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Puzzo M, De Santo M, Morelli C, Leggio A, Catalano S, Pasqua L. Colorectal Cancer: Current and Future Therapeutic Approaches and Related Technologies Addressing Multidrug Strategies Against Multiple Level Resistance Mechanisms. Int J Mol Sci 2025; 26:1313. [PMID: 39941081 PMCID: PMC11818749 DOI: 10.3390/ijms26031313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/31/2025] [Accepted: 02/01/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission.
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Affiliation(s)
- Marianna Puzzo
- Laboratory of Clinical, Biomolecular and Genetic Analyses Unit, Annunziata Hospital, 87100 Cosenza, Italy; (M.P.); (S.C.)
| | - Marzia De Santo
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Catia Morelli
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Antonella Leggio
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Stefania Catalano
- Laboratory of Clinical, Biomolecular and Genetic Analyses Unit, Annunziata Hospital, 87100 Cosenza, Italy; (M.P.); (S.C.)
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
| | - Luigi Pasqua
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
- Department of Environmental Engineering, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy
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Raudales A, Schager B, Hancock D, Narayana K, Sharma S, Reeson P, Oshanyk A, Cheema M, Körbelin J, Brown CE. Angiogenesis in the mature mouse cortex is governed in a regional- and Notch1-dependent manner. Cell Rep 2024; 43:115029. [PMID: 39612246 DOI: 10.1016/j.celrep.2024.115029] [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: 05/31/2024] [Revised: 10/10/2024] [Accepted: 11/13/2024] [Indexed: 12/01/2024] Open
Abstract
Cerebral angiogenesis is well appreciated in development and after injury, but the extent to which it occurs across cortical regions in normal adult mice and the underlying mechanisms are incompletely understood. Using in vivo imaging, we show that angiogenesis in anterior-medial cortical regions (retrosplenial and sensorimotor cortex) was exceptionally rare. By contrast, angiogenesis was significantly elevated in posterior-lateral regions such as visual cortex, primarily within 200 μm of the cortical surface. There was no effect of sex on angiogenesis rates, nor were there regional differences in vessel pruning (for either sex). To understand the mechanisms, we surveyed gene expression and found that Notch-related genes were enriched in ultra-stable retrosplenial cortex. Using endothelial-specific knockdown of Notch1, cerebral angiogenesis was significantly increased along with genes implicated in angiogenesis (Apln, Angpt2, Cdkn1a). Our study shows that angiogenesis is regionally dependent and that manipulations of Notch1 could unlock the angiogenic potential of the mature vasculature.
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Affiliation(s)
- Alejandra Raudales
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Ben Schager
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Dominique Hancock
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Kamal Narayana
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Sorabh Sharma
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Patrick Reeson
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Adam Oshanyk
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Manjinder Cheema
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Jakob Körbelin
- Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Craig E Brown
- Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada; Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
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Salazar-Saura I, Pinilla-Sala M, Megías J, Navarro L, Roselló-Sastre E, San-Miguel T. Pericytes in Glioblastoma: Hidden Regulators of Tumor Vasculature and Therapy Resistance. Cancers (Basel) 2024; 17:15. [PMID: 39796646 PMCID: PMC11718950 DOI: 10.3390/cancers17010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/19/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025] Open
Abstract
Glioblastoma IDH wild type (GB), the most common malignant primary brain tumor, is characterized by rapid proliferation, extensive infiltration into surrounding brain tissue, and significant resistance to current therapies. Median survival is only 15 months despite extensive clinical efforts. The tumor microenvironment (TME) in GB is highly specialized, supporting the tumor's aggressive behavior and its ability to evade conventional treatments. One critical component is the aberrant vascular network that complicates the delivery of chemotherapy across the blood-brain barrier. Antiangiogenic therapies emerged as a promising option but have shown limited efficacy in extending the survival of these patients. Comprehension of the complex vascular network of GB may be a key to overcoming the limitations of current therapies. Pericytes are gaining recognition within the context of the TME. These mural cells are essential for vascular integrity and may contribute to tumor progression and therapeutic resistance. Although their role has been evidenced in other tumors, they remain underexplored in GB. Pericytes are known to respond to tumor hypoxia and interact with vascular endothelia, influencing responses to DNA damage and antiangiogenic treatments. They actively regulate not only angiogenesis but also the different vasculogenic strategies for tumor neovascularization. Additionally, they affect leukocyte trafficking and tumor-associated macrophages. This review aims to integrate the various functions controlled by pericytes to favor deeper investigation into their actionable potential. Pericytes may represent a promising target for novel therapeutic strategies in order to improve patient outcomes.
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Affiliation(s)
- Irene Salazar-Saura
- Pathology Service, Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain; (I.S.-S.); (L.N.); (E.R.-S.)
| | - María Pinilla-Sala
- Research Group on Tumors of the Central Nervous System, Pathology Department, University of Valencia, 46010 Valencia, Spain;
- INCLIVA Foundation, 46010 Valencia, Spain
| | - Javier Megías
- Research Group on Tumors of the Central Nervous System, Pathology Department, University of Valencia, 46010 Valencia, Spain;
- INCLIVA Foundation, 46010 Valencia, Spain
| | - Lara Navarro
- Pathology Service, Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain; (I.S.-S.); (L.N.); (E.R.-S.)
| | - Esther Roselló-Sastre
- Pathology Service, Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain; (I.S.-S.); (L.N.); (E.R.-S.)
| | - Teresa San-Miguel
- Research Group on Tumors of the Central Nervous System, Pathology Department, University of Valencia, 46010 Valencia, Spain;
- INCLIVA Foundation, 46010 Valencia, Spain
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4
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Roesler J, Spitzer D, Jia X, Aasen SN, Sommer K, Roller B, Olshausen N, Hebach NR, Albinger N, Ullrich E, Zhu L, Wang F, Macas J, Forster MT, Steinbach JP, Sevenich L, Devraj K, Thorsen F, Karreman MA, Plate KH, Reiss Y, Harter PN. Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis. Neuro Oncol 2024; 26:2084-2099. [PMID: 38831719 PMCID: PMC11534324 DOI: 10.1093/neuonc/noae094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that are dependent on Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF). METHODS In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and postmortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcomes were analyzed in BM patients. RESULTS Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human BM negatively correlated with survival. CONCLUSIONS Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevents the outgrowth of macrometastases.
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Affiliation(s)
- Jenny Roesler
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Daniel Spitzer
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Xiaoxiong Jia
- Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, China
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin, China
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
- Neurosurgery Department, Tianjin Huanhu Hospital, Tianjin, China
| | - Synnøve Nymark Aasen
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
- Department of Biomedicine, Kristian Gerhard Jebsen Brain Tumour Research Centre, University of Bergen, Bergen, Norway
| | - Kathleen Sommer
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Bastian Roller
- Goethe University, University Hospital, Dr. Senckenberg Institute for Neurooncology, Frankfurt, Germany
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Niels Olshausen
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nils R Hebach
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nawid Albinger
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
- Department of Pediatrics, Experimental Immunology and Cell Therapy, Goethe University, University Hospital, Frankfurt, Germany
| | - Evelyn Ullrich
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
- Department of Pediatrics, Experimental Immunology and Cell Therapy, Goethe University, University Hospital, Frankfurt, Germany
| | - Ling Zhu
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Fan Wang
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Jadranka Macas
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Marie-Therese Forster
- Department of Neurosurgery, Goethe University, University Hospital, Frankfurt, Germany
| | - Joachim P Steinbach
- German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
- Goethe University, University Hospital, Dr. Senckenberg Institute for Neurooncology, Frankfurt, Germany
| | - Lisa Sevenich
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Frankfurt, Germany
- German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
| | - Kavi Devraj
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad, India
| | - Frits Thorsen
- Department of Biomedicine, Molecular Imaging Center, University of Bergen, Bergen, Norway
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China
- Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway
| | - Matthia A Karreman
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Karl H Plate
- German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Yvonne Reiss
- German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
| | - Patrick N Harter
- Center for Neuropathology and Prion Research, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
- German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt, Germany
- Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany
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Zhang J, Li S, Kuang C, Shen Y, Yu H, Chen F, Tang R, Mao S, Lv L, Qi M, Zhang J, Yuan K. CD74 + fibroblasts proliferate upon mechanical stretching to promote angiogenesis in keloids. FASEB J 2024; 38:e70103. [PMID: 39400419 DOI: 10.1096/fj.202401302r] [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: 06/09/2024] [Revised: 09/07/2024] [Accepted: 09/30/2024] [Indexed: 10/15/2024]
Abstract
The healing of human skin wounds is susceptible to perturbation caused by excessive mechanical stretching, resulting in enlarged scars, hypertrophic scars, or even keloids in predisposed individuals. Keloids are fibro-proliferative scar tissues that extend beyond the initial wound boundary, consisting of the actively progressing periphery and the quiescent center. The stretch-associated outgrowth and enhanced angiogenesis are two features of the periphery of keloids. However, which cell population is responsible for transducing the mechanical stimulation to the progression of keloids remains unclear. Herein, through integrative analysis of single-cell RNA sequencing of keloids, we identified CD74+ fibroblasts, a previously unappreciated subset of fibroblasts with pro-angiogenic and stretch-induced proliferative capacities, as a key player in stretch-induced progression of keloids. Immunostaining of keloid cryosections depicted a predominant distribution of CD74+ fibroblasts in the periphery, interacting with the vasculature. In vitro tube formation assays on purified CD74+ fibroblasts ascertained their pro-angiogenic function. BrdU assays revealed that these cells proliferate upon stretching, through PIEZO1-mediated calcium influx and the downstream ERK and AKT signaling. Collectively, our findings propose a model wherein CD74+ fibroblasts serve as pivotal drivers of stretch-induced keloid progression, fueled by their proliferative and pro-angiogenic activities. Targeting the attributes of CD74+ fibroblasts holds promise as a therapeutic strategy for the management of keloids.
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Affiliation(s)
- Jingheng Zhang
- Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuyao Li
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chunmei Kuang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yunfan Shen
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Haibin Yu
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fang Chen
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruijun Tang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Song Mao
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lu Lv
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Min Qi
- Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jianglin Zhang
- Department of Dermatology, Shenzhen People's Hospital, Shenzhen, Guangdong, China
- The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China
- The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Kai Yuan
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
- Furong Laboratory, Central South University, Changsha, Hunan, China
- The Biobank of Xiangya Hospital, Central South University, Changsha, Hunan, China
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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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Sherman JH, Bobak A, Arsiwala T, Lockman P, Aulakh S. Targeting drug resistance in glioblastoma (Review). Int J Oncol 2024; 65:80. [PMID: 38994761 PMCID: PMC11251740 DOI: 10.3892/ijo.2024.5668] [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: 05/21/2022] [Accepted: 05/16/2024] [Indexed: 07/13/2024] Open
Abstract
Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. The current standard of care includes surgery, radiation therapy, temozolomide; and tumor‑treating fields leads to dismal overall survival. There are far limited treatments upon recurrence. Therapies to date are ineffective as a result of several factors, including the presence of the blood‑brain barrier, blood tumor barrier, glioma stem‑like cells and genetic heterogeneity in GBM. In the present review, the potential mechanisms that lead to treatment resistance in GBM and the measures which have been taken so far to attempt to overcome the resistance were discussed. The complex biology of GBM and lack of comprehensive understanding of the development of therapeutic resistance in GBM demands discovery of novel antigens that are targetable and provide effective therapeutic strategies.
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Affiliation(s)
- Jonathan H. Sherman
- Department of Neurosurgery, Rockefeller Neuroscience Institute, West Virginia University, Martinsburg, WV 25401, USA
| | - Adam Bobak
- Department of Biology, Seton Hill University, Greensburg, PA 15601, USA
| | - Tasneem Arsiwala
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA
| | - Paul Lockman
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA
| | - Sonikpreet Aulakh
- Section of Hematology/Oncology, Department of Internal Medicine, West Virginia University, Morgantown, WV 26506, USA
- Department of Neuroscience, West Virginia University, Morgantown, WV 26505, USA
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8
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De Palma M, Hanahan D. Milestones in tumor vascularization and its therapeutic targeting. NATURE CANCER 2024; 5:827-843. [PMID: 38918437 DOI: 10.1038/s43018-024-00780-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 04/22/2024] [Indexed: 06/27/2024]
Abstract
Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future.
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Affiliation(s)
- Michele De Palma
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
| | - Douglas Hanahan
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
- Swiss Cancer Center Léman (SCCL), Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
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9
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Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol 2024; 17:31. [PMID: 38720342 PMCID: PMC11077829 DOI: 10.1186/s13045-024-01544-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
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Affiliation(s)
- Hao Lin
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Chaxian Liu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ankang Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Duanwu Zhang
- Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
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10
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Qiu Y, Che B, Zhang W, Zhang A, Ge J, Du D, Li J, Peng X, Shao J. The ubiquitin-like protein FAT10 in hepatocellular carcinoma cells limits the efficacy of anti-VEGF therapy. J Adv Res 2024; 59:97-109. [PMID: 37328057 PMCID: PMC11081941 DOI: 10.1016/j.jare.2023.06.006] [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: 02/13/2023] [Revised: 06/09/2023] [Accepted: 07/12/2023] [Indexed: 06/18/2023] Open
Abstract
INTRODUCTION The efficacy of anti-vascular endothelial growth factor (VEGF) therapy is limited. However, the key factors involved in limiting the efficacy of anti-VEGF therapy and the underlying mechanisms remain unclear. OBJECTIVES To investigate the effects and mechanisms of human leukocyte antigen F locus-adjacent transcript 10 (FAT10), a ubiquitin-like protein, in limiting the efficacy of anti-VEGF therapy in hepatocellular carcinoma (HCC) cells. METHODS FAT10 was knocked out in HCC cells using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 technology. Bevacizumab (BV), an anti-VEGF monoclonal antibody, was used to evaluate the efficacy of anti-VEGF therapy in vivo. Mechanisms of FAT10 action were assessed by RNA sequencing, glutathione S-transferase pulldown assays and in vivo ubiquitination assays. RESULTS FAT10 accelerated VEGF-independent angiogenesis in HCC cells which limited BV efficacy and BV-aggravated hypoxia and inflammation promoted FAT10 expression. FAT10 overexpression increased levels of proteins involved in several signaling pathways in HCC cells, resulting in upregulation of VEGF and multiple non-VEGF proangiogenic factors. Upregulation of multiple FAT10-mediated non-VEGF signals compensated for the inhibition of VEGF signaling by BV, enhancing VEGF-independent angiogenesis and promoting HCC growth. CONCLUSIONS Our preclinical findings identify FAT10 in HCC cells as a key factor limiting the efficacy of anti-VEGF therapy and elucidate its underlying mechanisms. This study provides new mechanistic insights into the development of antiangiogenic therapies.
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Affiliation(s)
- Yumin Qiu
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
| | - Ben Che
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
| | - Wenming Zhang
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
| | - A.V. Zhang
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
| | - Jin Ge
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
| | - Dongnian Du
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
| | - Jiajuan Li
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
| | | | - Jianghua Shao
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang 330000, China
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11
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Ezaki T, Tanaka T, Tamura R, Ohara K, Yamamoto Y, Takei J, Morimoto Y, Imai R, Kuranai Y, Akasaki Y, Toda M, Murayama Y, Miyake K, Sasaki H. Status of alternative angiogenic pathways in glioblastoma resected under and after bevacizumab treatment. Brain Tumor Pathol 2024; 41:61-72. [PMID: 38619734 PMCID: PMC11052834 DOI: 10.1007/s10014-024-00481-0] [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: 10/20/2023] [Accepted: 03/25/2024] [Indexed: 04/16/2024]
Abstract
Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group (p = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns (p = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.
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Affiliation(s)
- Taketo Ezaki
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Toshihide Tanaka
- Department of Neurosurgery, The Jikei University School, of Medicine Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa-shi, Chiba, 277-8567, Japan.
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan.
| | - Ryota Tamura
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Kentaro Ohara
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Yohei Yamamoto
- Department of Neurosurgery, The Jikei University School of Medicine Daisan Hospital, 4-11-1 Izumi-Motomachi, Komae-Shi, Tokyo, 201-8601, Japan
| | - Jun Takei
- Department of Neurosurgery, The Jikei University School of Medicine Katsushika Medical Center, 6-41-2 Aoto, Katsushika-Ku, Tokyo, 125-8506, Japan
| | - Yukina Morimoto
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Ryotaro Imai
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Yuki Kuranai
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Yasuharu Akasaki
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Masahiro Toda
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Yuichi Murayama
- Department of Neurosurgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Keisuke Miyake
- Department of Neurological Surgery, Faculty of medicine, Kagawa University Graduate School of Medicine, 1750-1 Miki-Choho, Ikenobe, Kita-Gun, Kagawa, 761-0793, Japan
| | - Hikaru Sasaki
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
- Department of Neurosurgery, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa-Shi, Chiba, 272-8513, Japan
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12
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Mohapatra L, Tripathi AS, Mishra D, Yasir M, Maurya RK, Prajapati BG, Alka. Colorectal cancer: understanding of disease. COLORECTAL CANCER 2024:1-27. [DOI: 10.1016/b978-0-443-13870-6.00010-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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13
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Kang N, Fan B, Sun Y, Xue P, Liu Y. Novel specific anti-ESM1 antibodies overcome tumor bevacizumab resistance by suppressing angiogenesis and metastasis. Cancer Sci 2023; 114:4413-4425. [PMID: 37715566 PMCID: PMC10637069 DOI: 10.1111/cas.15939] [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: 03/31/2023] [Revised: 08/07/2023] [Accepted: 08/13/2023] [Indexed: 09/17/2023] Open
Abstract
Suppressing tumors through anti-angiogenesis has been established as an effective clinical treatment strategy. Bevacizumab, a monoclonal antibody, is commonly used in various indications. However, two major challenges limit the long-term efficacy of bevacizumab: drug resistance and side effects. Bevacizumab resistance has been extensively studied at the molecular level, but no drug candidates have been developed for clinical use to overcome this resistance. In a previous study conducted by our team, a major finding was that high expression of ESM1 in bevacizumab-resistant tumors is associated with an unfavorable response to treatment. In particular, an increase in ESM1 expression contributes to heightened lung metastasis and microvascular density, which ultimately decreases the tumor's sensitivity to bevacizumab. In contrast, the silencing of ESM1 results in reduced angiogenesis and suppressed tumor growth in tumors resistant to bevacizumab. We put forward the hypothesis that targeting ESM1 could serve as a therapeutic strategy in overcoming bevacizumab resistance. In this study, a variety of anti-ESM1 antibodies with high affinity to human ESM1 were successfully prepared and characterized. Our in vivo study confirmed the establishment of a bevacizumab-resistant human colorectal cancer model and further demonstrated that the addition of anti-ESM1 monoclonal antibodies to bevacizumab treatment significantly improved tumor response while downregulating DLL4 and MMP9. In conclusion, our study suggests that anti-hESM1 monoclonal antibodies have the potential to alleviate or overcome bevacizumab resistance, thereby providing new strategies and drug candidates for clinical research in the treatment of bevacizumab-resistant colorectal cancer.
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Affiliation(s)
- Nannan Kang
- School of Life Science & TechnologyChina Pharmaceutical UniversityNanjingChina
| | - Buxi Fan
- School of Life Science & TechnologyChina Pharmaceutical UniversityNanjingChina
| | - Yao Sun
- School of Life Science & TechnologyChina Pharmaceutical UniversityNanjingChina
| | - Peilin Xue
- School of Life Science & TechnologyChina Pharmaceutical UniversityNanjingChina
| | - Yu Liu
- School of Life Science & TechnologyChina Pharmaceutical UniversityNanjingChina
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14
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Srivastava R, Dodda M, Zou H, Li X, Hu B. Tumor Niches: Perspectives for Targeted Therapies in Glioblastoma. Antioxid Redox Signal 2023; 39:904-922. [PMID: 37166370 PMCID: PMC10654996 DOI: 10.1089/ars.2022.0187] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 05/12/2023]
Abstract
Significance: Glioblastoma (GBM), the most common and lethal primary brain tumor with a median survival rate of only 15 months and a 5-year survival rate of only 6.8%, remains largely incurable despite the intensive multimodal treatment of surgical resection and radiochemotherapy. Developing effective new therapies is an unmet need for patients with GBM. Recent Advances: Targeted therapies, such as antiangiogenesis therapy and immunotherapy, show great promise in treating GBM based upon increasing knowledge about brain tumor biology. Single-cell transcriptomics reveals the plasticity, heterogeneity, and dynamics of tumor cells during GBM development and progression. Critical Issues: While antiangiogenesis therapy and immunotherapy have been highly effective in some types of cancer, the disappointing results from clinical trials represent continued challenges in applying these treatments to GBM. Molecular and cellular heterogeneity of GBM is developed temporally and spatially, which profoundly contributes to therapeutic resistance and tumor recurrence. Future Directions: Deciphering mechanisms of tumor heterogeneity and mapping tumor niche trajectories and functions will provide a foundation for the development of more effective therapies for GBM patients. In this review, we discuss five different tumor niches and the intercellular and intracellular communications among these niches, including the perivascular, hypoxic, invasive, immunosuppressive, and glioma-stem cell niches. We also highlight the cellular and molecular biology of these niches and discuss potential strategies to target these tumor niches for GBM therapy. Antioxid. Redox Signal. 39, 904-922.
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Affiliation(s)
- Rashmi Srivastava
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- John G. Rangos Sr. Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Meghana Dodda
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- John G. Rangos Sr. Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Han Zou
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- John G. Rangos Sr. Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Xuejun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Changsha, China
| | - Baoli Hu
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- John G. Rangos Sr. Research Center, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Cancer Biology Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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15
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Roos-Mattila M, Kaprio T, Mustonen H, Hagström J, Saharinen P, Haglund C, Seppänen H. The possible dual role of Ang-2 in the prognosis of pancreatic cancer. Sci Rep 2023; 13:18725. [PMID: 37907568 PMCID: PMC10618172 DOI: 10.1038/s41598-023-45194-0] [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: 05/15/2023] [Accepted: 10/17/2023] [Indexed: 11/02/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) features a dense desmoplastic stroma, which raises the intratumoral interstitial pressure leading to vascular collapse and hypoxia, inducing angiogenesis. Vascular growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), increase in PDAC. A high VEGF and a high circulating Ang-2 associate with shorter survival in PDAC. In addition to the circulatory Ang-2, PDAC endothelial and epithelial cells express Ang-2. No correlation between tumor epithelial nor endothelial cell Ang-2 expression and survival has been published. We aimed to examine Ang-2 expression and survival. This study comprised PDAC surgical patients at Helsinki University Hospital in 2000-2013. Ang-2 immunohistochemistry staining was completed on 168 PDAC patient samples. Circulating Ang-2 levels were measured using ELISA in the sera of 196 patients. Ang-2 levels were assessed against clinical data and patient outcomes. A low tumor epithelial Ang-2 expression predicted shorter disease-specific survival (DSS) compared with a high expression (p = 0.003). A high serum Ang-2 associated with shorter DSS compared with a low circulating Ang-2 (p = 0.016). Ang-2 seemingly plays a dual role in PDAC survival. Further studies are needed to determine the mechanisms causing tumor cell Ang-2 expression and its positive association with survival.
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Affiliation(s)
- Matilda Roos-Mattila
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tuomas Kaprio
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Department of Pathology, Haartmaninkatu 3 (PB 21), University of Helsinki, 00014, Helsinki, Finland.
| | - Harri Mustonen
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jaana Hagström
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Pipsa Saharinen
- Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Seppänen
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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16
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Nafe R, Hattingen E. The Spectrum of Molecular Pathways in Gliomas-An Up-to-Date Review. Biomedicines 2023; 11:2281. [PMID: 37626776 PMCID: PMC10452344 DOI: 10.3390/biomedicines11082281] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
During the last 20 years, molecular alterations have gained increasing significance in the diagnosis and biological assessment of tumors. Gliomas represent the largest group of tumors of the central nervous system, and the main aim of this review is to present the current knowledge on molecular pathways and their alterations in gliomas. A wide range of new insights has been gained, including evidence for the involvement of the WNT pathway or the hippo pathway in the pathobiology of gliomas, indicating a broad involvement of different pathways formerly not considered to play a central role in gliomas. Even new aspects of angiogenic, apoptotic, and metabolic pathways are presented, as well as the rapidly growing field of epigenetic processes, including non-coding RNAs. The two major conclusions drawn from the present review are the distinct interconnectivity of the whole spectrum of molecular pathways and the prominent role of non-coding RNAs, especially circular RNAs, in the regulation of specific targets. All these new insights are discussed, even considering the topic of the resistance to therapy of gliomas, along with aspects that are still incompletely understood, like the role of hydroxymethylation, or even ferroptosis, in the pathobiology of gliomas.
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Affiliation(s)
- Reinhold Nafe
- Department of Neuroradiology, Clinics of Johann Wolfgang Goethe-University, Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany;
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17
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Chin SM, Reina G, Chau NDQ, Chabrol T, Wion D, Bouamrani A, Gay E, Nishina Y, Bianco A, Berger F. Functional Graphene for Peritumoral Brain Microenvironment Modulation Therapy in Glioblastoma. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2208227. [PMID: 36732906 DOI: 10.1002/smll.202208227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/09/2023] [Indexed: 05/04/2023]
Abstract
Peritumoral brain invasion is the main target to cure glioblastoma. Chemoradiotherapy and targeted therapies fail to combat peritumoral relapse. Brain inaccessibility and tumor heterogeneity explain this failure, combined with overlooking the peritumor microenvironment. Reduce graphene oxide (rGO) provides a unique opportunity to modulate the local brain microenvironment. Multimodal graphene impacts are reported on glioblastoma cells in vitro but fail when translated in vivo because of low diffusion. This issue is solved by developing a new rGO formulation involving ultramixing during the functionalization with polyethyleneimine (PEI) leading to the formation of highly water-stable rGO-PEI. Wide mice brain diffusion and biocompatibility are demonstrated. Using an invasive GL261 model, an anti-invasive effect is observed. A major unexpected modification of the peritumoral area is also observed with the neutralization of gliosis. In vitro, mechanistic investigations are performed using primary astrocytes and cytokine array. The result suggests that direct contact of rGO-PEIUT neutralizes astrogliosis, decreasing several proinflammatory cytokines that would explain a bystander tumor anti-invasive effect. rGO also significantly downregulates several proinvasive/protumoral cytokines at the tumor cell level. The results open the way to a new microenvironment anti-invasive nanotherapy using a new graphene nanomaterial that is optimized for in vivo brain delivery.
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Affiliation(s)
- Shan Min Chin
- Emmanuel Gay, François Berger, INSERM UMR1205, Brain Tech Lab, Grenoble Alpes University, Grenoble, 38000, France
| | - Giacomo Reina
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - Ngoc Do Quyen Chau
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - Tanguy Chabrol
- Emmanuel Gay, François Berger, INSERM UMR1205, Brain Tech Lab, Grenoble Alpes University, Grenoble, 38000, France
| | - Didier Wion
- Emmanuel Gay, François Berger, INSERM UMR1205, Brain Tech Lab, Grenoble Alpes University, Grenoble, 38000, France
| | - Ali Bouamrani
- Emmanuel Gay, François Berger, INSERM UMR1205, Brain Tech Lab, Grenoble Alpes University, Grenoble, 38000, France
| | - Emmanuel Gay
- Emmanuel Gay, François Berger, INSERM UMR1205, Brain Tech Lab, Grenoble Alpes University, Grenoble, 38000, France
| | - Yuta Nishina
- Graduate School of Natural Science and Technology, Okayama University, Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
- Research Core for Interdisciplinary Sciences, Okayama University, Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
| | - Alberto Bianco
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - François Berger
- Emmanuel Gay, François Berger, INSERM UMR1205, Brain Tech Lab, Grenoble Alpes University, Grenoble, 38000, France
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18
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Erices JI, Bizama C, Niechi I, Uribe D, Rosales A, Fabres K, Navarro-Martínez G, Torres Á, San Martín R, Roa JC, Quezada-Monrás C. Glioblastoma Microenvironment and Invasiveness: New Insights and Therapeutic Targets. Int J Mol Sci 2023; 24:ijms24087047. [PMID: 37108208 PMCID: PMC10139189 DOI: 10.3390/ijms24087047] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 04/29/2023] Open
Abstract
Glioblastoma (GBM) is the most common and malignant primary brain cancer in adults. Without treatment the mean patient survival is approximately 6 months, which can be extended to 15 months with the use of multimodal therapies. The low effectiveness of GBM therapies is mainly due to the tumor infiltration into the healthy brain tissue, which depends on GBM cells' interaction with the tumor microenvironment (TME). The interaction of GBM cells with the TME involves cellular components such as stem-like cells, glia, endothelial cells, and non-cellular components such as the extracellular matrix, enhanced hypoxia, and soluble factors such as adenosine, which promote GBM's invasiveness. However, here we highlight the role of 3D patient-derived glioblastoma organoids cultures as a new platform for study of the modeling of TME and invasiveness. In this review, the mechanisms involved in GBM-microenvironment interaction are described and discussed, proposing potential prognosis biomarkers and new therapeutic targets.
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Affiliation(s)
- José Ignacio Erices
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
- Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Ignacio Niechi
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
- Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Daniel Uribe
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Arnaldo Rosales
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
- Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Karen Fabres
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Giovanna Navarro-Martínez
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
- Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Ángelo Torres
- Escuela de Medicina Veterinaria, Facultad de Recursos Naturales y Medicina Veterinaria, Universidad Santo Tomás, Talca 8370003, Chile
| | - Rody San Martín
- Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Claudia Quezada-Monrás
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
- Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile
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19
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Caverzán MD, Beaugé L, Oliveda PM, Cesca González B, Bühler EM, Ibarra LE. Exploring Monocytes-Macrophages in Immune Microenvironment of Glioblastoma for the Design of Novel Therapeutic Strategies. Brain Sci 2023; 13:brainsci13040542. [PMID: 37190507 DOI: 10.3390/brainsci13040542] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Gliomas are primary malignant brain tumors. These tumors seem to be more and more frequent, not only because of a true increase in their incidence, but also due to the increase in life expectancy of the general population. Among gliomas, malignant gliomas and more specifically glioblastomas (GBM) are a challenge in their diagnosis and treatment. There are few effective therapies for these tumors, and patients with GBM fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the last decade, it is now appreciated that these tumors are composed of numerous distinct tumoral and non-tumoral cell populations, which could each influence the overall tumor biology and response to therapies. Monocytes have been proved to actively participate in tumor growth, giving rise to the support of tumor-associated macrophages (TAMs). In GBM, TAMs represent up to one half of the tumor mass cells, including both infiltrating macrophages and resident brain microglia. Infiltrating macrophages/monocytes constituted ~ 85% of the total TAM population, they have immune functions, and they can release a wide array of growth factors and cytokines in response to those factors produced by tumor and non-tumor cells from the tumor microenvironment (TME). A brief review of the literature shows that this cell population has been increasingly studied in GBM TME to understand its role in tumor progression and therapeutic resistance. Through the knowledge of its biology and protumoral function, the development of therapeutic strategies that employ their recruitment as well as the modulation of their immunological phenotype, and even the eradication of the cell population, can be harnessed for therapeutic benefit. This revision aims to summarize GBM TME and localization in tumor niches with special focus on TAM population, its origin and functions in tumor progression and resistance to conventional and experimental GBM treatments. Moreover, recent advances on the development of TAM cell targeting and new cellular therapeutic strategies based on monocyte/macrophages recruitment to eradicate GBM are discussed as complementary therapeutics.
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20
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Choi BJ, Park MH, Park KH, Han WH, Yoon HJ, Jung HY, Hong JY, Chowdhury MR, Kim KY, Lee J, Song IS, Pang M, Choi MK, Gulbins E, Reichel M, Kornhuber J, Hong CW, Kim C, Kim SH, Schuchman EH, Jin HK, Bae JS. Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease. Nat Commun 2023; 14:1631. [PMID: 36959217 PMCID: PMC10036484 DOI: 10.1038/s41467-023-37316-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 03/10/2023] [Indexed: 03/25/2023] Open
Abstract
Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.
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Affiliation(s)
- Byung Jo Choi
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea
| | - Min Hee Park
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Kang Ho Park
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Wan Hui Han
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Hee Ji Yoon
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Hye Yoon Jung
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Ju Yeon Hong
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Md Riad Chowdhury
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Kyung Yeol Kim
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Jihoon Lee
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea
| | - Im-Sook Song
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea
| | - Minyeong Pang
- College of Pharmacy, Dankook University, Cheon-an, South Korea
| | - Min-Koo Choi
- College of Pharmacy, Dankook University, Cheon-an, South Korea
| | - Erich Gulbins
- Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Martin Reichel
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
| | - Chang-Won Hong
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Changho Kim
- Department of Emergency Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Seung Hyun Kim
- Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea
| | - Edward H Schuchman
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hee Kyung Jin
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea.
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea.
| | - Jae-Sung Bae
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea.
- Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea.
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21
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Zhu X, Fang Y, Chen Y, Chen Y, Hong W, Wei W, Tu J. Interaction of tumor-associated microglia/macrophages and cancer stem cells in glioma. Life Sci 2023; 320:121558. [PMID: 36889666 DOI: 10.1016/j.lfs.2023.121558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023]
Abstract
Glioma is the most common tumor of the primary central nervous system, and its malignant phenotype has been shown to be closely related to glioma stem cells (GSCs). Although temozolomide has significantly improved the therapeutic outcome of glioma with a high penetration rate of the blood-brain barrier, resistance is often present in patients. Moreover, evidence has shown that the crosstalk between GSCs and tumor-associated microglia/macrophages (TAMs) affect the clinical occurrence, growth, and multi-tolerance of chemoradiotherapy in gliomas. Here, we highlight its vital roles in the maintenance of the stemness of GSCs and the ability of GSCs to recruit TAMs to the tumor microenvironment and promote their polarization into tumor-promoting macrophages, hence providing groundwork for future research into new treatment strategies of cancer.
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Affiliation(s)
- Xiangling Zhu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yilong Fang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yizhao Chen
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yu Chen
- Department of Gynecology, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Wenming Hong
- Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Wei
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
| | - Jiajie Tu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
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22
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Tumor Vasculature as an Emerging Pharmacological Target to Promote Anti-Tumor Immunity. Int J Mol Sci 2023; 24:ijms24054422. [PMID: 36901858 PMCID: PMC10002465 DOI: 10.3390/ijms24054422] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 02/25/2023] Open
Abstract
Tumor vasculature abnormality creates a microenvironment that is not suitable for anti-tumor immune response and thereby induces resistance to immunotherapy. Remodeling of dysfunctional tumor blood vessels by anti-angiogenic approaches, known as vascular normalization, reshapes the tumor microenvironment toward an immune-favorable one and improves the effectiveness of immunotherapy. The tumor vasculature serves as a potential pharmacological target with the capacity of promoting an anti-tumor immune response. In this review, the molecular mechanisms involved in tumor vascular microenvironment-modulated immune reactions are summarized. In addition, the evidence of pre-clinical and clinical studies for the combined targeting of pro-angiogenic signaling and immune checkpoint molecules with therapeutic potential are highlighted. The heterogeneity of endothelial cells in tumors that regulate tissue-specific immune responses is also discussed. The crosstalk between tumor endothelial cells and immune cells in individual tissues is postulated to have a unique molecular signature and may be considered as a potential target for the development of new immunotherapeutic approaches.
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23
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Tang YL, Li DD, Duan JY, Sheng LM, Wang X. Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments. World J Gastroenterol 2023; 29:926-948. [PMID: 36844139 PMCID: PMC9950860 DOI: 10.3748/wjg.v29.i6.926] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/24/2022] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.
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Affiliation(s)
- Yuan-Ling Tang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dan-Dan Li
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yu Duan
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei-Ming Sheng
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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24
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Steidl E, Filipski K, Hattingen E, Steinbach JP, Maurer GD. Longitudinal study on MRI and neuropathological findings: Neither DSC-perfusion derived rCBVmax nor vessel densities correlate between newly diagnosed and progressive glioblastoma. PLoS One 2023; 18:e0274400. [PMID: 36724187 PMCID: PMC9891512 DOI: 10.1371/journal.pone.0274400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/26/2022] [Indexed: 02/02/2023] Open
Abstract
INTRODUCTION When evaluating MRIs for glioblastoma progression, previous scans are usually included into the review. Nowadays dynamic susceptibility contrast (DSC)-perfusion is an essential component in MR-diagnostics of gliomas, since the extent of hyperperfusion upon first diagnosis correlates with gene expression and survival. We aimed to investigate if this initial perfusion signature also characterizes the glioblastoma at time of progression. If so, DSC-perfusion data from the initial diagnosis could be of diagnostic benefit in follow-up assessments. METHODS We retrospectively identified 65 patients with isocitrate dehydrogenase wildtype glioblastoma who had received technically identical DSC-perfusion measurements at initial diagnosis and at time of first progression. We determined maximum relative cerebral blood volume values (rCBVmax) by standardized re-evaluation of the data including leakage correction. In addition, the corresponding tissue samples from 24 patients were examined histologically for the maximum vessel density within the tumor. Differences (paired t-test/ Wilcoxon matched pairs test) and correlations (Spearman) between the measurements at both timepoints were calculated. RESULTS The rCBVmax was consistently lower at time of progression compared to rCBVmax at time of first diagnosis (p < .001). There was no correlation between the rCBVmax values at both timepoints (r = .12). These findings were reflected in the histological examination, with a lower vessel density in progressive glioblastoma (p = .01) and no correlation between the two timepoints (r = -.07). CONCLUSION Our results suggest that the extent of hyperperfusion in glioblastoma at first diagnosis is not a sustaining tumor characteristic. Hence, the rCBVmax at initial diagnosis should be disregarded when reviewing MRIs for glioblastoma progression.
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Affiliation(s)
- Eike Steidl
- Institute of Neuroradiology, Goethe University Hospital, Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- * E-mail:
| | - Katharina Filipski
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Neurology (Edinger Institute), Goethe University Hospital, Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
| | - Elke Hattingen
- Institute of Neuroradiology, Goethe University Hospital, Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
| | - Joachim P. Steinbach
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
- Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt am Main, Germany
| | - Gabriele D. Maurer
- Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt am Main, Germany
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25
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Lee E, Lee EA, Kong E, Chon H, Llaiqui-Condori M, Park CH, Park BY, Kang NR, Yoo JS, Lee HS, Kim HS, Park SH, Choi SW, Vestweber D, Lee JH, Kim P, Lee WS, Kim I. An agonistic anti-Tie2 antibody suppresses the normal-to-tumor vascular transition in the glioblastoma invasion zone. Exp Mol Med 2023; 55:470-484. [PMID: 36828931 PMCID: PMC9981882 DOI: 10.1038/s12276-023-00939-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 12/05/2022] [Accepted: 12/08/2022] [Indexed: 02/26/2023] Open
Abstract
Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in the invasion-associated vascular transition. As angiopoietin-2 (ANGPT2) was expressed in only a portion of the central tumor vessels, we developed a ligand-independent tunica interna endothelial cell kinase 2 (Tie2)-activating antibody that can result in Tie2 phosphorylation in vivo. This agonistic anti-Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to the effects of VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition is spatiotemporally associated with GBM invasion and may be controlled by Tie2 activation via a novel mechanism of action.
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Affiliation(s)
- Eunhyeong Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Eun-Ah Lee
- R&D Center, PharmAbcine Inc., Daejeon, 34047, Republic of Korea
| | - Eunji Kong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Haemin Chon
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Melissa Llaiqui-Condori
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Cheon Ho Park
- R&D Center, PharmAbcine Inc., Daejeon, 34047, Republic of Korea
| | - Beom Yong Park
- R&D Center, PharmAbcine Inc., Daejeon, 34047, Republic of Korea
| | - Nu Ri Kang
- R&D Center, PharmAbcine Inc., Daejeon, 34047, Republic of Korea
| | - Jin-San Yoo
- R&D Center, PharmAbcine Inc., Daejeon, 34047, Republic of Korea
| | - Hyun-Soo Lee
- Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Hyung-Seok Kim
- Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, 61463, Republic of Korea
| | - Sung-Hong Park
- Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Seung-Won Choi
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University, Seoul, 06351, Republic of Korea
| | - Dietmar Vestweber
- Max Planck Institute for Molecular Biomedicine, D-48149, Muenster, Germany
| | - Jeong Ho Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.,BioMedical Research Center, KAIST, Daejeon, 34141, Republic of Korea.,SoVarGen, Inc., Daejeon, 34051, Republic of Korea
| | - Pilhan Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.,Graduate School of Nanoscience and Technology, Daejeon, 34141, Republic of Korea.,KI for Health Science and Technology, KAIST, Daejeon, 34141, Republic of Korea
| | - Weon Sup Lee
- R&D Center, PharmAbcine Inc., Daejeon, 34047, Republic of Korea.
| | - Injune Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea. .,BioMedical Research Center, KAIST, Daejeon, 34141, Republic of Korea.
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26
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Yang Z, Suda G, Maehara O, Ohara M, Yoda T, Sasaki T, Kohya R, Yoshida S, Hosoda S, Tokuchi Y, Kitagataya T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Ogawa K, Ohnishi S, Sakamoto N. Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:593. [PMID: 36765554 PMCID: PMC9913372 DOI: 10.3390/cancers15030593] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/10/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies.
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Grants
- JP22fk0310501, JP22fk0210072, JP22fk0310518, JP22fk0210103, JP22fk0210113, JP22fk0210064, JP22fk0210066, JP22fk0210104, JP22fk0210111, JP22fk0210112, JP22fk0310524, and JP22fk0210067 Japan Agency for Medical Research and Development
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Affiliation(s)
- Zijian Yang
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Osamu Maehara
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 001-0021, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Tomoka Yoda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Takashi Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Risako Kohya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 001-0021, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 001-0021, Japan
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27
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Reiss Y, Bauer S, David B, Devraj K, Fidan E, Hattingen E, Liebner S, Melzer N, Meuth SG, Rosenow F, Rüber T, Willems LM, Plate KH. The neurovasculature as a target in temporal lobe epilepsy. Brain Pathol 2023; 33:e13147. [PMID: 36599709 PMCID: PMC10041171 DOI: 10.1111/bpa.13147] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
The blood-brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target.
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Affiliation(s)
- Yvonne Reiss
- Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt, Germany.,Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany
| | - Sebastian Bauer
- Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany.,Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe University, Frankfurt, Germany
| | - Bastian David
- Department of Epileptology, University Hospital Bonn, Bonn, Germany
| | - Kavi Devraj
- Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt, Germany.,Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany
| | - Elif Fidan
- Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt, Germany.,Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany
| | - Elke Hattingen
- Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany.,Institute of Neuroradiology, Center of Neurology and Neurosurgery, University Hospital, Goethe University, Frankfurt, Germany
| | - Stefan Liebner
- Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt, Germany.,Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany
| | - Nico Melzer
- Department of Neurology, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany
| | - Sven G Meuth
- Department of Neurology, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany
| | - Felix Rosenow
- Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany.,Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe University, Frankfurt, Germany
| | - Theodor Rüber
- Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany.,Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe University, Frankfurt, Germany.,Department of Epileptology, University Hospital Bonn, Bonn, Germany
| | - Laurent M Willems
- Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany.,Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe University, Frankfurt, Germany
| | - Karl H Plate
- Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt, Germany.,Center for Personalized Translational Epilepsy Research (CePTER), University Hospital, Goethe University, Frankfurt, Germany
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28
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Lehmann F, Potthoff AL, Borger V, Heimann M, Ehrentraut SF, Schaub C, Putensen C, Weller J, Bode C, Vatter H, Herrlinger U, Schuss P, Schäfer N, Schneider M. Unplanned intensive care unit readmission after surgical treatment in patients with newly diagnosed glioblastoma - forfeiture of surgically achieved advantages? Neurosurg Rev 2023; 46:30. [PMID: 36593389 PMCID: PMC9807543 DOI: 10.1007/s10143-022-01938-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/15/2022] [Accepted: 12/24/2022] [Indexed: 01/04/2023]
Abstract
Postoperative intensive care unit (ICU) monitoring is an established option to ensure patient safety after resection of newly diagnosed glioblastoma. In contrast, secondary unplanned ICU readmission following complicating events during the initial postoperative course might be associated with severe morbidity and impair initially intended surgical benefit. In the present study, we assessed the prognostic impact of secondary ICU readmission and aimed to identify preoperatively ascertainable risk factors for the development of such adverse events in patients treated surgically for newly diagnosed glioblastoma. Between 2013 and 2018, 240 patients were surgically treated for newly diagnosed glioblastoma at the authors' neuro-oncological center. Secondary ICU readmission was defined as any unplanned admission to the ICU during initial hospital stay. A multivariable logistic regression analysis was performed to identify preoperatively measurable risk factors for unplanned ICU readmission. Nineteen of 240 glioblastoma patients (8%) were readmitted to the ICU. Median overall survival of patients with unplanned ICU readmission was 9 months compared to 17 months for patients without secondary ICU readmission (p=0.008). Multivariable analysis identified "preoperative administration of dexamethasone > 7 days" (p=0.002) as a significant and independent predictor of secondary unplanned ICU admission. Secondary ICU readmission following surgery for newly diagnosed glioblastoma is significantly associated with poor survival and thus may negate surgically achieved prerequisites for further treatment. This underlines the indispensability of precise patient selection as well as the importance of further scientific debate on these highly relevant aspects for patient safety.
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Affiliation(s)
- Felix Lehmann
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
| | | | - Valeri Borger
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
| | - Muriel Heimann
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
| | - Stefan Felix Ehrentraut
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Christina Schaub
- Division of Clinical Neuro-Oncology, Department of Neurology, University Hospital Bonn, Bonn, Germany
| | - Christian Putensen
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Johannes Weller
- Division of Clinical Neuro-Oncology, Department of Neurology, University Hospital Bonn, Bonn, Germany
| | - Christian Bode
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Hartmut Vatter
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
| | - Ulrich Herrlinger
- Division of Clinical Neuro-Oncology, Department of Neurology, University Hospital Bonn, Bonn, Germany
| | - Patrick Schuss
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
- Department of Neurosurgery, BG Klinikum Unfallkrankenhaus Berlin gGmbH, Berlin, Germany
| | - Niklas Schäfer
- Division of Clinical Neuro-Oncology, Department of Neurology, University Hospital Bonn, Bonn, Germany
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29
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Anagnostakis F, Piperi C. Targeting Options of Tumor-Associated Macrophages (TAM) Activity in Gliomas. Curr Neuropharmacol 2023; 21:457-470. [PMID: 35048810 PMCID: PMC10207914 DOI: 10.2174/1570159x20666220120120203] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/10/2021] [Accepted: 01/16/2022] [Indexed: 11/22/2022] Open
Abstract
Tumor-associated macrophages (TAMs), the most plastic cells of the hematopoietic system, exhibit increased tumor-infiltrating properties and functional heterogeneity depending on tumor type and associated microenvironment. TAMs constitute a major cell type of cancer-related inflammation, commonly enhancing tumor growth. They are profoundly involved in glioma pathogenesis, contributing to many cancer hallmarks such as angiogenesis, survival, metastasis, and immunosuppression. Efficient targeting of TAMs presents a promising approach to tackle glioma progression. Several targeting options involve chemokine signaling axes inhibitors and antibodies, antiangiogenic factors, immunomodulatory molecules, surface immunoglobulins blockers, receptor and transcription factor inhibitors, as well as microRNAs (miRNAs), administered either as standalone or in combination with other conventional therapies. Herein, we provide a critical overview of current therapeutic approaches targeting TAMs in gliomas with the promising outcome.
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Affiliation(s)
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527Athens, Greece
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30
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Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC. Life (Basel) 2022; 12:life12122092. [PMID: 36556457 PMCID: PMC9786126 DOI: 10.3390/life12122092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/29/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
Angiopoietin-2 (Ang-2) has been implicated in the development of several types of cancer, including lung malignancy. In the present study, we examined the impact of Ang-2 serum concentration on the development, dissemination, and 5-year overall survival of NSCLC and SCLC. A total of 99 patients with lung cancer were tested. The OS of NSCLC and SCLC patients was estimated using Kaplan−Meier curves and compared through log-rank test. The median serum level of Ang-2 at baseline in both NSCLC and SCLC patients was significantly higher than that of controls (p < 0.0001). The Ang-2 serum concentration was not related to metastasis, neither in NSCLC nor in SCLC cases. The OS was found to be significantly shorter for stage IIIβ NSCLC patients with a high baseline Ang-2 serum concentration (p = 0.012), while Cox regression analysis showed that Ang-2 is a significant independent factor for poor prognosis for stage IIIβ NSCLC (hazard ratio = 2.97, 95% CI: 1.05−8.40, p = 0.04). The concentration of Ang-2 has no impact on the prognosis of SCLC. Ang-2 could be considered as a significant molecular marker that enables the prediction of NSCLC and SCLC development, and is involved in the poor prognosis of stage IIIβ NSCLC.
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31
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Wei J, Yang Y, Wang G, Liu M. Current landscape and future directions of bispecific antibodies in cancer immunotherapy. Front Immunol 2022; 13:1035276. [PMID: 36389699 PMCID: PMC9650279 DOI: 10.3389/fimmu.2022.1035276] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/14/2022] [Indexed: 07/31/2023] Open
Abstract
Recent advances in cancer immunotherapy using monoclonal antibodies have dramatically revolutionized the therapeutic strategy against advanced malignancies, inspiring the exploration of various types of therapeutic antibodies. Bispecific antibodies (BsAbs) are recombinant molecules containing two different antigens or epitopes identifying binding domains. Bispecific antibody-based tumor immunotherapy has gained broad potential in preclinical and clinical investigations in a variety of tumor types following regulatory approval of newly developed technologies involving bispecific and multispecific antibodies. Meanwhile, a series of challenges such as antibody immunogenicity, tumor heterogeneity, low response rate, treatment resistance, and systemic adverse effects hinder the application of BsAbs. In this review, we provide insights into the various architecture of BsAbs, focus on BsAbs' alternative different mechanisms of action and clinical progression, and discuss relevant approaches to overcome existing challenges in BsAbs clinical application.
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Affiliation(s)
- Jing Wei
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yueyao Yang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Gang Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Ming Liu
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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32
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Ghochani Y, Muthukrishnan SD, Sohrabi A, Kawaguchi R, Condro MC, Bastola S, Gao F, Qin Y, Mottahedeh J, Iruela-Arispe ML, Rao N, Laks DR, Liau LM, Mathern GW, Goldman SA, Carmichael ST, Nakano I, Coppola G, Seidlits SK, Kornblum HI. A molecular interactome of the glioblastoma perivascular niche reveals integrin binding sialoprotein as a mediator of tumor cell migration. Cell Rep 2022; 41:111511. [PMID: 36261010 PMCID: PMC9642966 DOI: 10.1016/j.celrep.2022.111511] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 06/22/2022] [Accepted: 09/26/2022] [Indexed: 12/01/2022] Open
Abstract
Glioblastoma (GBM) is characterized by extensive microvascular hyperproliferation. In addition to supplying blood to the tumor, GBM vessels also provide trophic support to glioma cells and serve as conduits for migration into the surrounding brain, promoting recurrence. Here, we enrich CD31-expressing glioma vascular cells (GVCs) and A2B5-expressing glioma tumor cells (GTCs) from primary GBM and use RNA sequencing to create a comprehensive molecular interaction map of the secreted and extracellular factors elaborated by GVCs that can interact with receptors and membrane molecules on GTCs. To validate our findings, we utilize functional assays, including a hydrogel-based migration assay and in vivo mouse models to demonstrate that one identified factor, the little-studied integrin binding sialoprotein (IBSP), enhances tumor growth and promotes the migration of GTCs along the vasculature. This perivascular niche interactome will serve as a resource to the research community in defining the potential functions of the GBM vasculature.
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Affiliation(s)
- Yasmin Ghochani
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Sree Deepthi Muthukrishnan
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Alireza Sohrabi
- Department of Bioengineering, UCLA, 410 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Riki Kawaguchi
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Michael C Condro
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Soniya Bastola
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, 410 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Fuying Gao
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Yue Qin
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Jack Mottahedeh
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - M Luisa Iruela-Arispe
- Department of Cell and Developmental Biology, Northwestern University, 303 E. Superior St. SQBRC 8-300, Chicago, IL 60611, USA
| | - Nagesh Rao
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Dan R Laks
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Voyager Therapeutics, 64 Sidney St., Cambridge, MA 02139, USA
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Gary W Mathern
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Department of Neurosurgery, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center and University of Copenhagen Faculty of Medical Sciences, 601 Elmwood Ave, Box 645, Rochester, NY 14642, USA
| | - S Thomas Carmichael
- Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Ichiro Nakano
- Research and Development Center for Precision Medicine, Tsukuba University, Tsukuba, Japan
| | - Giovanni Coppola
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
| | - Stephanie K Seidlits
- Department of Bioengineering, UCLA, 410 Westwood Plaza, Los Angeles, CA 90095, USA.
| | - Harley I Kornblum
- Department of Psychiatry and the Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Departments of Pediatrics and Pharmacology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
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33
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Design, construction and in vivo functional assessment of a hinge truncated sFLT01. Gene Ther 2022; 30:347-361. [PMID: 36114375 DOI: 10.1038/s41434-022-00362-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 08/05/2022] [Accepted: 08/26/2022] [Indexed: 11/08/2022]
Abstract
Gene therapy for the treatment of ocular neovascularization has reached clinical trial phases. The AAV2-sFLT01 construct was already evaluated in a phase 1 open-label trial administered intravitreally to patients with advanced neovascular age-related macular degeneration. SFLT01 protein functions by binding to VEGF and PlGF molecules and inhibiting their activities simultaneously. It consists of human VEGFR1/Flt-1 (hVEGFR1), a polyglycine linker, and the Fc region of human IgG1. The IgG1 upper hinge region of the sFLT01 molecule makes it vulnerable to radical attacks and prone to causing immune reactions. This study pursued two goals: (i) minimizing the immunogenicity and vulnerability of the molecule by designing a truncated molecule called htsFLT01 (hinge truncated sFLT01) that lacked the IgG1 upper hinge and lacked 2 amino acids from the core hinge region; and (ii) investigating the structural and functional properties of the aforesaid chimeric molecule at different levels (in silico, in vitro, and in vivo). Molecular dynamics simulations and molecular mechanics energies combined with Poisson-Boltzmann and surface area continuum solvation calculations revealed comparable free energy of binding and binding affinity for sFLT01 and htsFLT01 to their cognate ligands. Conditioned media from human retinal pigment epithelial (hRPE) cells that expressed htsFLT01 significantly reduced tube formation in HUVECs. The AAV2-htsFLT01 virus suppressed vascular development in the eyes of newborn mice. The htsFLT01 gene construct is a novel anti-angiogenic tool with promising improvements compared to existing treatments.
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34
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Sanati M, Afshari AR, Amini J, Mollazadeh H, Jamialahmadi T, Sahebkar A. Targeting angiogenesis in gliomas: Potential role of phytochemicals. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105192] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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35
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Luo X, Zou W, Wei Z, Yu S, Zhao Y, Wu Y, Wang A, Lu Y. Inducing vascular normalization: A promising strategy for immunotherapy. Int Immunopharmacol 2022; 112:109167. [PMID: 36037653 DOI: 10.1016/j.intimp.2022.109167] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/12/2022] [Accepted: 08/12/2022] [Indexed: 11/30/2022]
Abstract
In solid tumors, the vasculature is highly abnormal in structure and function, resulting in the formation of an immunosuppressive tumor microenvironment by limiting immune cells infiltration into tumors. Vascular normalization is receiving much attention as an alternative strategy to anti-angiogenic therapy, and its potential therapeutic targets include signaling pathways, angiogenesis-related genes, and metabolic pathways. Endothelial cells play an important role in the formation of blood vessel structure and function, and their metabolic processes drive blood vessel sprouting in parallel with the control of genetic signals in cancer. The feedback loop between vascular normalization and immunotherapy has been discussed extensively in many reviews. In this review, we summarize the impact of aberrant tumor vascular structure and function on drug delivery, metastasis, and anti-tumor immune responses. In addition, we present evidences for the mutual regulation of immune vasculature. Based on the importance of endothelial metabolism in controlling angiogenesis, we elucidate the crosstalk between endothelial cells and immune cells from the perspective of metabolic pathways and propose that targeting abnormal endothelial metabolism to achieve vascular normalization can be an alternative strategy for cancer treatment, which provides a new theoretical basis for future research on the combination of vascular normalization and immunotherapy.
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Affiliation(s)
- Xin Luo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Zou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhonghong Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Suyun Yu
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yang Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yuanyuan Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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36
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Liu N, Liu M, Fu S, Wang J, Tang H, Isah AD, Chen D, Wang X. Ang2-Targeted Combination Therapy for Cancer Treatment. Front Immunol 2022; 13:949553. [PMID: 35874764 PMCID: PMC9305611 DOI: 10.3389/fimmu.2022.949553] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/13/2022] [Indexed: 11/21/2022] Open
Abstract
Angiopoietin-2 (Ang2), a member of the angiopoietin family, is widely involved in the process of vascular physiology, bone physiology, adipose tissue physiology and the occurrence and development of inflammation, cardiac hypertrophy, rheumatoid, tumor and other diseases under pathological conditions. Proliferation and metastasis of cancer largely depend on angiogenesis. Therefore, anti-angiogenesis has become the target of tumor therapy. Due to the Ang2 plays a key role in promoting angiogenesis and stability in vascular physiology, the imbalance of its expression is an important condition for the occurrence and development of cancer. It has been proved that blocking Ang2 can inhibit the growth, invasion and metastasis of cancer cells. In recent years, research has been constantly supplemented. We focus on the mechanisms that regulate the expression of Ang2 mRNA and protein levels in different cancers, contributing to a better understanding of how Ang2 exerts different effects in different cancers and stages, as well as facilitating more specific targeting of relevant molecules in cancer therapy. At the same time, the importance of Ang2 in cancer growth, metastasis, prognosis and combination therapy is pointed out. And finally, we will discuss the current investigations and future challenges of combining Ang2 inhibition with chemotherapy, immunotherapy, and radiotherapy to increase its efficacy in cancer patients. This review provides a theoretical reference for the development of new targets and effective combination therapy strategies for cancer treatment in the future.
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Affiliation(s)
| | | | | | | | | | | | - Deyu Chen
- *Correspondence: Xu wang, ; Deyu Chen,
| | - Xu Wang
- *Correspondence: Xu wang, ; Deyu Chen,
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37
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Thakur A, Faujdar C, Sharma R, Sharma S, Malik B, Nepali K, Liou JP. Glioblastoma: Current Status, Emerging Targets, and Recent Advances. J Med Chem 2022; 65:8596-8685. [PMID: 35786935 PMCID: PMC9297300 DOI: 10.1021/acs.jmedchem.1c01946] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
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Glioblastoma (GBM) is a highly malignant
brain tumor characterized
by a heterogeneous population of genetically unstable and highly infiltrative
cells that are resistant to chemotherapy. Although substantial efforts
have been invested in the field of anti-GBM drug discovery in the
past decade, success has primarily been confined to the preclinical
level, and clinical studies have often been hampered due to efficacy-,
selectivity-, or physicochemical property-related issues. Thus, expansion
of the list of molecular targets coupled with a pragmatic design of
new small-molecule inhibitors with central nervous system (CNS)-penetrating
ability is required to steer the wheels of anti-GBM drug discovery
endeavors. This Perspective presents various aspects of drug discovery
(challenges in GBM drug discovery and delivery, therapeutic targets,
and agents under clinical investigation). The comprehensively covered
sections include the recent medicinal chemistry campaigns embarked
upon to validate the potential of numerous enzymes/proteins/receptors
as therapeutic targets in GBM.
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Affiliation(s)
- Amandeep Thakur
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Chetna Faujdar
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201307, India
| | - Ram Sharma
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Sachin Sharma
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Basant Malik
- Department of Sterile Product Development, Research and Development-Unit 2, Jubiliant Generics Ltd., Noida 201301, India
| | - Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Jing Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
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Huang M, Lin Y, Wang C, Deng L, Chen M, Assaraf YG, Chen ZS, Ye W, Zhang D. New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects. Drug Resist Updat 2022; 64:100849. [PMID: 35842983 DOI: 10.1016/j.drup.2022.100849] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival benefits to many cancer patients, resistance to antiangiogenic drugs frequently occurs during clinical treatment, leading to poor outcomes and treatment failure. Cumulative evidence has demonstrated that the intricate interplay among tumor cells, bone marrow-derived cells, and local stromal cells critically allows for tumor escape from antiangiogenic therapy. Currently, drug resistance has become the main challenge that hinders the therapeutic efficacies of antiangiogenic therapy. In this review, we describe and summarize the cellular and molecular mechanisms conferring tumor drug resistance to antiangiogenic therapy, which was predominantly associated with redundancy in angiogenic signaling molecules (e.g., VEGFs, GM-CSF, G-CSF, and IL17), alterations in biological processes of tumor cells (e.g., tumor invasiveness and metastasis, stemness, autophagy, metabolic reprogramming, vessel co-option, and vasculogenic mimicry), increased recruitment of bone marrow-derived cells (e.g., myeloid-derived suppressive cells, tumor-associated macrophages, and tumor-associated neutrophils), and changes in the biological functions and features of local stromal cells (e.g., pericytes, cancer-associated fibroblasts, and endothelial cells). We also review potential biomarkers to predict the response to antiangiogenic therapy in cancer patients, which mainly consist of imaging biomarkers, cellular and extracellular proteins, a certain type of bone marrow-derived cells, local stromal cell content (e.g., pericyte coverage) as well as serum or plasma biomarkers (e.g., non-coding RNAs). Finally, we highlight the recent advances in combination strategies with the aim of enhancing the response to antiangiogenic therapy in cancer patients and mouse models. This review introduces a comprehensive understanding of the mechanisms and biomarkers associated with the evasion of antiangiogenic therapy in cancer, providing an outlook for developing more effective approaches to promote the therapeutic efficacy of antiangiogenic therapy.
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Affiliation(s)
- Maohua Huang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China
| | - Yuning Lin
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Chenran Wang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Lijuan Deng
- Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Minfeng Chen
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Institute for Biotechnology, St. John's University, NY 11439, USA.
| | - Wencai Ye
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
| | - Dongmei Zhang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
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Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities. Cancers (Basel) 2022; 14:cancers14051319. [PMID: 35267626 PMCID: PMC8909866 DOI: 10.3390/cancers14051319] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Macrophages are a specialized immune cell type found in both invertebrates and vertebrates. Versatile in functionality, macrophages carry out important tasks such as cleaning cellular debris in healthy tissues and mounting immune responses during infection. In many cancer types, macrophages make up a significant portion of tumor tissue, and these are aptly called tumor-associated macrophages. In gliomas, a group of primary brain tumors, these macrophages are found in very high frequency. Tumor-associated macrophages can promote glioma development and influence the outcome of various therapeutic regimens. At the same time, these cells provide various potential points of intervention for therapeutic approaches in glioma patients. The significance of tumor-associated macrophages in the glioma microenvironment and potential therapeutic targets are the focus of this review. Abstract Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, pose challenges towards developing effective treatments. The glioma microenvironment, in addition, is also thought to play a critical role during tumor development and treatment course. Unlike most other solid tumors, the glioma microenvironment is dominated by macrophages and microglia—collectively known as tumor-associated macrophages (TAMs). TAMs, like their homeostatic counterparts, are plastic in nature and can polarize to either pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the glioma microenvironment, which fosters tumor development, contributes to tumor aggressiveness and recurrence and, very importantly, impedes the therapeutic effect of various treatment regimens. However, through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state which is of great therapeutic interest. In this review, we will discuss various aspects of TAMs in the context of glioma. The focus will be on the basic biology of TAMs in the central nervous system (CNS), potential biomarkers, critical evaluation of model systems for studying TAMs and finally, special attention will be given to the potential targeted therapeutic options that involve the TAM compartment in gliomas.
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Jain S, Chalif EJ, Aghi MK. Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma. Front Oncol 2022; 11:812916. [PMID: 35096619 PMCID: PMC8790087 DOI: 10.3389/fonc.2021.812916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/17/2021] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.
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Affiliation(s)
- Saket Jain
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Eric J Chalif
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Manish K Aghi
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
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Zhao P, Anami Y, Gao P, Fan X, Li L, Tsuchikama K, Zhang N, An Z. Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model. MAbs 2022; 14:2057269. [PMID: 35388745 PMCID: PMC8993059 DOI: 10.1080/19420862.2022.2057269] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is a common and aggressive brain cancer that accounts for 60% of adult brain tumors. Anti-angiogenesis therapy is an attractive option due to the high vasculature density of GBM. However, the best-known anti-angiogenic therapeutics, bevacizumab, and aflibercept, have failed to show significant benefits in GBM patients. One of the reasons is the limited brain penetration of antibody-based therapies due to existence of the blood-brain barrier (BBB), which is further strengthened by the blood vessel normalization effects induced by anti-angiogenic therapies. To investigate if increased drug concentration in the brain by transferrin receptor (TfR)-mediated delivery across the BBB can enhance efficacy of anti-angiogenic antibody therapies, we first identified an antibody that binds to the apical domain of the mouse TfR and does not compete with the natural ligand transferrin (Tf) binding to TfR. Then, we engineered two bispecific antibodies fusing a vascular endothelial growth factor (VEGF)-Trap with the TfR-targeting antibody. Characterization of the two bispecific formats using multiple in vitro assays, which include endocytosis, cell surface and whole-cell TfR levels, human umbilical vein endothelial cell growth inhibition, and binding affinity, demonstrated that the VEGF-Trap fused with a monovalent αTfR (VEGF-Trap/moAb4) has desirable endocytosis without the induction of TfR degradation. Peripherally administered VEGF-Trap/moAb4 improved the brain concentration of VEGF-Trap by more than 10-fold in mice. The distribution of VEGF-Trap/moAb4 was validated to be in the brain parenchyma, indicating the molecule was not trapped inside the vasculature. Moreover, improved VEGF-Trap brain distribution significantly inhibited the angiogenesis of U-87 MG GBM tumors in a mouse model.
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Affiliation(s)
- Peng Zhao
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Yasuaki Anami
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Peng Gao
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Xuejun Fan
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Leike Li
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Kyoji Tsuchikama
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Ningyan Zhang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Zhiqiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USA
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Izadpanah A, Daneshimehr F, Willingham K, Barabadi Z, Braun SE, Dumont A, Mostany R, Chandrasekar B, Alt EU, Izadpanah R. Targeting TRAF3IP2 inhibits angiogenesis in glioblastoma. Front Oncol 2022; 12:893820. [PMID: 36046049 PMCID: PMC9421153 DOI: 10.3389/fonc.2022.893820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/21/2022] [Indexed: 11/25/2022] Open
Abstract
Increased vascularization, also known as neoangiogenesis, plays a major role in many cancers, including glioblastoma multiforme (GBM), by contributing to their aggressive growth and metastasis. Although anti-angiogenic therapies provide some clinical improvement, they fail to significantly improve the overall survival of GBM patients. Since various pro-angiogenic mediators drive GBM, we hypothesized that identifying targetable genes that broadly inhibit multiple pro-angiogenic mediators will significantly promote favorable outcomes. Here, we identified TRAF3IP2 (TRAF3-interacting protein 2) as a critical regulator of angiogenesis in GBM. We demonstrated that knockdown of TRAF3IP2 in an intracranial model of GBM significantly reduces vascularization. Targeting TRAF3IP2 significantly downregulated VEGF, IL6, ANGPT2, IL8, FZGF2, PGF, IL1β, EGF, PDGFRB, and VEGFR2 expression in residual tumors. Our data also indicate that exogenous addition of VEGF partially restores angiogenesis by TRAF3IP2-silenced cells, suggesting that TRAF3IP2 promotes angiogenesis through VEGF- and non-VEGF-dependent mechanisms. These results indicate the anti-angiogenic and anti-tumorigenic potential of targeting TRAF3IP2 in GBM, a deadly cancer with limited treatment options.
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Affiliation(s)
- Amin Izadpanah
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, United States
| | - Fatemeh Daneshimehr
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, United States
| | - Kurtis Willingham
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, United States
| | - Zahra Barabadi
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, United States
| | - Stephen E. Braun
- Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, LA, United States
| | - Aaron Dumont
- Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA, United States
| | - Ricardo Mostany
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Bysani Chandrasekar
- Department of Medicine, University of Missouri School of Medicine and Harry S. Truman Veterans Memorial Hospital, Columbia, MO, United States
| | - Eckhard U. Alt
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Medicine, Isarklinikum Munich, Munich, Germany
| | - Reza Izadpanah
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States
- *Correspondence: Reza Izadpanah,
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Waibl Polania J, Lerner EC, Wilkinson DS, Hoyt-Miggelbrink A, Fecci PE. Pushing Past the Blockade: Advancements in T Cell-Based Cancer Immunotherapies. Front Immunol 2021; 12:777073. [PMID: 34868044 PMCID: PMC8636733 DOI: 10.3389/fimmu.2021.777073] [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: 09/14/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022] Open
Abstract
Successful cancer immunotherapies rely on a replete and functional immune compartment. Within the immune compartment, T cells are often the effector arm of immune-based strategies due to their potent cytotoxic capabilities. However, many tumors have evolved a variety of mechanisms to evade T cell-mediated killing. Thus, while many T cell-based immunotherapies, such as immune checkpoint inhibition (ICI) and chimeric antigen receptor (CAR) T cells, have achieved considerable success in some solid cancers and hematological malignancies, these therapies often fail in solid tumors due to tumor-imposed T cell dysfunctions. These dysfunctional mechanisms broadly include reduced T cell access into and identification of tumors, as well as an overall immunosuppressive tumor microenvironment that elicits T cell exhaustion. Therefore, novel, rational approaches are necessary to overcome the barriers to T cell function elicited by solid tumors. In this review, we will provide an overview of conventional immunotherapeutic strategies and the various barriers to T cell anti-tumor function encountered in solid tumors that lead to resistance. We will also explore a sampling of emerging strategies specifically aimed to bypass these tumor-imposed boundaries to T cell-based immunotherapies.
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Affiliation(s)
| | - Emily C Lerner
- Duke Medical School, Duke University Medical Center, Durham, NC, United States
| | - Daniel S Wilkinson
- Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
| | | | - Peter E Fecci
- Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
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Tang J, Li Y, Liu B, Liang W, Hu S, Shi M, Zeng J, Li M, Huang M. Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma. Pathol Oncol Res 2021; 27:1609997. [PMID: 34867089 PMCID: PMC8641556 DOI: 10.3389/pore.2021.1609997] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/28/2021] [Indexed: 12/02/2022]
Abstract
Glioblastoma (GBM) is the most aggressive type of brain tumor. Microvascular proliferation and abnormal vasculature are the hallmarks of the GBM, aggravating disease progression and increasing patient morbidity. Here, we uncovered a key role of ETS1 on vascular abnormality in glioblastoma. ETS1 was upregulated in endothelial cells from human tumors compared to endothelial cells from paired control brain tissue. Knockdown of Ets1 in mouse brain endothelial cells inhibited cell migration and proliferation, and suppressed expression of genes associated with vascular abnormality in GBM. ETS1 upregulation in tumor ECs was dependent on TGFβ signaling, and targeting TGFβ signaling by inhibitor decreased tumor angiogenesis and vascular abnormality in CT-2A glioma model. Our results identified ETS1 as a key factor regulating tumor angiogenesis, and suggested that TGFβ inhibition may suppress the vascular abnormality driven by ETS1.
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Affiliation(s)
- Jiefu Tang
- Trauma Center, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, China
| | - Yaling Li
- Department of Obstetrics and Gynaecology, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Boxuan Liu
- Precision Medicine Center, The Second People's Hospital of Huaihua, Huaihua, China
| | - Wei Liang
- Department of Orthopaedics, The Second People's Hospital of Huaihua, Huaihua, China
| | - Sanbao Hu
- Department of Orthopaedics, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Meilian Shi
- Department of Infectious Diseases, The Second People's Hospital of Huaihua, Huaihua, China
| | - Jie Zeng
- Department of Orthopaedics, The Second People's Hospital of Huaihua, Huaihua, China
| | - Mingzhen Li
- Precision Medicine Center, The Second People's Hospital of Huaihua, Huaihua, China
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Hermawan A, Putri H. Systematic analysis of potential targets of the curcumin analog pentagamavunon-1 (PGV-1) in overcoming resistance of glioblastoma cells to bevacizumab. Saudi Pharm J 2021; 29:1289-1302. [PMID: 34819791 PMCID: PMC8596150 DOI: 10.1016/j.jsps.2021.09.015] [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: 04/08/2021] [Accepted: 09/24/2021] [Indexed: 12/26/2022] Open
Abstract
Background Glioblastoma is one of the most aggressive and deadliest malignant tumors. Acquired resistance decreases the effectiveness of bevacizumab in glioblastoma treatment and thus increases the mortality rate in patients with glioblastoma. In this study, the potential targets of pentagamavunone-1 (PGV-1), a curcumin analog, were explored as a complementary treatment to bevacizumab in glioblastoma therapy. Methods Target prediction, data collection, and analysis were conducted using the similarity ensemble approach (SEA), SwissTargetPrediction, STRING DB, and Gene Expression Omnibus (GEO) datasets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted using Webgestalt and DAVID, respectively. Hub genes were selected based on the highest degree scores using the CytoHubba. Analysis of genetic alterations and gene expression as well as Kaplan–Meier survival analysis of selected genes were conducted with cBioportal and GEPIA. Immune infiltration correlations between selected genes and immune cells were analyzed with database TIMER 2.0. Results We found 374 targets of PGV-1, 1139 differentially expressed genes (DEGs) from bevacizumab-resistant-glioblastoma cells. A Venn diagram analysis using these two sets of data resulted in 21 genes that were identified as potential targets of PGV-1 against bevacizumab resistance (PBR). PBR regulated the metabolism of xenobiotics by cytochrome P450. Seven potential therapeutic PBR, namely GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110 were found to have genetic alterations in 1.2%–30% of patients with glioblastoma. Analysis using the GEPIA database showed that the mRNA expression of ADAM10, AKR1B1, and HSD17B10 was significantly upregulated in glioblastoma patients. Kaplan–Meier survival analysis showed that only patients with low mRNA expression of AKR1B1 had significantly better overall survival than the patients in the high mRNA group. We also found a correlation between PBR and immune cells and thus revealed the potential of PGV-1 as an immunotherapeutic agent via targeting of PBR. Conclusion This study highlighted seven PBR, namely, GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110. This study also emphasized the potential of PBR as a target for immunotherapy with PGV-1. Further validation of the results of this study is required for the development of PGV-1 as an adjunct to immunotherapy for glioblastoma to counteract bevacizumab resistance.
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Key Words
- ADAM10, a disintegrant and metalloproteinase 10
- AKRs, Aldo keto reductases
- Bevacizumab resistance
- Bioinformatics
- CAFs, Cancer-associated fibroblasts
- COX-2, cyclooxigenase-2
- DEGs, differentially expressed genes
- DT, Direct targets of PGV-1
- GSTM1, glutathione S-transferase mu 1
- GSTP1, glutathione S-transferase Pi-1
- Glioblastoma
- HSD17B10, Human type 10 17beta-hydroxysteroid dehydrogenase
- Immunotherapy
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- PBR, potential therapeutic target genes of PGV-1 against bevacizumab resistance glioblastoma
- PGV-1
- PGV-1, Pentagamavunon-1
- PTGS2, prostaglandin-endoperoxide synthase 2
- ROS, reactive oxygen species
- SEA, Similarity ensemble approach
- Target prediction
- VEGF, vascular endothelial growth factor
- Webgestalt, WEB-based GEne SeT AnaLysis Toolkit
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Affiliation(s)
- Adam Hermawan
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Herwandhani Putri
- Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
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Ott PA, Nazzaro M, Pfaff KL, Gjini E, Felt KD, Wolff JO, Buchbinder EI, Haq R, Sullivan RJ, Lawrence DP, McDermott DF, Severgnini M, Giobbie-Hurder A, Rodig SJ, Stephen Hodi F. Combining CTLA-4 and angiopoietin-2 blockade in patients with advanced melanoma: a phase I trial. J Immunother Cancer 2021; 9:jitc-2021-003318. [PMID: 34772758 PMCID: PMC8593712 DOI: 10.1136/jitc-2021-003318] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2021] [Indexed: 01/08/2023] Open
Abstract
Background Angiogenic factors promote the growth of tumor vasculature, modulate lymphocyte trafficking into tumors, and inhibit maturation of dendritic cells. We hypothesized that MEDI3617, a human IgG1 kappa monoclonal antibody directed against human angiopoietin-2, in combination with tremelimumab (treme), an IgG2 monoclonal antibody blocking cytotoxic T-lymphocyte-associated protein- (CTLA-4), is safe in patients with advanced melanoma. Methods In a phase I, 3+3 dose escalation trial, patients with metastatic or unresectable melanoma received treme in combination with MEDI3617. The primary objectives of the study were safety and determination of recommended phase II dose (RP2D). The secondary objectives included determination of 6-month and 1-year overall survival and best overall response rate. Immune cell populations and soluble factors were assessed in peripheral blood and metastatic tumors using Fluorescence activated cell sorting (FACS), Luminex, and multiplexed immunofluorescence. Results Fifteen patients (median age: 62) were enrolled in the study (3 patients in cohort 1: treme at 10 mg/kg and MEDI3617 at 200 mg; and 12 patients in cohort 2: treme at 10 mg/kg and MEDI3617 at 600 mg). The most common all-grade treatment-related adverse events were rash, pruritus, fatigue, and extremity edema. No dose-limiting toxicities were observed. Cohort 2 was determined to be the RP2D. There were no patients with confirmed immune-related complete response or immune-related partial response. Six of 15 patients had immune-related stable disease, resulting in a disease control rate of 0.40 (95% CI 0.16 to 0.68). An increase in frequencies of circulating inducible T-cell costimulator (ICOS)+ and human leukocyte antigen (HLA)-DR+ CD4+ and CD8+ T cells and production of Interleukin-2 and Interleukin-10 was observed post therapy. Conclusions Tremelimumab in combination with MEDI3617 is safe in patients with advanced melanoma. Angiopoietin-2 inhibition in combination with immune checkpoint inhibition warrants further exploration. Trial registration number NCT02141542.
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Affiliation(s)
- Patrick A Ott
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA .,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Matthew Nazzaro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kathleen L Pfaff
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Evisa Gjini
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kristen D Felt
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Jacquelyn O Wolff
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Elizabeth I Buchbinder
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Rizwan Haq
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Ryan J Sullivan
- Harvard Medical School, Boston, Massachusetts, USA.,Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Donald P Lawrence
- Harvard Medical School, Boston, Massachusetts, USA.,Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - David F McDermott
- Harvard Medical School, Boston, Massachusetts, USA.,Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Mariano Severgnini
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Anita Giobbie-Hurder
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Scott J Rodig
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - F Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA.,Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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47
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Ye Z, Ai X, Zhao L, Fei F, Wang P, Zhou S. Phenotypic plasticity of myeloid cells in glioblastoma development, progression, and therapeutics. Oncogene 2021; 40:6059-6070. [PMID: 34556813 DOI: 10.1038/s41388-021-02010-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 08/16/2021] [Accepted: 09/06/2021] [Indexed: 02/08/2023]
Abstract
Glioblastoma (GBM) is the most common and malignant type of intracranial tumors with poor prognosis. Accumulating evidence suggests that phenotypic alterations of infiltrating myeloid cells in the tumor microenvironment are important for GBM progression. Conventional tumor immunotherapy commonly targets T-cells, while innate immunity as a therapeutic target is an emerging field. Targeting infiltrating myeloid cells that induce immune suppression in the TME provides a novel direction to improve the prognosis of patients with GBM. The factors released by tumor cells recruit myeloid cells into tumor bed and reprogram infiltrating myeloid cells into immunostimulatory/immunosuppressive phenotypes. Reciprocally, infiltrating myeloid cells, especially microglia/macrophages, regulate GBM progression and affect therapeutic efficacy. Herein, we revisited biological characteristics and functions of infiltrating myeloid cells and discussed the recent advances in immunotherapies targeting infiltrating myeloid cells in GBM. With an evolving understanding of the complex interactions between infiltrating myeloid cells and tumor cells in the tumor microenvironment, we will expand novel immunotherapeutic regimens targeting infiltrating myeloid cells in GBM treatment and improve the outcomes of GBM patients.
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Affiliation(s)
- Zengpanpan Ye
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, P. R. China
| | - Xiaolin Ai
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, P. R. China
| | - Linjie Zhao
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Fan Fei
- Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital; School of Medicine, University of Electronic Science and Technology of China, No.32 West Second Section First Ring Road, Chengdu, 610072, Sichuan, China.
| | - Ping Wang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, P. R. China.
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, P. R. China.
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48
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Huang H, Georganaki M, Conze LL, Laviña B, van Hooren L, Vemuri K, van de Walle T, Ramachandran M, Zhang L, Pontén F, Bergqvist M, Smits A, Betsholtz C, Dejana E, Magnusson PU, He L, Lugano R, Dimberg A. ELTD1-deletion reduces vascular abnormality and improves T-cell recruitment after PD-1 blockade in glioma. Neuro Oncol 2021; 24:398-411. [PMID: 34347079 PMCID: PMC8917395 DOI: 10.1093/neuonc/noab181] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background Tumor vessels in glioma are molecularly and functionally abnormal, contributing to treatment resistance. Proteins differentially expressed in glioma vessels can change vessel phenotype and be targeted for therapy. ELTD1 (Adgrl4) is an orphan member of the adhesion G-protein-coupled receptor family upregulated in glioma vessels and has been suggested as a potential therapeutic target. However, the role of ELTD1 in regulating vessel function in glioblastoma is poorly understood. Methods ELTD1 expression in human gliomas and its association with patient survival was determined using tissue microarrays and public databases. The role of ELTD1 in regulating tumor vessel phenotype was analyzed using orthotopic glioma models and ELTD1−/− mice. Endothelial cells isolated from murine gliomas were transcriptionally profiled to determine differentially expressed genes and pathways. The consequence of ELTD1 deletion on glioma immunity was determined by treating tumor-bearing mice with PD-1-blocking antibodies. Results ELTD1 levels were upregulated in human glioma vessels, increased with tumor malignancy, and were associated with poor patient survival. Progression of orthotopic gliomas was not affected by ELTD1 deletion, however, tumor vascular function was improved in ELTD1−/− mice. Bioinformatic analysis of differentially expressed genes indicated increased inflammatory response and decreased proliferation in tumor endothelium in ELTD1−/− mice. Consistent with an enhanced inflammatory response, ELTD1 deletion improved T-cell infiltration in GL261-bearing mice after PD-1 checkpoint blockade. Conclusion Our data demonstrate that ELTD1 participates in inducing vascular dysfunction in glioma, and suggest that targeting of ELTD1 may normalize the vessels and improve the response to immunotherapy.
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Affiliation(s)
- Hua Huang
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Maria Georganaki
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Lei Liu Conze
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Bàrbara Laviña
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Luuk van Hooren
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Kalyani Vemuri
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Tiarne van de Walle
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Mohanraj Ramachandran
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Lei Zhang
- Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Fredrik Pontén
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Michael Bergqvist
- Center for Research and Development, Uppsala University, Gävle Hospital, Gävle.,Department of Radiation Sciences and Oncology, Umeå University Hospital, Umeå
| | - Anja Smits
- Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, S-41345 Gothenburg, Sweden
| | - Christer Betsholtz
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Elisabetta Dejana
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Peetra U Magnusson
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Liqun He
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Roberta Lugano
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
| | - Anna Dimberg
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden
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49
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Yang M, Chen X, Zhang J, Xiong E, Wang Q, Fang W, Li L, Fei F, Gong A. ME2 Promotes Proneural-Mesenchymal Transition and Lipogenesis in Glioblastoma. Front Oncol 2021; 11:715593. [PMID: 34381734 PMCID: PMC8351415 DOI: 10.3389/fonc.2021.715593] [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: 05/27/2021] [Accepted: 07/12/2021] [Indexed: 12/20/2022] Open
Abstract
Malic enzyme 2 (ME2) catalyzes the formation of pyruvate from malic acid and is abnormally expressed in some tumors. However, the exact effects of ME2 on proneural–mesenchymal transition (PMT) and lipogenesis in glioblastoma multiforme (GBM) remain unexplored. Here, we found that ME2 expression was significantly higher in GBM than in normal brain tissues and negatively correlated with overall survival of patients with GBM. Furthermore, we demonstrated that ME2 was positively correlated with mesenchymal features in GBM and promoted proliferation, migration, and invasion of glioma cells. Moreover, ME2 upregulated the expression of mesenchymal markers (N-cadherin, vimentin, YKL40, and MET), whereas it inhibited the expression of proneural maker OLIG2, indicating that ME2 might promote PMT in GBM. We also found that ME2 inhibited the production of mitochondrial reactive oxygen species and AMPK phosphorylation, resulting in SREBP-1 maturation and nuclear localization and enhancing the ACSS2 lipogenesis pathway. Taken together, these results suggest that ME2 promotes PMT and is linked with reprogramming of lipogenesis via AMPK–SREBP-1–ACSS2 signaling in GBM. Therefore, ME2 has potential as a new classification marker in GBM and could provide a new approach to glioma treatment.
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Affiliation(s)
- Mengting Yang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xi Chen
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Junyao Zhang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ermeng Xiong
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Qianqian Wang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Wenjing Fang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Li
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Fei Fei
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Aihua Gong
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
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50
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Wang Y, Salvucci O, Ohnuki H, Tran AD, Ha T, Feng J, DiPrima M, Kwak H, Wang D, Yu Y, Kruhlak M, Tosato G. Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth. EMBO Mol Med 2021; 13:e14089. [PMID: 34102002 PMCID: PMC8261520 DOI: 10.15252/emmm.202114089] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
The tyrosine phosphatase SHP2 is oncogenic in cancers driven by receptor-tyrosine-kinases, and SHP2 inhibition reduces tumor growth. Here, we report that SHP2 is an essential promoter of endothelial cell survival and growth in the remodeling tumor vasculature. Using genetic and chemical approaches to inhibit SHP2 activity in endothelial cells, we show that SHP2 inhibits pro-apoptotic STAT3 and stimulates proliferative ERK1/2 signaling. Systemic SHP2 inhibition in mice bearing tumor types selected for SHP2-independent tumor cell growth promotes degeneration of the tumor vasculature and blood extravasation; reduces tumor vascularity and blood perfusion; and increases tumor necrosis. Reduction of tumor growth ensues, independent of SHP2 targeting in the tumor cells, blocking immune checkpoints, or recruiting macrophages. We also show that inhibiting the Angiopoietin/TIE2/AKT cascade magnifies the vascular and anti-tumor effects of SHP2 inhibition by blocking tumor endothelial AKT signaling, not a target of SHP2. Since the SHP2 and Ang2/TIE2 pathways are active in vascular endothelial cells of human melanoma and colon carcinoma, SHP2 inhibitors alone or with Ang2/TIE2 inhibitors hold promise to effectively target the tumor endothelium.
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Affiliation(s)
- Yuyi Wang
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Ombretta Salvucci
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Hidetaka Ohnuki
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Andy D Tran
- Center for Cancer Research Microscopy CoreLaboratory of Cancer Biology and GeneticsNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Taekyu Ha
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Jing‐Xin Feng
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Michael DiPrima
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Hyeongil Kwak
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Dunrui Wang
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Yanlin Yu
- Laboratory of Cancer Biology and GeneticsCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Michael Kruhlak
- Center for Cancer Research Microscopy CoreLaboratory of Cancer Biology and GeneticsNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Giovanna Tosato
- Laboratory of Cellular OncologyCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
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