immune cells. The latter can be isolated either from the tumor or from patient or donor blood as peripheral blood mononuclear cells (PBMCs). We also discuss the challenges to generate GBM PDOXs based on humanized mouse models to validate efficacy of immunotherapies in vivo. A detailed characterization of such models at the cellular and molecular level is needed to understand the potential and limitations for various immune activating strategies. Increasing the availability of immunocompetent GBM models will improve research on emerging immune therapeutic approaches against aggressive brain cancer.
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Affiliation(s)
- Eliane Klein
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Ann-Christin Hau
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Anaïs Oudin
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Anna Golebiewska
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Simone P. Niclou
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Department of Biomedicine, University of Bergen, Bergen, Norway
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20
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Golebiewska A, Hau AC, Oudin A, Stieber D, Yabo YA, Baus V, Barthelemy V, Klein E, Bougnaud S, Keunen O, Wantz M, Michelucci A, Neirinckx V, Muller A, Kaoma T, Nazarov PV, Azuaje F, De Falco A, Flies B, Richart L, Poovathingal S, Arns T, Grzyb K, Mock A, Herold-Mende C, Steino A, Brown D, May P, Miletic H, Malta TM, Noushmehr H, Kwon YJ, Jahn W, Klink B, Tanner G, Stead LF, Mittelbronn M, Skupin A, Hertel F, Bjerkvig R, Niclou SP. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology. Acta Neuropathol 2020; 140:919-949. [PMID: 33009951 PMCID: PMC7666297 DOI: 10.1007/s00401-020-02226-7] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 11/29/2022]
Abstract
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
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Affiliation(s)
- Anna Golebiewska
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Ann-Christin Hau
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Anaïs Oudin
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Daniel Stieber
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
- National Center of Genetics, Laboratoire National de Santé, 3555, Dudelange, Luxembourg
| | - Yahaya A Yabo
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, 4367, Belvaux, Luxembourg
| | - Virginie Baus
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Vanessa Barthelemy
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Eliane Klein
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Sébastien Bougnaud
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Olivier Keunen
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
- Quantitative Biology Unit, Luxembourg Institute of Health, 1445, Strassen, Luxembourg
| | - May Wantz
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Alessandro Michelucci
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
- Neuro-Immunology Group, Department of Oncology, Luxembourg Institute of Health, 1526, Luxembourg, Luxembourg
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
| | - Virginie Neirinckx
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
| | - Arnaud Muller
- Quantitative Biology Unit, Luxembourg Institute of Health, 1445, Strassen, Luxembourg
| | - Tony Kaoma
- Quantitative Biology Unit, Luxembourg Institute of Health, 1445, Strassen, Luxembourg
| | - Petr V Nazarov
- Quantitative Biology Unit, Luxembourg Institute of Health, 1445, Strassen, Luxembourg
| | - Francisco Azuaje
- Quantitative Biology Unit, Luxembourg Institute of Health, 1445, Strassen, Luxembourg
| | - Alfonso De Falco
- National Center of Genetics, Laboratoire National de Santé, 3555, Dudelange, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, 4367, Belvaux, Luxembourg
- Luxembourg Center of Neuropathology, Luxembourg, Luxembourg
| | - Ben Flies
- National Center of Genetics, Laboratoire National de Santé, 3555, Dudelange, Luxembourg
| | - Lorraine Richart
- Faculty of Science, Technology and Medicine, University of Luxembourg, 4367, Belvaux, Luxembourg
- Luxembourg Center of Neuropathology, Luxembourg, Luxembourg
- National Center of Pathology, Laboratoire National de Santé, 3555, Dudelange, Luxembourg
- Department of Oncology, Luxembourg Institute of Health, 1526, Luxembourg, Luxembourg
| | - Suresh Poovathingal
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
| | - Thais Arns
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
| | - Kamil Grzyb
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
| | - Andreas Mock
- Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, 69120, Heidelberg, Germany
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, 69120, Heidelberg, Germany
- German Cancer Research Center (DKFZ) Heidelberg, 69120, Heidelberg, Germany
- German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
| | - Christel Herold-Mende
- Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, 69120, Heidelberg, Germany
| | - Anne Steino
- DelMar Pharmaceuticals, Inc., Vancouver, BC, Canada
- DelMar Pharmaceuticals, Inc., Menlo Park, CA, USA
| | - Dennis Brown
- DelMar Pharmaceuticals, Inc., Vancouver, BC, Canada
- DelMar Pharmaceuticals, Inc., Menlo Park, CA, USA
| | - Patrick May
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, 5019, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Tathiane M Malta
- Department of Neurosurgery, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Houtan Noushmehr
- Department of Neurosurgery, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Yong-Jun Kwon
- Department of Oncology, Luxembourg Institute of Health, 1526, Luxembourg, Luxembourg
| | - Winnie Jahn
- German Cancer Consortium (DKTK), 01307, Dresden, Germany
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307, Dresden, Germany
| | - Barbara Klink
- National Center of Genetics, Laboratoire National de Santé, 3555, Dudelange, Luxembourg
- Department of Oncology, Luxembourg Institute of Health, 1526, Luxembourg, Luxembourg
- German Cancer Consortium (DKTK), 01307, Dresden, Germany
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307, Dresden, Germany
- Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - Georgette Tanner
- Leeds Institute of Medical Research at St James's, St James's University Hospital, Leeds, UK
| | - Lucy F Stead
- Leeds Institute of Medical Research at St James's, St James's University Hospital, Leeds, UK
| | - Michel Mittelbronn
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
- Luxembourg Center of Neuropathology, Luxembourg, Luxembourg
- National Center of Pathology, Laboratoire National de Santé, 3555, Dudelange, Luxembourg
- Department of Oncology, Luxembourg Institute of Health, 1526, Luxembourg, Luxembourg
| | - Alexander Skupin
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
| | - Frank Hertel
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367, Belvaux, Luxembourg
- Department of Neurosurgery, Centre Hospitalier Luxembourg, 1210, Luxembourg, Luxembourg
| | - Rolf Bjerkvig
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg
- Department of Biomedicine, University of Bergen, 5019, Bergen, Norway
| | - Simone P Niclou
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg.
- Department of Biomedicine, University of Bergen, 5019, Bergen, Norway.
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Solimando AG, Summa SD, Vacca A, Ribatti D. Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling. Cancers (Basel) 2020; 12:cancers12113380. [PMID: 33203154 PMCID: PMC7696032 DOI: 10.3390/cancers12113380] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 11/08/2020] [Accepted: 11/12/2020] [Indexed: 12/11/2022] Open
Abstract
Simple Summary A clinical decision and study design investigating the level and extent of angiogenesis modulation aimed at vascular normalization without rendering tissues hypoxic is key and represents an unmet medical need. Specifically, determining the active concentration and optimal times of the administration of antiangiogenetic drugs is crucial to inhibit the growth of any microscopic residual tumor after surgical resection and in the pre-malignant and smolder neoplastic state. This review uncovers the pre-clinical translational insights crucial to overcome the caveats faced so far while employing anti-angiogenesis. This literature revision also explores how abnormalities in the tumor endothelium harm the crosstalk with an effective immune cell response, envisioning a novel combination with other anti-cancer drugs and immunomodulatory agents. These insights hold vast potential to both repress tumorigenesis and unleash an effective immune response. Abstract Cancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial–neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically.
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Affiliation(s)
- Antonio Giovanni Solimando
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine ‘G. Baccelli’, University of Bari Medical School, 70124 Bari, Italy;
- Istituto di Ricovero e Cura a Carattere Scientifico-IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy
- Correspondence: (A.G.S.); (D.R.); Tel.: +39-3395626475 (A.G.S.); +39-080-5478326 (D.R.)
| | - Simona De Summa
- Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy;
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine ‘G. Baccelli’, University of Bari Medical School, 70124 Bari, Italy;
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (A.G.S.); (D.R.); Tel.: +39-3395626475 (A.G.S.); +39-080-5478326 (D.R.)
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22
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Fabian C, Han M, Bjerkvig R, Niclou SP. Novel facets of glioma invasion. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 360:33-64. [PMID: 33962750 DOI: 10.1016/bs.ircmb.2020.08.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Malignant gliomas including Glioblastoma (GBM) are characterized by extensive diffuse tumor cell infiltration throughout the brain, which represents a major challenge in clinical disease management. While surgical resection is beneficial for patient outcome, it is well recognized that tumor cells at the invasive front or beyond stay behind and constitute a major source of tumor recurrence. Invasive glioma cells also represent a difficult therapeutic target since they are localized within normal functional brain areas with an intact blood brain barrier (BBB), thereby excluding most systemic drug treatments. Cell movement is mediated via the actin cytoskeleton where corresponding membrane protrusions play essential roles. This review provides an overview of the various paths of glioma cell invasion and underlines the specific aspects of the brain microenvironment. We highlight recent insight into tumor microtubes, neuro-glioma synapses and tumor metabolism which can regulate collective invasion processes. We also focus on the deregulation of actin cytoskeleton-related components in the context of glioma invasion, a deregulation that may be controlled by genomic alterations in tumor cells as well as by various external factors, including extracellular matrix (ECM) components and non-malignant stromal cells. Finally we critically assess the challenges and opportunities for therapeutically targeting glioma cell invasion.
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Affiliation(s)
- Carina Fabian
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Mingzhi Han
- Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Rolf Bjerkvig
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; Department of Biomedicine, University of Bergen, Bergen, Norway.
| | - Simone P Niclou
- NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; Department of Biomedicine, University of Bergen, Bergen, Norway.
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23
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Hossain JA, Latif MA, Ystaas LAR, Ninzima S, Riecken K, Muller A, Azuaje F, Joseph JV, Talasila KM, Ghimire J, Fehse B, Bjerkvig R, Miletic H. Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma. Neuro Oncol 2020; 21:890-900. [PMID: 30958558 DOI: 10.1093/neuonc/noz060] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy. METHODS Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed. RESULTS TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy. CONCLUSION Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.
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Affiliation(s)
- Jubayer A Hossain
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Md A Latif
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Lars A R Ystaas
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Sandra Ninzima
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center, Hamburg, Germany
| | - Arnaud Muller
- Bioinformatics Team, Center for Quantitative Biology, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Francisco Azuaje
- Bioinformatics Team, Center for Quantitative Biology, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Justin V Joseph
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | | | - Jiwan Ghimire
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center, Hamburg, Germany
| | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Norlux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
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24
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Vessel co-option and resistance to anti-angiogenic therapy. Angiogenesis 2019; 23:55-74. [PMID: 31865479 DOI: 10.1007/s10456-019-09698-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 11/22/2019] [Indexed: 12/20/2022]
Abstract
Vessel co-option is a non-angiogenic mechanism of tumour vascularisation in which cancer cells utilise pre-existing blood vessels instead of inducing new blood vessel formation. Vessel co-option has been observed across a range of different tumour types, in both primary cancers and metastatic disease. Importantly, vessel co-option is now implicated as a major mechanism that mediates resistance to conventional anti-angiogenic drugs and this may help to explain the limited efficacy of this therapeutic approach in certain clinical settings. This includes the use of anti-angiogenic drugs to treat advanced-stage/metastatic disease, treatment in the adjuvant setting and the treatment of primary disease. In this article, we review the available evidence linking vessel co-option with resistance to anti-angiogenic therapy in numerous tumour types, including breast, colorectal, lung and pancreatic cancer, glioblastoma, melanoma, hepatocellular carcinoma, and renal cell carcinoma. The finding that vessel co-option is a significant mechanism of resistance to anti-angiogenic therapy may have important implications for the future of anti-cancer therapy, including (a) predicting response to anti-angiogenic drugs, (b) the need to develop therapies that target both angiogenesis and vessel co-option in tumours, and (c) predicting the response to other therapeutic modalities, including immunotherapy.
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25
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Ravindran S, Rasool S, Maccalli C. The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing Piece of the Puzzle for the Efficient Targeting of these Cells with Immunotherapy. CANCER MICROENVIRONMENT 2019; 12:133-148. [PMID: 31758404 PMCID: PMC6937350 DOI: 10.1007/s12307-019-00233-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 10/17/2019] [Indexed: 12/14/2022]
Abstract
Cancer Stem Cells/Cancer Initiating Cells (CSCs/CICs) is a rare sub-population within a tumor that is responsible for tumor formation, progression and resistance to therapies. The interaction between CSCs/CICs and tumor microenvironment (TME) can sustain “stemness” properties and promote their survival and plasticity. This cross-talk is also pivotal in regulating and modulating CSC/CIC properties. This review will provide an overview of the mechanisms underlying the mutual interaction between CSCs/CICs and TME. Particular focus will be dedicated to the immunological profile of CSCs/CICs and its role in orchestrating cancer immunosurveillance. Moreover, the available immunotherapy strategies that can target CSCs/CICs and of their possible implementation will be discussed. Overall, the dissection of the mechanisms regulating the CSC/CIC-TME interaction is warranted to understand the plasticity and immunoregulatory properties of stem-like tumor cells and to achieve complete eradications of tumors through the optimization of immunotherapy.
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Affiliation(s)
- Shilpa Ravindran
- Research Department, Sidra Medicine, Al Luqta Street, PO Box 26999, Doha, Qatar
| | - Saad Rasool
- Research Department, Sidra Medicine, Al Luqta Street, PO Box 26999, Doha, Qatar
| | - Cristina Maccalli
- Research Department, Sidra Medicine, Al Luqta Street, PO Box 26999, Doha, Qatar.
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26
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Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival. Br J Cancer 2019; 121:545-555. [PMID: 31413318 PMCID: PMC6888814 DOI: 10.1038/s41416-019-0551-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/10/2019] [Accepted: 07/25/2019] [Indexed: 11/28/2022] Open
Abstract
Background Resistance to temozolomide (TMZ) is due in part to enhanced DNA repair mediated by high expression of O6-methyl guanine DNA methyltransferase (MGMT) that is often characterised by unmethylated promoter. Here, we investigated pre-treatment of glioblastoma (GBM) cells with the 26S-proteasome inhibitor bortezomib (BTZ) as a strategy to interfere with MGMT expression and thus sensitise them to TMZ. Methods Cell lines and patient GBM-derived cells were examined in vitro, and the latter also implanted orthotopically into NOD-SCID C.B.-Igh-1b/lcrTac-Prkdc mice to assess efficacy and tolerability of BTZ and TMZ combination therapy. MGMT promoter methylation was determined using pyrosequencing and PCR, protein signalling utilised western blotting while drug biodistribution was examined by LC-MS/MS. Statistical analysis utilised Analysis of variance and the Kaplan–Meier method. Results Pre-treatment with BTZ prior to temozolomide killed chemoresistant GBM cells with unmethylated MGMT promoter through MGMT mRNA and protein depletion in vitro without affecting methylation. Chymotryptic activity was abolished, processing of NFkB/p65 to activated forms was reduced and corresponded with low MGMT levels. BTZ crossed the blood–brain barrier, diminished proteasome activity and significantly prolonged animal survival. Conclusion BTZ chemosensitized resistant GBM cells, and the schedule may be amenable for temozolomide refractory patients with unmethylated MGMT promoter.
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Abstract
All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes.
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Affiliation(s)
- Elizabeth A Kuczynski
- Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
| | - Peter B Vermeulen
- HistoGeneX, Antwerp, Belgium
- Translational Cancer Research Unit, GZA Hospitals St Augustinus, University of Antwerp, Wilrijk-Antwerp, Belgium
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Robert S Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
- Oncology Translational Medicine Unit, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
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28
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Wu JB, Sarmiento AL, Fiset PO, Lazaris A, Metrakos P, Petrillo S, Gao ZH. Histologic features and genomic alterations of primary colorectal adenocarcinoma predict growth patterns of liver metastasis. World J Gastroenterol 2019; 25:3408-3425. [PMID: 31341365 PMCID: PMC6639555 DOI: 10.3748/wjg.v25.i26.3408] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/05/2019] [Accepted: 06/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Different histological growth patterns (HGPs) of colorectal carcinoma (CRC) liver metastasis are associated with patients' prognosis and response to antiangiogenic therapy. However, the relationship between HGPs of liver metastasis and clinicopathological and genomic characteristics of primary cancer has not been well established. AIM To assess whether certain clinicopathological and genomic features of primary CRC could predict the HGPs of liver metastasis. METHODS A total of 29 patients with paired resections of both primary CRC and liver metastasis were divided into two groups: A (15 cases with desmoplastic liver metastasis) and B (14 cases with replacement liver metastasis). Clinical information was obtained from patients' charts. Mismatch repair proteins, BRAFV600E, and PD-L1 were evaluated by immunohistochemistry. Five cases were selected randomly from each group for whole exome sequencing (WES) analysis. RESULTS In the primary tumor, expanding growth pattern, low tumor budding score (TBS), and Crohn's disease-like response (CDR) were associated with desmoplastic liver metastasis and better overall survival, whereas infiltrating growth pattern alone of primary carcinoma could predict the replacement liver metastasis and worse overall survival (P < 0.05). On WES analysis, primary carcinoma with desmoplastic liver metastasis showed mutations in APC (4/5); TP53 (3/5); KRAS, PIK3CA, and FAT4 (2/5); BRCA-1, BRCA2, BRAF, and DNAH5 (1/5), whereas primary carcinoma with replacement liver metastasis showed mutations in APC and TP53 (3/5); KRAS, FAT4, DNH5, SMAD, ERBB2, ERBB3, LRP1, and SDK1 (1/5). CONCLUSION The HGPs, TBS, and CDR of primary CRC as well as the presence of specific genetic mutations such as those in PIK3CA could be used to predict the HGPs of liver metastasis, response to therapy, and patients' prognosis.
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Affiliation(s)
- Jing-Bo Wu
- Department of Pathology, The Fifth People’s Hospital, Fudan University, Shanghai 200240, China
| | - Ali Lopez Sarmiento
- Department of Pathology, McGill University and the Research Institute of McGill University Health Center, Montreal H4A 3J1, Quebec, Canada
| | - Pierre-Olivier Fiset
- Department of Pathology, McGill University and the Research Institute of McGill University Health Center, Montreal H4A 3J1, Quebec, Canada
| | - Anthula Lazaris
- Cancer Research Program, The Research Institute of McGill University Health Center, Montreal H4A 3J1, Quebec, Canada
| | - Peter Metrakos
- Cancer Research Program, The Research Institute of McGill University Health Center, Montreal H4A 3J1, Quebec, Canada
| | - Stephanie Petrillo
- Cancer Research Program, The Research Institute of McGill University Health Center, Montreal H4A 3J1, Quebec, Canada
| | - Zu-Hua Gao
- Department of Pathology, McGill University and the Research Institute of McGill University Health Center, Montreal H4A 3J1, Quebec, Canada
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29
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McCoy MG, Nyanyo D, Hung CK, Goerger JP, R Zipfel W, Williams RM, Nishimura N, Fischbach C. Endothelial cells promote 3D invasion of GBM by IL-8-dependent induction of cancer stem cell properties. Sci Rep 2019; 9:9069. [PMID: 31227783 PMCID: PMC6588602 DOI: 10.1038/s41598-019-45535-y] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 06/06/2019] [Indexed: 12/14/2022] Open
Abstract
Rapid growth and perivascular invasion are hallmarks of glioblastoma (GBM) that have been attributed to the presence of cancer stem-like cells (CSCs) and their association with the perivascular niche. However, the mechanisms by which the perivascular niche regulates GBM invasion and CSCs remain poorly understood due in part to a lack of relevant model systems. To simulate perivascular niche conditions and analyze consequential changes of GBM growth and invasion, patient-derived GBM spheroids were co-cultured with brain endothelial cells (ECs) in microfabricated collagen gels. Integrating these systems with 3D imaging and biochemical assays revealed that ECs increase GBM invasiveness and growth through interleukin-8 (IL-8)-mediated enrichment of CSCs. Blockade of IL-8 inhibited these effects in GBM-EC co-cultures, while IL-8 supplementation increased CSC-mediated growth and invasion in GBM-monocultures. Experiments in mice confirmed that ECs and IL-8 stimulate intracranial tumor growth and invasion in vivo. Collectively, perivascular niche conditions promote GBM growth and invasion by increasing CSC frequency, and IL-8 may be explored clinically to inhibit these interactions.
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Affiliation(s)
- Michael G McCoy
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States
| | - Dennis Nyanyo
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States
| | - Carol K Hung
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States
| | - Julian Palacios Goerger
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States
| | - Warren R Zipfel
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States
| | - Rebecca M Williams
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States
| | - Nozomi Nishimura
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States
| | - Claudia Fischbach
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, United States.
- Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY, 14853, United States.
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30
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Norollahi SE, Mansour-Ghanaei F, Joukar F, Ghadarjani S, Mojtahedi K, Gharaei Nejad K, Hemmati H, Gharibpoor F, Khaksar R, Samadani AA. Therapeutic approach of Cancer stem cells (CSCs) in gastric adenocarcinoma; DNA methyltransferases enzymes in cancer targeted therapy. Biomed Pharmacother 2019; 115:108958. [PMID: 31075731 DOI: 10.1016/j.biopha.2019.108958] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/03/2019] [Accepted: 05/03/2019] [Indexed: 02/08/2023] Open
Abstract
Cancer stem cells (CSCs) show a remarkable sub class of cancer cells population which have a potential to organize and regulate stemness properties which possess a main particular responsibility for uncontrolled growth in carcinogenesis, production of different cancers in differentiated situation and also resistancy to radiotherapy and chemotherapy. Correspondingly, gastric cancer (GC) as a very serious type in cancer mortality in the world, has received a deep attention in molecular therapy recently. Besides the main characteristics of CSCs like differentiation, epithelial mesenchymal transition, self-renewal and metastasis, they are so effective in expression of stemness genes resistancy in radiotherapy and chemotherapy. In this way, the regulation of epigenetic elements including DNA methylation and the performance of DNA methyltransferase (DNMT) which is a notable epigenetic trait in GC, is of great importance. Inhibitors of DNA methylation are the first epigenetic drugs in cancer therapy. Considerably, recent studies indicate that low doses of DNMT inhibitors have a high potential in sustaining reduced DNA methylation and related with re-expression of silenced genes in tumorigenesis. Importantly, these certain doses have the ability to decrease the carcinogenesis and tumorigenesis in CSC populations within GC. Meaningly, the inhibition of DNMTs are able to reduce the accumulation of tumorigenic ability of GC CSCs. Furthermore, many epigenetic drugs have a great potential in cancer therapy, including histone methyltransferases, lysine demethylases, histone deacetylasesand, bromodomain and extra-terminal domain proteins and DNA methyltransferases inhibitors. In this review article, we try to focus on the therapeutic mechanism of DNMTs alongside with their impact on CSCs in GC.
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Affiliation(s)
- Syedeh Elham Norollahi
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Fariborz Mansour-Ghanaei
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Farahnaz Joukar
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Shervin Ghadarjani
- Department of Neurosurgery, Guilan University of Medical Sciences, Rasht, Iran
| | - Kourosh Mojtahedi
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Kaveh Gharaei Nejad
- Skin Research Center, Dermatology Department, Guilan University of Medical Sciences, Razi Hospital, Sardare Jangal Street, Rasht, Iran
| | - Hossein Hemmati
- Razi Clinical Research Development Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Faeze Gharibpoor
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran
| | - Roya Khaksar
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran.
| | - Ali Akbar Samadani
- Gastrointestinal and liver diseases research center, Guilan University of Medical Sciences, Rasht, Iran.
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31
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Sulheim E, Mørch Y, Snipstad S, Borgos SE, Miletic H, Bjerkvig R, Davies CDL, Åslund AK. Therapeutic Effect of Cabazitaxel and Blood-Brain Barrier opening in a Patient-Derived Glioblastoma Model. Nanotheranostics 2019; 3:103-112. [PMID: 30899638 PMCID: PMC6427936 DOI: 10.7150/ntno.31479] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/05/2019] [Indexed: 01/21/2023] Open
Abstract
Treatment of glioblastoma and other diseases in the brain is especially challenging due to the blood-brain barrier, which effectively protects the brain parenchyma. In this study we show for the first time that cabazitaxel, a semi-synthetic derivative of docetaxel can cross the blood-brain barrier and give a significant therapeutic effect in a patient-derived orthotopic model of glioblastoma. We show that the drug crosses the blood-brain barrier more effectively in the tumor than in the healthy brain due to reduced expression of p-glycoprotein efflux pumps in the vasculature of the tumor. Surprisingly, neither ultrasound-mediated blood-brain barrier opening (sonopermeation) nor drug formulation in polymeric nanoparticles could increase either accumulation of the drug in the brain or therapeutic effect. This indicates that for hydrophobic drugs, sonopermeation of the blood brain barrier might not be sufficient to achieve improved drug delivery. Nonetheless, our study shows that cabazitaxel is a promising drug for the treatment of brain tumors.
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Affiliation(s)
- Einar Sulheim
- Department of Physics, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim Norway
- Cancer Clinic, St.Olav's University Hospital, Trondheim Norway
| | - Yrr Mørch
- Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim Norway
| | - Sofie Snipstad
- Department of Physics, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim Norway
- Cancer Clinic, St.Olav's University Hospital, Trondheim Norway
| | - Sven Even Borgos
- Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim Norway
| | - Hrvoje Miletic
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
- Department of Biomedicine, University of Bergen, Norway
| | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Norway
- Department of Oncology, Luxembourg Institute of Health, Luxembourg
| | | | - Andreas K.O. Åslund
- Department of Physics, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Biotechnology and Nanomedicine, SINTEF AS, Trondheim Norway
- Stroke Unit, Department of internal medicine, St. Olav's University Hospital, Trondheim, Norway
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32
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Mastrella G, Hou M, Li M, Stoecklein VM, Zdouc N, Volmar MNM, Miletic H, Reinhard S, Herold-Mende CC, Kleber S, Eisenhut K, Gargiulo G, Synowitz M, Vescovi AL, Harter PN, Penninger JM, Wagner E, Mittelbronn M, Bjerkvig R, Hambardzumyan D, Schüller U, Tonn JC, Radke J, Glass R, Kälin RE. Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma. Cancer Res 2019; 79:2298-2313. [PMID: 30718358 DOI: 10.1158/0008-5472.can-18-0881] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 10/19/2018] [Accepted: 01/29/2019] [Indexed: 11/16/2022]
Abstract
Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes. SIGNIFICANCE: Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis.See related commentary by Amoozgar et al., p. 2104.
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Affiliation(s)
- Giorgia Mastrella
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Mengzhuo Hou
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Min Li
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Veit M Stoecklein
- Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Nina Zdouc
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Marie N M Volmar
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | | | - Christel C Herold-Mende
- Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Germany
| | - Susanne Kleber
- Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katharina Eisenhut
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | | | - Michael Synowitz
- Department of Neurosurgery, University Hospital Center Schleswig Holstein, Kiel, Germany
| | - Angelo L Vescovi
- IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Patrick N Harter
- Edinger-Institute (Neurological Institute), Goethe-University Medical School, Frankfurt am Main, Germany and German Cancer Consortium (DKTK), partner site Frankfurt/Mainz; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Josef M Penninger
- Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria
| | - Ernst Wagner
- Department of Pharmacy, LMU Munich, Munich, Germany
| | - Michel Mittelbronn
- Edinger-Institute (Neurological Institute), Goethe-University Medical School, Frankfurt am Main, Germany and German Cancer Consortium (DKTK), partner site Frankfurt/Mainz; German Cancer Research Center (DKFZ), Heidelberg, Germany.,Luxembourg Centre of Neuropathology (LCNP), Luxembourg and NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), and Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Dolores Hambardzumyan
- Department of Pediatrics and Aflac Cancer Center of Children's Health Care of Atlanta, Emory University School of Medicine, Atlanta, Georgia
| | - Ulrich Schüller
- Institute of Neuropathology and Department of Pediatric Haematology and Oncology, University Medical Center, Hamburg-Eppendorf and Research Institute Children's Cancer Center, Hamburg, Germany
| | - Jörg-Christian Tonn
- Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Josefine Radke
- Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, German; Berlin Institute of Health (BIH), Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany, Partner Site Berlin, Berlin, Germany
| | - Rainer Glass
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany.,German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Walter Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Roland E Kälin
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany. .,Walter Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
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33
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Eskilsson E, Røsland GV, Solecki G, Wang Q, Harter PN, Graziani G, Verhaak RGW, Winkler F, Bjerkvig R, Miletic H. EGFR heterogeneity and implications for therapeutic intervention in glioblastoma. Neuro Oncol 2019; 20:743-752. [PMID: 29040782 DOI: 10.1093/neuonc/nox191] [Citation(s) in RCA: 224] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Patients with glioblastoma (GBM) have a universally poor prognosis and are in urgent need of effective treatment strategies. Recent advances in sequencing techniques unraveled the complete genomic landscape of GBMs and revealed profound heterogeneity of individual tumors even at the single cell level. Genomic profiling has detected epidermal growth factor receptor (EGFR) gene alterations in more than half of GBMs. Major genetic events include amplification and mutation of EGFR. Yet, treatment strategies targeting EGFR have thus far failed in clinical trials. In this review, we discuss the clonal and functional heterogeneity of EGFRs in GBM development and critically reassess the potential of EGFRs as therapeutic targets.
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Affiliation(s)
- Eskil Eskilsson
- Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Gro V Røsland
- Department of Biomedicine, University of Bergen, Norway
| | - Gergely Solecki
- Department of Neurooncology, University Hospital Heidelberg, Germany
| | - Qianghu Wang
- Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.,Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Patrick N Harter
- Edinger-Institute, Goethe-University Medical School, Frankfurt am Main, Germany
| | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Roel G W Verhaak
- Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.,Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.,The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
| | - Frank Winkler
- Department of Neurooncology, University Hospital Heidelberg, Germany
| | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Norway.,KG Jebsen Brain Tumor Research Center, University of Bergen, Norway.,Norlux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Norway.,KG Jebsen Brain Tumor Research Center, University of Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
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Abstract
Cancer is a devastating disease characterized by uncontrolled and aggressive cell growth. Suicide gene therapy (SGT) facilitating induction of malignancy-specific cell death represents a novel therapeutic approach to treat cancer, which has been investigated in several cancer types with very promising results. In addition, SGT has been suggested as a safeguard in adoptive immunotherapy and regenerative-medicine settings. Generally, SGT consists of two steps-vector-mediated delivery of suicide genes into tumors and subsequent activation of the suicide mechanism, e.g., by administration of a specific prodrug. This chapter provides a framework of protocols for basic and translational research using the Herpes-simplex-virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system, the most widely used suicide gene approach. The protocols provide standard guidelines for the preparation of high-titer third-generation lentiviral vectors encoding a genetically improved HSV-TK version known as TK.007 and its application in in vitro and in vivo treatment setups.
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Affiliation(s)
- Jubayer A Hossain
- Department of Biomedicine, University of Bergen, Bergen, Norway.,KG Jebsen Brain Tumor Research Centre, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway. .,KG Jebsen Brain Tumor Research Centre, University of Bergen, Bergen, Norway. .,Department of Pathology, Haukeland University Hospital, Bergen, Norway.
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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35
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Johannessen TC, Hasan-Olive MM, Zhu H, Denisova O, Grudic A, Latif MA, Saed H, Varughese JK, Røsland GV, Yang N, Sundstrøm T, Nordal A, Tronstad KJ, Wang J, Lund-Johansen M, Simonsen A, Janji B, Westermarck J, Bjerkvig R, Prestegarden L. Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide. Int J Cancer 2018; 144:1735-1745. [PMID: 30289977 DOI: 10.1002/ijc.31912] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 08/15/2018] [Accepted: 08/30/2018] [Indexed: 01/08/2023]
Abstract
Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14-15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome-wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late-stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy-lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.
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Affiliation(s)
- Tor-Christian Johannessen
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Md Mahdi Hasan-Olive
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Huaiyang Zhu
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Oncology, Shandong Chest Hospital, Jinan, China
| | - Oxana Denisova
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
| | - Amra Grudic
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Md Abdul Latif
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Halala Saed
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Jobin K Varughese
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway
| | | | - Ning Yang
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.,Brain Science Research Institute, Shandong University, Jinan, China
| | - Terje Sundstrøm
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway
| | - Anne Nordal
- Department of Dermatology, Haukeland University Hospital, Bergen, Norway
| | | | - Jian Wang
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.,Brain Science Research Institute, Shandong University, Jinan, China
| | - Morten Lund-Johansen
- Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Anne Simonsen
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Bassam Janji
- Laboratory of Experimental Hemato-Oncology, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg
| | - Jukka Westermarck
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
| | - Rolf Bjerkvig
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.,NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg
| | - Lars Prestegarden
- Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Dermatology, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
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36
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Maccalli C, Rasul KI, Elawad M, Ferrone S. The role of cancer stem cells in the modulation of anti-tumor immune responses. Semin Cancer Biol 2018; 53:189-200. [DOI: 10.1016/j.semcancer.2018.09.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/12/2018] [Accepted: 09/17/2018] [Indexed: 02/07/2023]
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37
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Samadani AA, Norollahi SE, Rashidy-Pour A, Mansour-Ghanaei F, Nemati S, Joukar F, Afshar AM, Ghazanfari S, Safizadeh M, Rostami P, Gatei M. Cancer signaling pathways with a therapeutic approach: An overview in epigenetic regulations of cancer stem cells. Biomed Pharmacother 2018; 108:590-599. [DOI: 10.1016/j.biopha.2018.09.048] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 09/08/2018] [Accepted: 09/08/2018] [Indexed: 02/07/2023] Open
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Obad N, Espedal H, Jirik R, Sakariassen PO, Brekke Rygh C, Lund-Johansen M, Taxt T, Niclou SP, Bjerkvig R, Keunen O. Lack of functional normalisation of tumour vessels following anti-angiogenic therapy in glioblastoma. J Cereb Blood Flow Metab 2018; 38. [PMID: 28627960 PMCID: PMC6168744 DOI: 10.1177/0271678x17714656] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Neo-angiogenesis represents an important factor for the delivery of oxygen and nutrients to a growing tumour, and is considered to be one of the main pathodiagnostic features of glioblastomas (GBM). Anti-angiogenic therapy by vascular endothelial growth factor (VEGF) blocking agents has been shown to lead to morphological vascular normalisation resulting in a reduction of contrast enhancement as seen by magnetic resonance imaging (MRI). Yet the functional consequences of this normalisation and its potential for improved delivery of cytotoxic agents to the tumour are not known. The presented study aimed at determining the early physiologic changes following bevacizumab treatment. A time series of perfusion MRI and hypoxia positron emission tomography (PET) scans were acquired during the first week of treatment, in two human GBM xenograft models treated with either high or low doses of bevacizumab. We show that vascular morphology was normalised over the time period investigated, but vascular function was not improved, resulting in poor tumoural blood flow and increased hypoxia.
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Affiliation(s)
- Nina Obad
- 1 Department of Biomedecine, University of Bergen, Bergen, Norway.,2 Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.,3 KG Jebsen Brain Tumor research Center, University of Bergen, Bergen, Norway
| | - Heidi Espedal
- 1 Department of Biomedecine, University of Bergen, Bergen, Norway.,3 KG Jebsen Brain Tumor research Center, University of Bergen, Bergen, Norway
| | - Radovan Jirik
- 4 Institute of Scientific Instruments of the Czech Academy of Sciences, Brno, Czech Republic
| | | | - Cecilie Brekke Rygh
- 1 Department of Biomedecine, University of Bergen, Bergen, Norway.,5 Bergen University College, Bergen, Norway
| | - Morten Lund-Johansen
- 2 Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.,6 Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Torfinn Taxt
- 1 Department of Biomedecine, University of Bergen, Bergen, Norway
| | - Simone P Niclou
- 3 KG Jebsen Brain Tumor research Center, University of Bergen, Bergen, Norway.,7 Norlux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Rolf Bjerkvig
- 1 Department of Biomedecine, University of Bergen, Bergen, Norway.,3 KG Jebsen Brain Tumor research Center, University of Bergen, Bergen, Norway.,7 Norlux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Olivier Keunen
- 7 Norlux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
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van Dam PJ, Daelemans S, Ross E, Waumans Y, Van Laere S, Latacz E, Van Steen R, De Pooter C, Kockx M, Dirix L, Vermeulen PB. Histopathological growth patterns as a candidate biomarker for immunomodulatory therapy. Semin Cancer Biol 2018; 52:86-93. [PMID: 29355613 DOI: 10.1016/j.semcancer.2018.01.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 01/15/2018] [Accepted: 01/16/2018] [Indexed: 12/17/2022]
Abstract
The encroachment of a growing tumor upon the cells and structures of surrounding normal tissue results in a series of histopathological growth patterns (HGPs). These morphological changes can be assessed in hematoxylin-and-eosin (H&E) stained tissue sections from primary and metastatic tumors and have been characterized in a range of tissue types including liver, lung, lymph node and skin. HGPs in different tissues share certain general characteristics like the extent of angiogenesis, but also appropriate tissue-specific mechanisms which ultimately determine differences in the biology of HGP subtypes. For instance, in the well-characterized HGPs of liver metastases, the two main subtypes, replacement and desmoplastic, recapitulate two responses of the normal liver to injury: regeneration and fibrosis. HGP subtypes have distinct cytokine profiles and differing levels of lymphocytic infiltration which suggests that they are indicative of immune status in the tumor microenvironment. HGPs predict response to bevacizumab and are associated with overall survival (OS) after surgery for liver metastases in colorectal cancer (CRC). In addition, HGPs can change over time in response to therapy. With standard scoring methods being developed, HGPs represent an easily accessible, dynamic biomarker to consider when determining strategies for treatment using anti-VEGF and immunomodulatory drugs.
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Affiliation(s)
- Pieter-Jan van Dam
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium; HistoGeneX NV, Wilrijk, Antwerp, Belgium
| | | | | | | | - Steven Van Laere
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Emily Latacz
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Roanne Van Steen
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Christel De Pooter
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Mark Kockx
- HistoGeneX NV, Wilrijk, Antwerp, Belgium
| | - Luc Dirix
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Peter B Vermeulen
- Translational Cancer Research Unit (CORE), Gasthuiszusters Antwerpen Hospitals, University of Antwerp, Wilrijk, Antwerp, Belgium; HistoGeneX NV, Wilrijk, Antwerp, Belgium.
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40
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Mikkelsen VE, Stensjøen AL, Granli US, Berntsen EM, Salvesen Ø, Solheim O, Torp SH. Angiogenesis and radiological tumor growth in patients with glioblastoma. BMC Cancer 2018; 18:862. [PMID: 30176826 PMCID: PMC6122710 DOI: 10.1186/s12885-018-4768-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 08/22/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The preoperative growth of human glioblastomas (GBMs) has been shown to vary among patients. In animal studies, angiogenesis has been linked to hypoxia and faster growth of GBM, however, its relation to the growth of human GBMs is sparsely studied. We have therefore aimed to look for associations between radiological speed of growth and microvessel density (MVD) counts of the endothelial markers vWF (Factor VIII related antigen) and CD105 (endoglin). METHODS Preoperative growth was estimated from segmented tumor volumes of two preoperative T1-weighted postcontrast magnetic resonance imaging scans taken ≥14 days apart in patients with newly diagnosed GBMs. A Gompertzian growth curve was computed from the volume data and separated the patients into two groups of either faster or slower tumor growth than expected. MVD counts of the immunohistochemical markers von Willebrand factor (vWF) (a pan-endothelial marker) and CD105 (a marker of proliferating endothelial cells) were assessed for associations with fast-growing tumors using Mann-Whitney U tests and a multivariable binary logistic regression analysis. RESULTS We found that only CD105-MVD was significantly associated with faster growth in a univariable analysis (p = 0.049). However, CD105-MVD was no longer significant when corrected for the presence of thromboses and high cellular density in a multivariable model, where the latter features were significant independent predictors of faster growth with respective odds ratios 4.2 (95% confidence interval, 1.2, 14.3), p = 0.021 and 2.6 (95% confidence interval, 1.0, 6.5), p = 0.048. CONCLUSIONS MVDs of neither endothelial marker were independently associated with faster growth, suggesting angiogenesis-independent processes contribute to faster glioblastoma growth.
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Affiliation(s)
- Vilde Elisabeth Mikkelsen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Erling Skjalgssons gate 1, 7030, Trondheim, Norway.
| | - Anne Line Stensjøen
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway
| | - Unn Sophie Granli
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Erling Skjalgssons gate 1, 7030, Trondheim, Norway.,Cellular and Molecular Imaging Core Facility (CMIC), Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Erik Magnus Berntsen
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Department of Radiology and Nuclear Medicine, St. Olavs University Hospital, Trondheim, Norway
| | - Øyvind Salvesen
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway
| | - Ole Solheim
- Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway.,National Advisory Unit for Ultrasound and Image Guided Therapy, St. Olavs University Hospital, Trondheim, Norway.,Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway
| | - Sverre Helge Torp
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Erling Skjalgssons gate 1, 7030, Trondheim, Norway.,Department of Pathology, St. Olavs University Hospital, Trondheim, Norway
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41
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Donnem T, Reynolds AR, Kuczynski EA, Gatter K, Vermeulen PB, Kerbel RS, Harris AL, Pezzella F. Non-angiogenic tumours and their influence on cancer biology. Nat Rev Cancer 2018; 18:323-336. [PMID: 29520090 DOI: 10.1038/nrc.2018.14] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Solid tumours need a blood supply, and a large body of evidence has previously suggested that they can grow only if they induce the development of new blood vessels, a process known as tumour angiogenesis. On the basis of this hypothesis, it was proposed that anti-angiogenic drugs should be able to suppress the growth of all solid tumours. However, clinical experience with anti-angiogenic agents has shown that this is not always the case. Reports of tumours growing without the formation of new vessels can be found in the literature dating back to the 1800s, yet no formal recognition, description and demonstration of their special biological status was made until recently. In 1996, we formally recognized and described non-angiogenic tumours in lungs where the only blood vessels present were those originating from normal lung tissue. This is far from an isolated scenario, as non-angiogenic tumour growth has now been observed in tumours of many different organs in both humans and preclinical animal models. In this Opinion article, we summarize how these tumours were discovered and discuss what we know so far about their biology and the potential implications of this knowledge for cancer treatment.
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Affiliation(s)
- Tom Donnem
- Department of Oncology, University Hospital of North Norway, Tromso, Norway
- Institute of Clinical Medicine, The Arctic University of Norway, Tromso, Norway
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- Oncology Translational Medicine Unit, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - Elizabeth A Kuczynski
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
- Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - Kevin Gatter
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Peter B Vermeulen
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- Translational Cancer Research Unit, GZA, Hospitals St Augustinus, University of Antwerp, Wilrijk-Antwerp, Belgium
- HistoGeneX, Antwerp, Belgium
| | - Robert S Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Adrian L Harris
- Molecular Oncology Laboratories, Oxford University Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
| | - Francesco Pezzella
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
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42
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Ferrer VP, Moura Neto V, Mentlein R. Glioma infiltration and extracellular matrix: key players and modulators. Glia 2018; 66:1542-1565. [DOI: 10.1002/glia.23309] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 01/18/2018] [Accepted: 01/29/2018] [Indexed: 12/14/2022]
Affiliation(s)
| | | | - Rolf Mentlein
- Department of Anatomy; University of Kiel; Kiel Germany
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43
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Jin L, Li ZF, Wang DK, Sun M, Qi W, Ma Q, Zhang L, Chu C, Chan EY, Lee SS, Wise H, To KF, Shi Y, Zhou N, Cheung WT. Molecular and functional characterization of tumor-induced factor (TIF): Hamster homolog of CXCL3 (GROγ) displays tumor suppressive activity. Cytokine 2018; 102:62-75. [DOI: 10.1016/j.cyto.2017.12.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 12/11/2017] [Accepted: 12/15/2017] [Indexed: 12/20/2022]
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Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget 2017; 7:31955-71. [PMID: 27049916 PMCID: PMC5077988 DOI: 10.18632/oncotarget.7454] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 01/29/2016] [Indexed: 12/11/2022] Open
Abstract
The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.
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45
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Boyé K, Pujol N, D Alves I, Chen YP, Daubon T, Lee YZ, Dedieu S, Constantin M, Bello L, Rossi M, Bjerkvig R, Sue SC, Bikfalvi A, Billottet C. The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors. Nat Commun 2017; 8:1571. [PMID: 29146996 PMCID: PMC5691136 DOI: 10.1038/s41467-017-01686-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Accepted: 10/10/2017] [Indexed: 11/09/2022] Open
Abstract
CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3-A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for tumor biology.
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Affiliation(s)
- Kevin Boyé
- INSERM U1029, Pessac, 33615, France.,Université de Bordeaux, Pessac, 33615, France
| | - Nadège Pujol
- INSERM U1029, Pessac, 33615, France.,Université de Bordeaux, Pessac, 33615, France
| | | | - Ya-Ping Chen
- Institute of Bioinformatics and Structural Biology, NTHU, Hsinchu, 30055, Taiwan
| | - Thomas Daubon
- INSERM U1029, Pessac, 33615, France.,Université de Bordeaux, Pessac, 33615, France.,K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, 5009, Norway.,Department of Oncology, Luxembourg Institute of Health, Luxembourg, L-1526, Luxembourg
| | - Yi-Zong Lee
- Institute of Bioinformatics and Structural Biology, NTHU, Hsinchu, 30055, Taiwan
| | - Stephane Dedieu
- CNRS UMR 7369 MEDyC, Université de Reims Champagne-Ardenne, Reims, 51687, France
| | - Marion Constantin
- INSERM U1029, Pessac, 33615, France.,Université de Bordeaux, Pessac, 33615, France
| | - Lorenzo Bello
- Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Humanitas Resarch Hospital, Milan, 20089, Italy
| | - Marco Rossi
- Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Humanitas Resarch Hospital, Milan, 20089, Italy
| | - Rolf Bjerkvig
- K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, 5009, Norway.,Department of Oncology, Luxembourg Institute of Health, Luxembourg, L-1526, Luxembourg
| | - Shih-Che Sue
- Institute of Bioinformatics and Structural Biology, NTHU, Hsinchu, 30055, Taiwan
| | - Andreas Bikfalvi
- INSERM U1029, Pessac, 33615, France. .,Université de Bordeaux, Pessac, 33615, France.
| | - Clotilde Billottet
- INSERM U1029, Pessac, 33615, France. .,Université de Bordeaux, Pessac, 33615, France.
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van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S, Majeed AW, Eefsen RL, Coebergh van den Braak RRJ, Lazaris A, Fernandez MC, Galjart B, Laerum OD, Rayes R, Grünhagen DJ, Van de paer M, Sucaet Y, Mudhar HS, Schvimer M, Nyström H, Kockx M, Bird NC, Vidal-Vanaclocha F, Metrakos P, Simoneau E, Verhoef C, Dirix LY, Van Laere S, Gao ZH, Brodt P, Reynolds AR, Vermeulen PB. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer 2017; 117:1427-1441. [PMID: 28982110 PMCID: PMC5680474 DOI: 10.1038/bjc.2017.334] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 06/12/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
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Affiliation(s)
- Pieter-Jan van Dam
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Eric P van der Stok
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Laure-Anne Teuwen
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Gert G Van den Eynden
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet/BRIC, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sophia Frentzas
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Ali W Majeed
- Hepatobiliary Surgery, Sheffield Teaching Hospitals, Sheffield, UK
| | - Rikke L Eefsen
- Department of Oncology, Naestved Hospital, Naestved, Denmark
| | | | - Anthoula Lazaris
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Maria Celia Fernandez
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Boris Galjart
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ole Didrik Laerum
- The Finsen Laboratory and Department of Radiation Biology, Copenhagen University Hospital, University of Copenhagen, Denmark
| | - Roni Rayes
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Michelle Van de paer
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
| | - Yves Sucaet
- Department of Pathology, Faculty of Medicine, Vrije Universiteit Brussel, Brussels, Belgium
- Pathomation, Berchem, Belgium
| | | | - Michael Schvimer
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel
| | - Hanna Nyström
- Department of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Mark Kockx
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
| | - Nigel C Bird
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | | | - Peter Metrakos
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Eve Simoneau
- Department of Surgery, Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Luc Y Dirix
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Steven Van Laere
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
| | - Zu-hua Gao
- Department of Pathology and Oncology, McGill University, Montreal, QC, Canada
| | - Pnina Brodt
- Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- Early Clinical Development, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK
| | - Peter B Vermeulen
- Translational Cancer Research Unit, GZA Hospitals (St Augustinus), Wilrijk-Antwerp, Belgium
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- HistoGeneX, Sint-Bavostraat 78-80, Antwerp 2610, Belgium
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47
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Talasila KM, Røsland GV, Hagland HR, Eskilsson E, Flønes IH, Fritah S, Azuaje F, Atai N, Harter PN, Mittelbronn M, Andersen M, Joseph JV, Hossain JA, Vallar L, Noorden CJFV, Niclou SP, Thorsen F, Tronstad KJ, Tzoulis C, Bjerkvig R, Miletic H. The angiogenic switch leads to a metabolic shift in human glioblastoma. Neuro Oncol 2017; 19:383-393. [PMID: 27591677 DOI: 10.1093/neuonc/now175] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 07/09/2016] [Indexed: 12/23/2022] Open
Abstract
Background Invasion and angiogenesis are major hallmarks of glioblastoma (GBM) growth. While invasive tumor cells grow adjacent to blood vessels in normal brain tissue, tumor cells within neovascularized regions exhibit hypoxic stress and promote angiogenesis. The distinct microenvironments likely differentially affect metabolic processes within the tumor cells. Methods In the present study, we analyzed gene expression and metabolic changes in a human GBM xenograft model that displayed invasive and angiogenic phenotypes. In addition, we used glioma patient biopsies to confirm the results from the xenograft model. Results We demonstrate that the angiogenic switch in our xenograft model is linked to a proneural-to-mesenchymal transition that is associated with upregulation of the transcription factors BHLHE40, CEBPB, and STAT3. Metabolic analyses revealed that angiogenic xenografts employed higher rates of glycolysis compared with invasive xenografts. Likewise, patient biopsies exhibited higher expression of the glycolytic enzyme lactate dehydrogenase A and glucose transporter 1 in hypoxic areas compared with the invasive edge and lower-grade tumors. Analysis of the mitochondrial respiratory chain showed reduction of complex I in angiogenic xenografts and hypoxic regions of GBM samples compared with invasive xenografts, nonhypoxic GBM regions, and lower-grade tumors. In vitro hypoxia experiments additionally revealed metabolic adaptation of invasive tumor cells, which increased lactate production under long-term hypoxia. Conclusions The use of glycolysis versus mitochondrial respiration for energy production within human GBM tumors is highly dependent on the specific microenvironment. The metabolic adaptability of GBM cells highlights the difficulty of targeting one specific metabolic pathway for effective therapeutic intervention.
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Affiliation(s)
- Krishna M Talasila
- Department of Biomedicine, University of Bergen, Norway.,KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway
| | - Gro V Røsland
- Department of Biomedicine, University of Bergen, Norway
| | | | - Eskil Eskilsson
- The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Irene H Flønes
- Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Sabrina Fritah
- NorLux Neuro-oncology Laboratory, Luxembourg Institute of Health, Luxembourg
| | - Francisco Azuaje
- NorLux Neuro-oncology Laboratory, Luxembourg Institute of Health, Luxembourg
| | - Nadia Atai
- Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands
| | - Patrick N Harter
- Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michel Mittelbronn
- Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Andersen
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Justin V Joseph
- Department of Biomedicine, University of Bergen, Norway.,KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway
| | - Jubayer Al Hossain
- Department of Biomedicine, University of Bergen, Norway.,KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Laurent Vallar
- Department of Oncology, Luxembourg Institute of Health, Luxembourg
| | - Cornelis J F van Noorden
- Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands
| | - Simone P Niclou
- KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.,NorLux Neuro-oncology Laboratory, Luxembourg Institute of Health, Luxembourg
| | - Frits Thorsen
- KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.,Molecular Imaging Center, Department of Biomedicine, University of Bergen, Norway
| | | | | | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Norway.,KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.,Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Norway.,KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
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48
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Xu C, Liu X, Geng Y, Bai Q, Pan C, Sun Y, Chen X, Yu H, Wu Y, Zhang P, Wu W, Wang Y, Wu Z, Zhang J, Wang Z, Yang R, Lewis J, Bigner D, Zhao F, He Y, Yan H, Shen Q, Zhang L. Patient-derived DIPG cells preserve stem-like characteristics and generate orthotopic tumors. Oncotarget 2017; 8:76644-76655. [PMID: 29100338 PMCID: PMC5652732 DOI: 10.18632/oncotarget.19656] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 05/22/2017] [Indexed: 12/27/2022] Open
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor, with a median survival of less than one year. Due to enormous difficulties in the acquisition of DIPG specimens and the sophisticated technique required to perform brainstem orthotopic injection, only a handful of DIPG pre-clinical models are available. In this study, we successfully established eight patient-derived DIPG cell lines, mostly derived from treatment-naïve surgery or biopsy specimens. These patient-derived cell lines can be stably passaged in serum-free neural stem cell media and displayed distinct morphologies, growth rates and chromosome abnormalities. In addition, these cells retained genomic hallmarks identical to original human DIPG tumors. Notably, expression of several neural stem cell lineage markers was observed in DIPG cell lines. Moreover, three out of eight cell lines can form orthotopic tumors in mouse brainstem by stereotactic injection and these tumors faithfully represented the characteristics of human DIPG by magnetic resonance imaging (MRI) and histopathological staining. Taken together, we established DIPG pre-clinical models resembling human DIPG and they provided a valuable resource for future biological and therapeutic studies.
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Affiliation(s)
- Cheng Xu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaoqing Liu
- Center for Life Sciences, Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, China.,Peking-Tsinghua-NIBS Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yibo Geng
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qingran Bai
- Center for Life Sciences, Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, China.,Peking-Tsinghua-NIBS Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China
| | - Changcun Pan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yu Sun
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xin Chen
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Hai Yu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yuliang Wu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Peng Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wenhao Wu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yu Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhen Wu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Junting Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhaohui Wang
- Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA
| | - Rui Yang
- Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA
| | - Jenna Lewis
- Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA
| | - Darell Bigner
- Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA
| | | | - Yiping He
- Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA
| | - Hai Yan
- Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA
| | - Qin Shen
- Center for Life Sciences, Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, China
| | - Liwei Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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49
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Leiss L, Mutlu E, Øyan A, Yan T, Tsinkalovsky O, Sleire L, Petersen K, Rahman MA, Johannessen M, Mitra SS, Jacobsen HK, Talasila KM, Miletic H, Jonassen I, Li X, Brons NH, Kalland KH, Wang J, Enger PØ. Tumour-associated glial host cells display a stem-like phenotype with a distinct gene expression profile and promote growth of GBM xenografts. BMC Cancer 2017; 17:108. [PMID: 28173797 PMCID: PMC5294893 DOI: 10.1186/s12885-017-3109-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 02/03/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Little is known about the role of glial host cells in brain tumours. However, supporting stromal cells have been shown to foster tumour growth in other cancers. METHODS We isolated stromal cells from patient-derived glioblastoma (GBM) xenografts established in GFP-NOD/scid mice. With simultaneous removal of CD11b+ immune and CD31+ endothelial cells by fluorescence activated cell sorting (FACS), we obtained a population of tumour-associated glial cells, TAGs, expressing markers of terminally differentiaed glial cell types or glial progenitors. This cell population was subsequently characterised using gene expression analyses and immunocytochemistry. Furthermore, sphere formation was assessed in vitro and their glioma growth-promoting ability was examined in vivo. Finally, the expression of TAG related markers was validated in human GBMs. RESULTS TAGs were highly enriched for the expression of glial cell proteins including GFAP and myelin basic protein (MBP), and immature markers such as Nestin and O4. A fraction of TAGs displayed sphere formation in stem cell medium. Moreover, TAGs promoted brain tumour growth in vivo when co-implanted with glioma cells, compared to implanting only glioma cells, or glioma cells and unconditioned glial cells from mice without tumours. Genome-wide microarray analysis of TAGs showed an expression profile distinct from glial cells from healthy mice brains. Notably, TAGs upregulated genes associated with immature cell types and self-renewal, including Pou3f2 and Sox2. In addition, TAGs from highly angiogenic tumours showed upregulation of angiogenic factors, including Vegf and Angiopoietin 2. Immunohistochemistry of three GBMs, two patient biopsies and one GBM xenograft, confirmed that the expression of these genes was mainly confined to TAGs in the tumour bed. Furthermore, their expression profiles displayed a significant overlap with gene clusters defining prognostic subclasses of human GBMs. CONCLUSIONS Our data demonstrate that glial host cells in brain tumours are functionally distinct from glial cells of healthy mice brains. Furthermore, TAGs display a gene expression profile with enrichment for genes related to stem cells, immature cell types and developmental processes. Future studies are needed to delineate the biological mechanisms regulating the brain tumour-host interplay.
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Affiliation(s)
- Lina Leiss
- Neuro Clinic, Haukeland University Hospital, Bergen, Norway.,Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Ercan Mutlu
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.
| | - Anne Øyan
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Microbiology and Immunology, Haukeland University Hospital, Bergen, Norway
| | - Tao Yan
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.,Brain Science Research Institute, Shandong University, 107# Wenhua Xi Road, Jinan, 250012, People's Republic of China
| | - Oleg Tsinkalovsky
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Linda Sleire
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Kjell Petersen
- Computational Biology Unit, Uni Computing, Uni Research AS, Bergen, Norway
| | - Mohummad Aminur Rahman
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Mireille Johannessen
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Sidhartha S Mitra
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA
| | - Hege K Jacobsen
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Krishna M Talasila
- Translational Cancer Research Group, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Hrvoje Miletic
- Translational Cancer Research Group, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway
| | - Inge Jonassen
- Computational Biology Unit, Uni Computing, Uni Research AS, Bergen, Norway.,Department of Informatics, University of Bergen, Bergen, Norway
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.,Brain Science Research Institute, Shandong University, 107# Wenhua Xi Road, Jinan, 250012, People's Republic of China
| | - Nicolaas H Brons
- Core Facility Flow Cytometry, Centre de Recherche Public de la Santé (CRP-Santé), L-1526, Luxembourg, Luxembourg
| | - Karl-Henning Kalland
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Microbiology and Immunology, Haukeland University Hospital, Bergen, Norway
| | - Jian Wang
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.,Brain Science Research Institute, Shandong University, 107# Wenhua Xi Road, Jinan, 250012, People's Republic of China
| | - Per Øyvind Enger
- Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway
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50
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Abstract
Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.
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Affiliation(s)
- Tan Boon Toh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Jhin Jieh Lim
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Centre for Translational Medicine, National University of Singapore, 14 Medical Drive #12-01, Singapore, 117599 Singapore
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