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Akbari B, Hasan MM, Islam SM. Advances in targeted therapy for triple-negative breast cancer: a review of key antigens and recent advances. J Drug Target 2025:1-20. [PMID: 40515614 DOI: 10.1080/1061186x.2025.2520306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 05/16/2025] [Accepted: 06/09/2025] [Indexed: 06/16/2025]
Abstract
The most aggressive subtype of breast cancer is triple-negative breast cancer (TNBC), which affects about 10-15% of all breast cancer cases. TNBC is associated with a poor prognosis and drug resistance due to the lack of oestrogen, progesterone, and HER2 receptors. Developing targeted immunotherapy for TNBC was challenged by identifying TNBC-specific antigens that can be suitable targets for antibody and nanobody-based therapies. Evidence from cancer- targeted therapy demonstrates that treatment outcomes are more successful when the target antigen is either overexpressed in tumour tissue or exhibits tumour specificity. Several antigens have been overexpressed in TNBC, including programmed cell death protein 1 (PD-1), programmed death-ligand 1(PD-L1), mesothelin (MSLN), trophoblast cell-surface antigen 2 (Trop-2), tumour endothelial marker 8 (TEM8), etc. There have been investigations targeting these antigens with antibodies, nanobodies, small molecules, peptides, and miniproteins for targeted treatment of TNBC. Antibodies known as Aembrolizumab, Atezolizumab, and Sacituzumab Govitecan-hziy have been approved by the FDA, and many are under investigation. The present review discusses the antigens with high expression in TNBC, their role in cancer development and progression, and the targeted therapies like antibodies, recombinant proteins, and antibody-drug conjugates (ADC).
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Affiliation(s)
- Bahman Akbari
- Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Md Mehedi Hasan
- Department of Chemistry, Delaware State University, Dover, Delaware, USA
| | - Shahidul M Islam
- Department of Chemistry, Delaware State University, Dover, Delaware, USA
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Seban RD, Buvat I, Champion L, Bidard FC, Kieffer Y, Vincent-Salomon A, Peltier A, Mechta-Grigoriou F. Beyond FAP: ANTXR1 as a novel target for PET imaging and radio-ligand therapy in immuno-oncology? Eur J Nucl Med Mol Imaging 2025; 52:1948-1950. [PMID: 39907795 DOI: 10.1007/s00259-025-07126-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 01/29/2025] [Indexed: 02/06/2025]
Affiliation(s)
- Romain-David Seban
- Department of Nuclear Medicine, Institute of Women's Cancer, Institut Curie, 92210, Saint-Cloud, France.
- Laboratoire d'Imagerie Translationnelle en Oncologie, Inserm U1288, PSL University, Paris Saclay University, Institute of Women's Cancer, Institut Curie, 91400, Orsay, France.
| | - Irene Buvat
- Laboratoire d'Imagerie Translationnelle en Oncologie, Inserm U1288, PSL University, Paris Saclay University, Institute of Women's Cancer, Institut Curie, 91400, Orsay, France
| | - Laurence Champion
- Department of Nuclear Medicine, Institute of Women's Cancer, Institut Curie, 92210, Saint-Cloud, France
- Laboratoire d'Imagerie Translationnelle en Oncologie, Inserm U1288, PSL University, Paris Saclay University, Institute of Women's Cancer, Institut Curie, 91400, Orsay, France
| | - Francois-Clement Bidard
- Department of Medical Oncology, Institute of Women's Cancer, Institut Curie, 75006, Paris, France
- Circulating Tumor Biomarkers Laboratory, SiRIC, PSL Research University, Institute of Women's Cancer, Institut Curie, Paris, France
| | - Yann Kieffer
- Stress and Cancer Laboratory, Equipe Labélisée Par La Ligue Nationale Contre Le Cancer, Inserm U1339 - UMR3666 CNRS, PSL Research University, Institute of Women's Cancer, Institut Curie, 26, rue d'Ulm, F-75248, Paris, France
| | - Anne Vincent-Salomon
- Department of Diagnostic and Theranostic Medicine, Institute of Women's Cancer, Institut Curie, 75006, Paris, France
| | - Agathe Peltier
- Stress and Cancer Laboratory, Equipe Labélisée Par La Ligue Nationale Contre Le Cancer, Inserm U1339 - UMR3666 CNRS, PSL Research University, Institute of Women's Cancer, Institut Curie, 26, rue d'Ulm, F-75248, Paris, France
| | - Fatima Mechta-Grigoriou
- Stress and Cancer Laboratory, Equipe Labélisée Par La Ligue Nationale Contre Le Cancer, Inserm U1339 - UMR3666 CNRS, PSL Research University, Institute of Women's Cancer, Institut Curie, 26, rue d'Ulm, F-75248, Paris, France
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Ramos-Valle A, Domínguez A, Navarro N, Márquez-López A, Aviñó A, Eritja R, Fàbrega C, García-Hevia L, Fanarraga ML. Targeted Tumor Microenvironment Delivery of Floxuridine Prodrug via Soluble Silica Nanoparticles in Malignant Melanoma as a Model for Aggressive Cancer Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2407752. [PMID: 40259607 DOI: 10.1002/smll.202407752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 04/09/2025] [Indexed: 04/23/2025]
Abstract
Malignant melanoma presents a significant challenge in oncology due to its aggressive nature and high metastatic potential. Conventional systemic treatments often fail to effectively reach tumor sites, limiting their therapeutic impact. This study introduces a groundbreaking triple-strategy approach for treating malignant melanoma. A novel prodrug, an oligonucleotide, comprising 10 units of Floxuridine (5-fluoro-2'-deoxyuridine) (FdU) nucleoside antimetabolites are developed, to enhance half-life and reduce rapid metabolism. Encapsulated in soluble colloidal silica nanoparticles, this compound is protected and directed toward tumor neovasculature precursor endothelial cell receptors, ensuring local delivery. The strategy focuses on releasing the prodrug in the tumor microenvironment, aiming to eradicate both melanoma cells and their supportive structures. Efficacy is demonstrated in cell culture studies and preclinical models of malignant melanoma, showing a remarkable 50% reduction in tumor size after just three intravenous treatments. These findings underscore the transformative potential of targeting endothelial cell membrane proteins for drug delivery. This study paves the way for innovative targeted therapies, promising significant advancements in treatment strategies and improves outcomes for patients with metastatic cancers.
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Affiliation(s)
- Andrés Ramos-Valle
- The Nanomedicine Group, Instituto de Investigación Valdecilla-IDIVAL, Santander, 39011, Spain
- Department of Molecular Biology, Faculty of Medicine, Universidad de Cantabria, Santander, 39011, Spain
| | - Arnau Domínguez
- Dpt. Surfactants & Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Barcelona, 08034, Spain
- CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona, 08034, Spain
| | - Natalia Navarro
- Dpt. Surfactants & Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Barcelona, 08034, Spain
- CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona, 08034, Spain
| | - Ana Márquez-López
- The Nanomedicine Group, Instituto de Investigación Valdecilla-IDIVAL, Santander, 39011, Spain
- Department of Molecular Biology, Faculty of Medicine, Universidad de Cantabria, Santander, 39011, Spain
| | - Anna Aviñó
- Dpt. Surfactants & Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Barcelona, 08034, Spain
- CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona, 08034, Spain
| | - Ramon Eritja
- Dpt. Surfactants & Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Barcelona, 08034, Spain
- CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona, 08034, Spain
| | - Carme Fàbrega
- Dpt. Surfactants & Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Barcelona, 08034, Spain
- CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona, 08034, Spain
| | - Lorena García-Hevia
- The Nanomedicine Group, Instituto de Investigación Valdecilla-IDIVAL, Santander, 39011, Spain
- Department of Molecular Biology, Faculty of Medicine, Universidad de Cantabria, Santander, 39011, Spain
| | - Mónica L Fanarraga
- The Nanomedicine Group, Instituto de Investigación Valdecilla-IDIVAL, Santander, 39011, Spain
- Department of Molecular Biology, Faculty of Medicine, Universidad de Cantabria, Santander, 39011, Spain
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Wali AF, Talath S, Sridhar SB, El-Tanani M, Rangraze IR. Endosialin-directed CAR-T cell therapy: A promising approach for targeting triple-negative breast cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167852. [PMID: 40318845 DOI: 10.1016/j.bbadis.2025.167852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/03/2025] [Accepted: 04/14/2025] [Indexed: 05/07/2025]
Abstract
In triple-negative breast cancer, this review article explores into the utilization of Chimeric antigen receptor T-cell (CAR-T) cell therapy to target cells expressing endosialin. Even with all the new treatments available, breast cancer still kills more women than any other disease. Drug resistance and ineffective cancer cell targeting are two major problems with targeted medications, chemotherapy, and surgery. Among cancer treatments, CAR-T cell therapy stands out. To identify endosialin as a therapeutic target, it is essential to understand its molecular structure and its involvement in tumor angiogenesis and progression. An effective target for CAR-T cells is breast cancer, which overexpresses endosialin. The development of CARs that are specific to endosialin and the results of early trials are covered in relation to CAR-T cell therapy that targets endosialin. Perhaps the most effective cancer treatment is endosialin targeting, since it is expressed only in tumors and plays a crucial role in the course of cancer. This article reviews endosialin-directed CAR-T cell breast cancer treatments' safety and efficacy from current and completed clinical trials. Despite promising results, these trials reveal that clinical translation must overcome significant challenges. The report suggests further research and combination tactics to improve endosialin-targeted CAR-T cell treatment.
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Affiliation(s)
- Adil Farooq Wali
- Department of Pharmaceutical Chemistry, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates.
| | - Sirajunisa Talath
- Department of Pharmaceutical Chemistry, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
| | - Sathvik B Sridhar
- Department of Clinical Pharmacy & Pharmacology, RAK College of Pharmacy, RAK Medical & Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Mohamed El-Tanani
- RAK College of Pharmacy, RAK Medical and Health Science University, Ras Al Khaimah 11172, United Arab Emirates
| | - Imran Rashid Rangraze
- Department of Internal Medicine, RAK Medical & Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
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Li H, Yang Z, Huang J, Lin L, Shi D, Chu Y, Wu D, Cai Y, Li B, Lu J, Guo Q. CALCR interaction with ANTXR1 drives gastric tumor growth and metastasis via AKT signaling pathway. Sci Rep 2025; 15:11826. [PMID: 40195530 PMCID: PMC11977274 DOI: 10.1038/s41598-025-96310-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/27/2025] [Indexed: 04/09/2025] Open
Abstract
This study investigates the role of CALCR, a G-protein-coupled receptor, in gastric cancer (GC) progression and its interaction with ANTXR1. A total of 121 patients with gastric cancer were enrolled from the Department of General Surgery, Anyang Tumor Hospital, Anyang City, Henan Province, China. 218 tumor tissues and corresponding para-carcinoma tissues were collected from 109 patients, while adjacent tissues were retained from the remaining 12 cases. Kaplan-Meier analysis evaluated the prognostic value of m6A-related genes in GC. Immunohistochemistry (IHC) was conducted to evaluate CALCR expression. Quantitative real-time PCR (qRT-PCR), Western blot analysis, CCK-8 assays, flow cytometry and transwell assays were used to assess CALCR's role in cell proliferation, apoptosis, migration, and invasion. Co-immunoprecipitation experiments were performed to explore the interaction between CALCR and ANTXR1. Statistical analyses were conducted using SPSS 25.0 and GraphPad Prism 8.0, with p < 0.05 considered significant. IHC staining revealed that 53.2% (n = 58) of the tumor tissues exhibited high CALCR expression, compared to only 6.6% (n = 8) of the para-carcinoma tissues (p < 0.001). CALCR knockdown in GC cell lines significantly reduced proliferation (p < 0.01), increased apoptosis (p < 0.01), and inhibited migration and invasion (p < 0.001). In a nude mouse model, CALCR knockdown resulted in significantly reduced tumor growth and metastasis (p < 0.05). Co-immunoprecipitation showed that CALCR interacts with ANTXR1, leading to decreased AKT phosphorylation. CALCR is a crucial factor in GC progression, presenting a potential prognostic marker and therapeutic target. Targeting the CALCR-ANTXR1 axis and AKT pathway offers new avenues for GC treatment.
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Affiliation(s)
- Hongbo Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Zihan Yang
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Jingbo Huang
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Lele Lin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, 310009, China
| | - Dike Shi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, 310009, China
| | - Yiming Chu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, 310009, China
| | - Dan Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, 310009, China
| | - Yanna Cai
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Baozhong Li
- Department of General Surgery, Anyang Tumor Hospital, Henan Medical Key Laboratory of Precise Prevention and Treatment of Esophageal Cancer, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang, 455000, China
| | - Junyang Lu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qingqu Guo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, 310009, China.
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Niwata C, Nakagawa T, Naruse T, Sakuma M, Yamakado N, Akagi M, Ono S, Tobiume K, Gao J, Jimi E, Ohta K, Aikawa T. Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis. Discov Oncol 2025; 16:53. [PMID: 39815040 PMCID: PMC11735718 DOI: 10.1007/s12672-025-01763-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 01/02/2025] [Indexed: 01/18/2025] Open
Abstract
OBJECTIVES Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drug and suppresses T-cell proliferation and activity by inhibiting pyrimidine synthesis using dihydroorotase dehydrogenase (DHODH); however, several studies have demonstrated that LEF possesses anticancer and antiangiogenic effects in some malignant tumors. Therefore, we investigated the anticancer and antiangiogenic effects of LEF on oral squamous cell carcinoma (OSCC). METHODS To evaluate the inhibitory effect of LEF on OSCC, cell proliferation and wound-healing assays using human OSCC cell lines were performed. The DHODH inhibitory effect of LEF was evaluated by Western blot. To assess the suppression of pyrimidine biosynthesis induced by LEF on OSCC, cell proliferation assays with or without uridine supplementation were performed. The antiangiogenic effect of LEF was evaluated by in vitro tube formation assay using immortalized human umbilical vein endothelial cells, which were electroporatically transfected with hTERT. The tumor-suppressive effect of LEF in vivo was examined in both immunodeficient and syngeneic mice by implanting mouse OSCC cells. Tumor vascularization was evaluated by immunohistochemistry of the tumor extracted from syngeneic mice. RESULTS LEF dose-dependently inhibited OSCC proliferation and migration. LEF significantly inhibited DHODH expression, and uridine supplementation rescued the inhibitory effect of LEF. LEF dose-dependently suppressed endothelial tube formation. In the animal study, LEF significantly suppressed tumor growth in both immunodeficient and syngeneic mice. Histologically, LEF decreased DHODH expression and tumor vascularization. CONCLUSION LEF is a potent anticancer agent with antiangiogenic effects on OSCC and might be clinically applicable to OSCC by drug repositioning.
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Affiliation(s)
- Chieko Niwata
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Takayuki Nakagawa
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
| | - Takako Naruse
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Miyuki Sakuma
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Nao Yamakado
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Misaki Akagi
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Shigehiro Ono
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Kei Tobiume
- Graduate School of Biomedical & Health Sciences (Dentistry & Oral Health Sciences), Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Jing Gao
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Eijiro Jimi
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kouji Ohta
- Department of Public Oral Health, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Tomonao Aikawa
- Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
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Marei HE, Bedair K, Hasan A, Al-Mansoori L, Caratelli S, Sconocchia G, Gaiba A, Cenciarelli C. Current status and innovative developments of CAR-T-cell therapy for the treatment of breast cancer. Cancer Cell Int 2025; 25:3. [PMID: 39755633 PMCID: PMC11700463 DOI: 10.1186/s12935-024-03615-8] [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: 07/15/2024] [Accepted: 12/12/2024] [Indexed: 01/06/2025] Open
Abstract
Breast cancer will overtake all other cancers in terms of diagnoses in 2024. Breast cancer counts highest among women in terms of cancer incidence and death rates. Innovative treatment approaches are desperately needed because treatment resistance brought on by current clinical drugs impedes therapeutic efficacy. The T cell-based immunotherapy known as chimeric antigen receptor (CAR) T cell treatment, which uses the patient's immune cells to fight cancer, has demonstrated remarkable efficacy in treating hematologic malignancies; nevertheless, the treatment effects in solid tumors, like breast cancer, have not lived up to expectations. We discuss in detail the role of tumor-associated antigens in breast cancer, current clinical trials, barriers to the intended therapeutic effects of CAR-T cell therapy, and potential ways to increase treatment efficacy. Finally, our review aims to stimulate readers' curiosity by summarizing the most recent advancements in CAR-T cell therapy for breast cancer.
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Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35116, Egypt.
| | - Khaled Bedair
- Department of Social Sciences, College of Arts and Sciences, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| | - Layla Al-Mansoori
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Sara Caratelli
- Institute of Translational Pharmacology-CNR, Rome, Italy
| | | | - Alice Gaiba
- Institute of Translational Pharmacology-CNR, Rome, Italy
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Payen SH, Andrada K, Tara E, Petereit J, Verma SC, Rossetto CC. The cellular paraspeckle component SFPQ associates with the viral processivity factor ORF59 during lytic replication of Kaposi's Sarcoma-associated herpesvirus (KSHV). Virus Res 2024; 349:199456. [PMID: 39214388 PMCID: PMC11406446 DOI: 10.1016/j.virusres.2024.199456] [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: 06/03/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) relies on many cellular proteins to complete replication and generate new virions. Paraspeckle nuclear bodies consisting of core ribonucleoproteins splicing factor proline/glutamine-rich (SFPQ), Non-POU domain-containing octamer-binding protein (NONO), and paraspeckle protein component 1 (PSPC1) along with the long non-coding RNA NEAT1, form a complex that has been speculated to play an important role in viral replication. Paraspeckle bodies are multifunctional and involved in various processes including gene expression, mRNA splicing, and anti-viral defenses. To better understand the role of SFPQ during KSHV replication, we performed SFPQ immunoprecipitation followed by mass spectrometry from KSHV-infected cells. Proteomic analysis showed that during lytic reactivation, SFPQ associates with viral proteins, including ORF10, ORF59, and ORF61. These results are consistent with a previously reported ORF59 proteomics assay identifying SFPQ. To test if the association between ORF59 and SFPQ is important for replication, we first identified the region of ORF59 that associates with SFPQ using a series of 50 amino acid deletion mutants of ORF59 in the KSHV BACmid system. By performing co-immunoprecipitations, we identified the region spanning amino acids 101-150 of ORF59 as the association domain with SFPQ. Using this information, we generated a dominant negative polypeptide of ORF59 encompassing amino acids 101-150, that disrupted the association between SFPQ and full-length ORF59, and decreased virus production. Interestingly, when we tested other human herpesvirus processivity factors (EBV BMRF1, HSV-1 UL42, and HCMV UL44) by transfection of each expression plasmid followed by co-immunoprecipitation, we found a conserved association with SFPQ. These are limited studies that remain to be done in the context of infection but suggest a potential association of SFPQ with processivity factors across multiple herpesviruses.
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Affiliation(s)
- Shannon Harger Payen
- University of Nevada, Reno School of Medicine, Department of Microbiology & Immunology, Reno, NV 89557, USA
| | - Kayla Andrada
- University of Nevada, Reno School of Medicine, Department of Microbiology & Immunology, Reno, NV 89557, USA
| | - Evelyn Tara
- University of Nevada, Reno School of Medicine, Department of Microbiology & Immunology, Reno, NV 89557, USA
| | - Juli Petereit
- University of Nevada, Reno, Nevada Bioinformatics Center (RRID: SCR_017802), Reno, NV 89557, USA
| | - Subhash C Verma
- University of Nevada, Reno School of Medicine, Department of Microbiology & Immunology, Reno, NV 89557, USA
| | - Cyprian C Rossetto
- University of Nevada, Reno School of Medicine, Department of Microbiology & Immunology, Reno, NV 89557, USA.
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9
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Kandav G, Chandel A. Revolutionizing cancer treatment: an in-depth exploration of CAR-T cell therapies. Med Oncol 2024; 41:275. [PMID: 39400611 DOI: 10.1007/s12032-024-02491-6] [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: 07/02/2024] [Accepted: 08/27/2024] [Indexed: 10/15/2024]
Abstract
Cancer is a leading cause of fatality worldwide. Due to the heterogeneity of cancer cells the effectiveness of various conventional cancer treatment techniques is constrained. Thus, researchers are diligently investigating therapeutic approaches like immunotherapy for effective tumor managements. Immunotherapy harnesses the inherent potential of patient's immune system to achieve desired outcomes. Within the realm of immunotherapy, CAR-T (Chimeric Antigen Receptor T) cells, emerges as a revolutionary innovation for cancer therapy. The process of CAR-T cell therapy entails extracting the patient's T cells, altering them with customized receptors designed to specifically recognize and eradicate the tumor cells, and then reinfusing the altered cells into the patient's body. Although there has been significant progress with CAR-T cell therapy in certain cases of specific B-cell leukemia and lymphoma, its effectiveness is hindered in hematological and solid tumors due to the challenges such as severe toxicities, restricted tumor infiltration, cytokine release syndrome and antigen escape. Overcoming these obstacles requires innovative approaches to design more effective CAR-T cells, which require a competent and diverse team to develop and implement. This comprehensive review addresses numerous therapeutic issues and provides a strategic solution while providing a deep understanding of the structural intricacies and production processes of CAR-T cells. In addition, this review explores the practical aspects of CAR-T cell therapy in clinical settings.
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Affiliation(s)
- Gurpreet Kandav
- Chandigarh College of Pharmacy, Chandigarh Group of Colleges, Landran, Sahibzada Ajit Singh Nagar, Punjab, 140307, India.
| | - Akash Chandel
- Chandigarh College of Pharmacy, Chandigarh Group of Colleges, Landran, Sahibzada Ajit Singh Nagar, Punjab, 140307, India
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Kundu P, Jain R, Kanuri NN, Arimappamagan A, Santosh V, Kondaiah P. DNA Methylation in Recurrent Glioblastomas: Increased TEM8 Expression Activates the Src/PI3K/AKT/GSK-3β/B-Catenin Pathway. Cancer Genomics Proteomics 2024; 21:485-501. [PMID: 39191501 PMCID: PMC11363927 DOI: 10.21873/cgp.20466] [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: 04/01/2024] [Revised: 05/20/2024] [Accepted: 06/10/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND/AIM Glioblastomas (GBM) are infiltrative malignant brain tumors which mostly recur within a year's time following surgical resection and chemo-radiation therapy. Studies on glioblastoma cells following radio-chemotherapy, have been demonstrated to induce trans-differentiation, cellular plasticity, activation of DNA damage response and stemness. As glioblastomas are heterogenous tumors that develop treatment resistance and plasticity, we investigated if there exist genome-wide DNA methylation changes in recurrent tumors. MATERIALS AND METHODS Utilizing genome-wide DNA methylation arrays, we compared the DNA methylation profile of 11 primary (first occurrence) tumors with 13 recurrent (relapsed) GBM, to delineate the contribution of epigenetic changes associated with therapy exposure, therapy resistance, and relapse of disease. RESULTS Our data revealed 1,224 hypermethylated- and 526 hypomethylated-probes in recurrent glioblastomas compared to primary disease. We found differential methylation of solute carrier and ion channel genes, interleukin receptor/ligand genes, tumor-suppressor genes and genes associated with metastasis. We functionally characterized one such hypomethylated-up-regulated gene, namely anthrax toxin receptor 1/tumor endothelial marker 8 (ANTXR1/TEM8), whose expression was validated to be significantly up-regulated in recurrent glioblastomas compared to primary tumors and confirmed by immunohistochemistry. Using overexpression and knockdown approaches, we showed that TEM8 induces proliferation, invasion, migration, and chemo-radioresistance in glioblastoma cells. Additionally, we demonstrated a novel mechanism of β-catenin stabilization and activation of the β-catenin transcriptional program due to TEM8 overexpression via a Src/PI3K/AKT/GSK3β/β-catenin pathway. CONCLUSION We report genome-wide DNA methylation changes in recurrent GBM and suggest involvement of the TEM8 gene in GBM recurrence and progression.
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Affiliation(s)
- Paramita Kundu
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
- Breast Cancer Now Toby Robins Research Centre, Department of Breast Research, The Institute of Cancer Research, London, U.K
| | - Ruchi Jain
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
- Al Jalila Genomics Centre, Al Jalila Children's Hospital, Dubai, United Arab Emirates
| | - Nandaki Nag Kanuri
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | | | - Vani Santosh
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Paturu Kondaiah
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India;
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11
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Chen K, Li WD, Li XQ. The role of m6A in angiogenesis and vascular diseases. iScience 2024; 27:110082. [PMID: 39055919 PMCID: PMC11269316 DOI: 10.1016/j.isci.2024.110082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2024] Open
Abstract
Angiogenesis, whether physiological or pathological, plays a pivotal role in various physiological and disease conditions. This intricate process relies on a complex and meticulously orchestrated signal transduction network that connects endothelial cells, their associated parietal cells (VSMCs and pericytes), and various other cell types, including immune cells. Given the significance of m6A and its connection to angiogenesis and vascular disease, researchers must adopt a comprehensive and ongoing approach to their investigations. This study aims to ascertain whether a common key mechanism of m6A exists in angiogenesis and vascular diseases and to elucidate the potential application of m6A in treating vascular diseases.
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Affiliation(s)
- Ke Chen
- Department of Vascular Surgery, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Wen-Dong Li
- Department of Vascular Surgery, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Xiao-Qiang Li
- Department of Vascular Surgery, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
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12
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Jahantab MB, Salehi M, Koushki M, Farrokhi Yekta R, Amiri-Dashatan N, Rezaei-Tavirani M. Modelling of miRNA-mRNA Network to Identify Gene Signatures with Diagnostic and Prognostic Value in Gastric Cancer: Evidence from In-Silico and In-Vitro Studies. Rep Biochem Mol Biol 2024; 13:281-300. [PMID: 39995653 PMCID: PMC11847593 DOI: 10.61186/rbmb.13.2.281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 12/08/2024] [Indexed: 02/26/2025]
Abstract
Background Gastric cancer (GC) is a prevalent malignancy with high recurrence. Advances in systems biology have identified molecular pathways and biomarkers. This study focuses on discovering gene and miRNA biomarkers for diagnosing and predicting survival in GC patients. Methods Three sets of genes (GSE19826, GSE81948, and GSE112369) and two sets of miRNA expression (GSE26595, GSE78775) were obtained from the Gene Expression Omnibus (GEO), and subsequently, differentially expressed genes (DEGs) and miRNAs (DEMs) were identified. Functional pathway enrichment, DEG-miR-TF-protein-protein interaction network, DEM-mRNA network, ROC curve, and survival analyses were performed. Finally, qRT-PCR was applied to validate our results. Results From the high-throughput profiling studies of GC, we investigated 10 candidate mRNA and 7 candidate miRNAs as potential biomarkers. Expression analysis of these hubs revealed that 5 miRNAs (including miR-141-3p, miR-204-5p, miR-338-3p, miR-609, and miR-369-5p) were significantly upregulated compared to the controls. The genes with the highest degree included 6 upregulated and 4 downregulated genes in tumor samples compared to controls. The expression of miR-141-3p, miR-204-5p, SESTD1, and ANTXR1 were verified in vitro from these hub DEMs and DEGs. The findings indicated a decrease in the expression of miR-141-3p and miR-204-5p and increased expression of SESTD1 and ANTXR1 in GC cell lines compared to the GES-1 cell line. Conclusions The current investigation successfully recognized a set of prospective miRNAs and genes that may serve as potential biomarkers for GC's early diagnosis and prognosis.
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Affiliation(s)
- Mohammad Bagher Jahantab
- Clinical Research Development Unit, Shahid Jalil Hospital, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Mohammad Salehi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Mehdi Koushki
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Reyhaneh Farrokhi Yekta
- Proteomics Research Center, School of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Nasrin Amiri-Dashatan
- Proteomics Research Center, School of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Zanjan Metabolic Diseases Research Center, Health and Metabolic Diseases Research Institute, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, School of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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13
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Kareff SA, Corbett V, Hallenbeck P, Chauhan A. TEM8 in Oncogenesis: Protein Biology, Pre-Clinical Agents, and Clinical Rationale. Cells 2023; 12:2623. [PMID: 37998358 PMCID: PMC10670355 DOI: 10.3390/cells12222623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/01/2023] [Accepted: 11/08/2023] [Indexed: 11/25/2023] Open
Abstract
The TEM8 protein represents an emerging biomarker in many solid tumor histologies. Given the various roles it plays in oncogenesis, including but not limited to angiogenesis, epithelial-to-mesenchymal transition, and cell migration, TEM8 has recently served and will continue to serve as the target of novel oncologic therapies. We review herein the role of TEM8 in oncogenesis. We review its normal function, highlight the additional roles it plays in the tumor microenvironment, and synthesize pre-clinical and clinical data currently available. We underline the protein's prognostic and predictive abilities in various solid tumors by (1) highlighting its association with more aggressive disease biology and poor clinical outcomes and (2) assessing its associated clinical trial landscape. Finally, we offer future directions for clinical studies involving TEM8, including incorporating pre-clinical agents into clinical trials and combining previously tested oncologic therapies with currently available treatments, such as immunotherapy.
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Affiliation(s)
- Samuel A. Kareff
- University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital, Miami, FL 33136, USA
| | | | | | - Aman Chauhan
- Division of Medical Oncology, Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
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14
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Zhou C, Liang A, Zhang J, Leng J, Xi B, Zhou B, Yang Y, Zhu R, Zhong L, Jiang X, Wan D. Depleting ANTXR1 suppresses glioma growth via deactivating PI3K/AKT pathway. Cell Cycle 2023; 22:2097-2112. [PMID: 37974357 PMCID: PMC10732648 DOI: 10.1080/15384101.2023.2275900] [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: 08/30/2021] [Accepted: 10/22/2023] [Indexed: 11/19/2023] Open
Abstract
Gliomas are commonly known as primary brain tumors and associated with frequent recurrence and an unsatisfactory prognosis despite extensive research in the underlying molecular mechanisms. We aimed to examine the role of ANTXR1 in glioma tumorigenesis and explore its downstream regulatory mechanism. ANTXR1 expression in clinical specimens and its relationship with some pathological characteristics were detected using immunohistochemical staining. After silencing/upregulating ANTXR1 through lentiviral transfection in glioma cell lines, qRT-PCR and western blotting were used to examine mRNA and protein levels, and cell phenotype was also detected. ANTXR1-knockdown and -overexpression cells were then processed by AKT activator and PI3K inhibitor, respectively, to verify downstream PI3K/AKT pathway regulated by ANTXR1. Xenograft nude mice models were constructed to verify the role of ANTXR1 in vivo. We found overexpression of ANTXR1 in both cell lines in comparison with those in normal brain tissues. Glioma cell growth and migratory ability were dramatically impaired as a result of silencing ANTXR1 by shANTXR1 lentiviruses. ANTXR1 blockade also accelerated cell apoptosis and held back cell cycle via targeting G2 phrase during cell mitosis. In vivo xenograft models verified in vitro findings above. Further exploration disclosed that AKT activator promoted anti-tumor effects mediated by ANTXR1 knockdown, while PI3K inhibitor limited pro-tumor effects mediated by ANTXR1 overexpression, indicating that ANTXR1 functioned in glioma cells through regulating PI3K/AKT pathway. ANTXR1 could play an indispensable role in glioma tumorigenesis via activating PI3K/AKT-mediated cell growth. Our study provides a theoretical basis for targeting ANTXR1 as a molecular target in glioma clinical therapeutics.
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Affiliation(s)
- Chaoyang Zhou
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Aijun Liang
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Jianzhong Zhang
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Jingxing Leng
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Bin Xi
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Bin Zhou
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Yu Yang
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Ronglan Zhu
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Liangchen Zhong
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Xingxing Jiang
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
| | - Dengfeng Wan
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi Province, China
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15
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Chen Q, Shen L, Liao T, Qiu Y, Lei Y, Wang X, Chen L, Zhao Y, Niu L, Wang Y, Zhang S, Zhu L, Gan M. A Novel tRNA-Derived Fragment, tRF GlnCTG, Regulates Angiogenesis by Targeting Antxr1 mRNA. Int J Mol Sci 2023; 24:14552. [PMID: 37833999 PMCID: PMC10572189 DOI: 10.3390/ijms241914552] [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: 09/08/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
As a novel non-coding RNA with important functions corresponding to various cellular stresses, the function of tRFs in angiogenesis remains unclear. Firstly, small RNA sequencing was performed on normal and post-muscle injury mouse tibialis anterior muscle to identify and analyse differentially expressed tRF/tiRNA. tRNA GlnCTG-derived fragments (tRFGlnCTG) were found to be overexpressed in high abundance in the damaged muscle. Subsequent in vitro experiments revealed that the overexpression of tRFGlnCTG suppressed the vascular endothelial cells' viability, cell cycle G1/S transition, proliferation, migration, and tube-formation capacity. Similarly, in vivo experiments showed that the tRFGlnCTG decreased the relative mRNA levels of vascular endothelial cell markers and pro-angiogenic factors and reduced the proportion of CD31-positive cells. Finally, luciferase activity analysis confirmed that the tRFGlnCTG directly targeted the 3'UTR of Antxr1, leading to a significant reduction in the mRNA expression of the target gene. These results suggest that tRFGlnCTG is a key regulator of vascular endothelial cell function. The results provide a new idea for further exploration of the molecular mechanisms that regulate angiogenesis.
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Affiliation(s)
- Qiuyang Chen
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Linyuan Shen
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Tianci Liao
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Yanhao Qiu
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Yuhang Lei
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Xingyu Wang
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Lei Chen
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Ye Zhao
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Lili Niu
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Yan Wang
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Shunhua Zhang
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Li Zhu
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Mailin Gan
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (Q.C.); (L.S.); (T.L.); (Y.Q.); (Y.L.); (X.W.)
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
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16
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Taskinen JH, Ruhanen H, Matysik S, Käkelä R, Olkkonen VM. Systemwide effects of ER-intracellular membrane contact site disturbance in primary endothelial cells. J Steroid Biochem Mol Biol 2023; 232:106349. [PMID: 37321512 DOI: 10.1016/j.jsbmb.2023.106349] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/09/2023] [Accepted: 06/11/2023] [Indexed: 06/17/2023]
Abstract
Membrane contact sites (MCS) make up a crucial route of inter-organelle non-vesicular transport within the cell. Multiple proteins are involved in this process, which includes the ER-resident proteins vesicle associated membrane protein associated protein A and -B (VAPA/B) that form MCS between the ER and other membrane compartments. Currently most functional data on VAP depleted phenotypes have shown alterations in lipid homeostasis, induction of ER stress, dysfunction of UPR and autophagy, as well as neurodegeneration. Literature on concurrent silencing of VAPA/B is still sparse; therefore, we investigated how it affects the macromolecule pools of primary endothelial cells. Our transcriptomics results showed significant upregulation in genes related to inflammation, ER and Golgi dysfunction, ER stress, cell adhesion, as well as Coat Protein Complex-I and -II (COP-I, COP-II) vesicle transport. Genes related to cellular division were downregulated, as well as key genes of lipid and sterol biosynthesis. Lipidomics analyses revealed reductions in cholesteryl esters, very long chain highly unsaturated and saturated lipids, whereas increases in free cholesterol and relatively short chain unsaturated lipids were evident. Furthermore, the knockdown resulted in an inhibition of angiogenesis in vitro. We speculate that ER MCS depletion has led to multifaceted outcomes, which include elevated ER free cholesterol content and ER stress, alterations in lipid metabolism, ER-Golgi function and vesicle transport, which have led to a reduction in angiogenesis. The silencing also induced an inflammatory response, consistent with upregulation of markers of early atherogenesis. To conclude, ER MCS mediated by VAPA/B play a crucial role in maintaining cholesterol traffic and sustain normal endothelial functions.
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Affiliation(s)
- Juuso H Taskinen
- Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290 Helsinki, Finland
| | - Hanna Ruhanen
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Viikinkaari 1, PO BOX 65, 00014 University of Helsinki, Finland; Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, University of Helsinki, Viikinkaari 1, PO BOX 65, 00014 University of Helsinki, Finland
| | - Silke Matysik
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | - Reijo Käkelä
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Viikinkaari 1, PO BOX 65, 00014 University of Helsinki, Finland; Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, University of Helsinki, Viikinkaari 1, PO BOX 65, 00014 University of Helsinki, Finland
| | - Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290 Helsinki, Finland; Department of Anatomy, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
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17
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Márquez-López A, Fanarraga ML. AB Toxins as High-Affinity Ligands for Cell Targeting in Cancer Therapy. Int J Mol Sci 2023; 24:11227. [PMID: 37446406 DOI: 10.3390/ijms241311227] [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: 05/15/2023] [Revised: 06/30/2023] [Accepted: 07/06/2023] [Indexed: 07/15/2023] Open
Abstract
Conventional targeted therapies for the treatment of cancer have limitations, including the development of acquired resistance. However, novel alternatives have emerged in the form of targeted therapies based on AB toxins. These biotoxins are a diverse group of highly poisonous molecules that show a nanomolar affinity for their target cell receptors, making them an invaluable source of ligands for biomedical applications. Bacterial AB toxins, in particular, are modular proteins that can be genetically engineered to develop high-affinity therapeutic compounds. These toxins consist of two distinct domains: a catalytically active domain and an innocuous domain that acts as a ligand, directing the catalytic domain to the target cells. Interestingly, many tumor cells show receptors on the surface that are recognized by AB toxins, making these high-affinity proteins promising tools for developing new methods for targeting anticancer therapies. Here we describe the structure and mechanisms of action of Diphtheria (Dtx), Anthrax (Atx), Shiga (Stx), and Cholera (Ctx) toxins, and review the potential uses of AB toxins in cancer therapy. We also discuss the main advances in this field, some successful results, and, finally, the possible development of innovative and precise applications in oncology based on engineered recombinant AB toxins.
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Affiliation(s)
- Ana Márquez-López
- The Nanomedicine Group, Institute Valdecilla-IDIVAL, 39011 Santander, Spain
| | - Mónica L Fanarraga
- The Nanomedicine Group, Institute Valdecilla-IDIVAL, 39011 Santander, Spain
- Molecular Biology Department, Faculty of Medicine, Universidad de Cantabria, 39011 Santander, Spain
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18
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Jin J, Cong J, Lei S, Zhang Q, Zhong X, Su Y, Lu M, Ma Y, Li Z, Wang L, Zhu N, Yang J. Cracking the code: Deciphering the role of the tumor microenvironment in osteosarcoma metastasis. Int Immunopharmacol 2023; 121:110422. [PMID: 37302370 DOI: 10.1016/j.intimp.2023.110422] [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: 03/20/2023] [Revised: 05/19/2023] [Accepted: 05/30/2023] [Indexed: 06/13/2023]
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. It is characterized by a rapid progression, poor prognosis, and early pulmonary metastasis. Over the past 30 years, approximately 85% of patients with osteosarcoma have experienced metastasis. The five-year survival of patients with lung metastasis during the early stages of treatment is less than 20%. The tumor microenvironment (TME) not only provides conditions for tumor cell growth but also releases a variety of substances that can promote the metastasis of tumor cells to other tissues and organs. Currently, there is limited research on the role of the TME in osteosarcoma metastasis. Therefore, to explore methods for regulating osteosarcoma metastasis, further investigations must be conducted from the perspective of the TME. This will help to identify new potential biomarkers for predicting osteosarcoma metastasis and assist in the discovery of new drugs that target regulatory mechanisms for clinical diagnosis and treatment. This paper reviews the research progress on the mechanism of osteosarcoma metastasis based on TME theory, which will provide guidance for the clinical treatment of osteosarcoma.
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Affiliation(s)
- Jiamin Jin
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical University, Guangxi, Guilin 541001, China; Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Jiacheng Cong
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Shangbo Lei
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Qiujin Zhang
- Department of Immunology, Guilin Medical University, Guilin 541199, China
| | - Xinyi Zhong
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Yingying Su
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Mingchuan Lu
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Yifen Ma
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Zihe Li
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Liyan Wang
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical University, Guangxi, Guilin 541001, China
| | - Ningxia Zhu
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China.
| | - Jinfeng Yang
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical University, Guangxi, Guilin 541001, China; Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China.
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The New Frontier of Immunotherapy: Chimeric Antigen Receptor T (CAR-T) Cell and Macrophage (CAR-M) Therapy against Breast Cancer. Cancers (Basel) 2023; 15:cancers15051597. [PMID: 36900394 PMCID: PMC10000829 DOI: 10.3390/cancers15051597] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
Breast cancer represents one of the most common tumor histologies. To date, based on the specific histotype, different therapeutic strategies, including immunotherapies, capable of prolonging survival are used. More recently, the astonishing results that were obtained from CAR-T cell therapy in haematological neoplasms led to the application of this new therapeutic strategy in solid tumors as well. Our article will deal with chimeric antigen receptor-based immunotherapy (CAR-T cell and CAR-M therapy) in breast cancer.
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20
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ANTXR1 as a potential sensor of extracellular mechanical cues. Acta Biomater 2023; 158:80-86. [PMID: 36638946 DOI: 10.1016/j.actbio.2023.01.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 12/18/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023]
Abstract
Cell adhesion molecules mediate cell-cell or cell-matrix interactions, some of which are mechanical sensors, such as integrins. Emerging evidence indicates that anthrax toxin receptor 1 (ANTXR1), a newly identified cell adhesion molecule, can also sense extracellular mechanical signals such as hydrostatic pressure and extracellular matrix (ECM) rigidity. ANTXR1 can interact with ECM through connecting intracellular cytoskeleton and ECM molecules (just like integrins) to regulate numerous biological processes, such as cell adhesion, cell migration or ECM homeostasis. Although with high structural similarity to integrins, its functions and downstream signal transduction are independent from those of integrins. In this perspective, based on existing evidence in literature, we analyzed the structural and functional evidence that ANTXR1 can act as a potential sensor for extracellular mechanical cues. To our knowledge, this is the first in-depth overview of ANTXR1 from the perspective of mechanobiology. STATEMENT OF SIGNIFICANCE: An overview of ANTXR1 from the perspective of mechanobiology; An analysis of mechanical sensitivity of ANTXR1 in structure and function; A summary of existing evidence of ANTXR1 as a potential mechanosensor.
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21
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Nasiri F, Kazemi M, Mirarefin SMJ, Mahboubi Kancha M, Ahmadi Najafabadi M, Salem F, Dashti Shokoohi S, Evazi Bakhshi S, Safarzadeh Kozani P, Safarzadeh Kozani P. CAR-T cell therapy in triple-negative breast cancer: Hunting the invisible devil. Front Immunol 2022; 13. [DOI: https:/doi.org/10.3389/fimmu.2022.1018786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is known as the most intricate and hard-to-treat subtype of breast cancer. TNBC cells do not express the well-known estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expressed by other breast cancer subtypes. This phenomenon leaves no room for novel treatment approaches including endocrine and HER2-specific antibody therapies. To date, surgery, radiotherapy, and systemic chemotherapy remain the principal therapy options for TNBC treatment. However, in numerous cases, these approaches either result in minimal clinical benefit or are nonfunctional, resulting in disease recurrence and poor prognosis. Nowadays, chimeric antigen receptor T cell (CAR-T) therapy is becoming more established as an option for the treatment of various types of hematologic malignancies. CAR-Ts are genetically engineered T lymphocytes that employ the body’s immune system mechanisms to selectively recognize cancer cells expressing tumor-associated antigens (TAAs) of interest and efficiently eliminate them. However, despite the clinical triumph of CAR-T therapy in hematologic neoplasms, CAR-T therapy of solid tumors, including TNBC, has been much more challenging. In this review, we will discuss the success of CAR-T therapy in hematological neoplasms and its caveats in solid tumors, and then we summarize the potential CAR-T targetable TAAs in TNBC studied in different investigational stages.
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22
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Nasiri F, Kazemi M, Mirarefin SMJ, Mahboubi Kancha M, Ahmadi Najafabadi M, Salem F, Dashti Shokoohi S, Evazi Bakhshi S, Safarzadeh Kozani P, Safarzadeh Kozani P. CAR-T cell therapy in triple-negative breast cancer: Hunting the invisible devil. Front Immunol 2022; 13:1018786. [PMID: 36483567 PMCID: PMC9722775 DOI: 10.3389/fimmu.2022.1018786] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/24/2022] [Indexed: 11/23/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is known as the most intricate and hard-to-treat subtype of breast cancer. TNBC cells do not express the well-known estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expressed by other breast cancer subtypes. This phenomenon leaves no room for novel treatment approaches including endocrine and HER2-specific antibody therapies. To date, surgery, radiotherapy, and systemic chemotherapy remain the principal therapy options for TNBC treatment. However, in numerous cases, these approaches either result in minimal clinical benefit or are nonfunctional, resulting in disease recurrence and poor prognosis. Nowadays, chimeric antigen receptor T cell (CAR-T) therapy is becoming more established as an option for the treatment of various types of hematologic malignancies. CAR-Ts are genetically engineered T lymphocytes that employ the body's immune system mechanisms to selectively recognize cancer cells expressing tumor-associated antigens (TAAs) of interest and efficiently eliminate them. However, despite the clinical triumph of CAR-T therapy in hematologic neoplasms, CAR-T therapy of solid tumors, including TNBC, has been much more challenging. In this review, we will discuss the success of CAR-T therapy in hematological neoplasms and its caveats in solid tumors, and then we summarize the potential CAR-T targetable TAAs in TNBC studied in different investigational stages.
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Affiliation(s)
- Fatemeh Nasiri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Department of Production Platforms & Analytics, Human Health Therapeutics Research Centre, National Research Council Canada, Montreal, QC, Canada
| | - Mehrasa Kazemi
- Department of Laboratory Medicine, Thalassemia Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | | | - Maral Mahboubi Kancha
- Department of Medical Nanotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Milad Ahmadi Najafabadi
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Faeze Salem
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Setareh Dashti Shokoohi
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sahar Evazi Bakhshi
- Department of Anatomical Sciences, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Pouya Safarzadeh Kozani
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Pooria Safarzadeh Kozani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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23
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Hsu KS, Dunleavey JM, Szot C, Yang L, Hilton MB, Morris K, Seaman S, Feng Y, Lutz EM, Koogle R, Tomassoni-Ardori F, Saha S, Zhang XM, Zudaire E, Bajgain P, Rose J, Zhu Z, Dimitrov DS, Cuttitta F, Emenaker NJ, Tessarollo L, St. Croix B. Cancer cell survival depends on collagen uptake into tumor-associated stroma. Nat Commun 2022; 13:7078. [PMID: 36400786 PMCID: PMC9674701 DOI: 10.1038/s41467-022-34643-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022] Open
Abstract
Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma. Tumor-associated stromal cells processed collagen into glutamine, which was then released and internalized by cancer cells. Under chronic nutrient starvation, a condition driven by the high metabolic demand of tumors, cancer cells exploited glutamine to survive, an effect that could be reversed by blocking collagen uptake with TEM8 neutralizing antibodies. These studies reveal that cancer cells exploit collagen-consuming stromal cells for survival, exposing an important vulnerability across solid tumors with implications for developing improved anticancer therapy.
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Affiliation(s)
- Kuo-Sheng Hsu
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - James M. Dunleavey
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Christopher Szot
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Liping Yang
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Mary Beth Hilton
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA ,grid.418021.e0000 0004 0535 8394Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD 21702 USA
| | - Karen Morris
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA ,grid.418021.e0000 0004 0535 8394Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD 21702 USA
| | - Steven Seaman
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Yang Feng
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Emily M. Lutz
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Robert Koogle
- grid.418021.e0000 0004 0535 8394MCGP, NCI, Frederick, MD 21702 USA
| | | | - Saurabh Saha
- BioMed Valley Discoveries, Inc, Kansas City, MO 64111 USA ,Present Address: Centessa Pharmaceuticals, Cambridge, MA 02139 USA
| | - Xiaoyan M. Zhang
- BioMed Valley Discoveries, Inc, Kansas City, MO 64111 USA ,Present Address: Ikena Oncology, Cambridge, MA 02210 USA
| | - Enrique Zudaire
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA ,Present Address: Janssen Pharmaceutical Companies, J&J, R&D, Welsh Road McKean Road, Spring House, PA 19477 USA
| | - Pradip Bajgain
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Joshua Rose
- grid.48336.3a0000 0004 1936 8075Biomolecular Structure Section, Center for Structural Biology, NCI, NIH, Frederick, MD 21702 USA
| | - Zhongyu Zhu
- grid.48336.3a0000 0004 1936 8075Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702 USA ,grid.420872.bPresent Address: Lentigen Technology, Inc. 1201 Clopper Road, Gaithersburg, MD 20878 USA
| | - Dimiter S. Dimitrov
- grid.48336.3a0000 0004 1936 8075Protein Interactions Section, Cancer and Inflammation Program, NCI, NIH, Frederick, MD 21702 USA ,grid.21925.3d0000 0004 1936 9000Present Address: Center for Antibody Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA
| | - Frank Cuttitta
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
| | - Nancy J. Emenaker
- grid.48336.3a0000 0004 1936 8075Division of Cancer Prevention, NCI, NIH, Bethesda, MD 20892 USA
| | - Lino Tessarollo
- grid.48336.3a0000 0004 1936 8075Neural Development Section, MCGP, NCI, NIH, Frederick, MD 21702 USA
| | - Brad St. Croix
- grid.48336.3a0000 0004 1936 8075Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702 USA
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FANG ZIQIAN, KILLICK CHARLOTTE, HALFPENNY CERITH, FREWER NATASHA, FREWER KATHRYNA, RUGE FIONA, JIANG WENG, YE LIN. Sex Hormone-regulated CMG2 Is Involved in Breast and Prostate Cancer Progression. Cancer Genomics Proteomics 2022; 19:703-710. [PMID: 36316045 PMCID: PMC9620450 DOI: 10.21873/cgp.20353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND/AIM Capillary morphogenesis gene 2 (CMG2) is involved in prostate and breast cancer progression. This study aimed to investigate sex hormone receptor-mediated regulation of CMG2 in breast and prostate cancer, and its implication in disease progression. MATERIALS AND METHODS Expression of CMG2, oestrogen receptor (ER) and androgen receptor (AR) was determined in breast and prostate cancer cell lines, respectively, using real-time quantitative PCR (QPCR) and western blot. Association between CMG2 and sex hormone receptors was analysed in a number of transcriptome datasets. Immunochemical staining was performed in tissue microarrays of breast cancer (BR1505D) and prostate cancer (PR8011A). CMG2 expression was determined in 17β-oestradiol treated breast cancer cells and AR over-expressing prostate cancer cells. RESULTS CMG2 was found to be inversely correlated with sex hormone receptors in breast and prostate cancer. Lower expression of CMG2 was associated with a poor prognosis in ER (+) breast cancer but not ER (-) tumours. Both ER (+) breast cancer cell lines and AR (+) prostate cancer cell lines presented lower expression of CMG2, which was increased following sex hormone deprivation. Exposure to 17-β-oestradiol and AR over-expression repressed CMG2 expression in breast cancer and prostate cancer cell lines, respectively. CONCLUSION CMG2 is inversely correlated with ER and AR status in breast and prostate cancer, respectively. ER and AR mediate repression of CMG2 expression in corresponding cancerous cells.
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25
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Kaminski MF, Bendzick L, Hopps R, Kauffman M, Kodal B, Soignier Y, Hinderlie P, Walker JT, Lenvik TR, Geller MA, Miller JS, Felices M. TEM8 Tri-specific Killer Engager binds both tumor and tumor stroma to specifically engage natural killer cell anti-tumor activity. J Immunother Cancer 2022; 10:e004725. [PMID: 36162918 PMCID: PMC9516302 DOI: 10.1136/jitc-2022-004725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND The tumor microenvironment contains stromal cells, including endothelial cells and fibroblasts, that aid tumor growth and impair immune cell function. Many solid tumors remain difficult to cure because of tumor-promoting stromal cells, but current therapies targeting tumor stromal cells are constrained by modest efficacy and toxicities. TEM8 is a surface antigen selectively upregulated on tumor and tumor stromal cells, endothelial cells and fibroblasts that may be targeted with specific natural killer (NK) cell engagement. METHODS A Tri-specific Killer Engager (TriKE) against TEM8-'cam1615TEM8'-was generated using a mammalian expression system. Its function on NK cells was assessed by evaluation of degranulation, inflammatory cytokine production, and killing against tumor and stroma cell lines in standard co-culture and spheroid assays. cam1615TEM8-mediated proliferation and STAT5 phosphorylation in NK cells was tested and compared with T cells by flow cytometry. NK cell proliferation, tumor infiltration, and tumor and tumor-endothelium killing by cam1615TEM8 and interleukin-15 (IL-15) were assessed in NOD scid gamma (NSG) mice. RESULTS cam1615TEM8 selectively stimulates NK cell degranulation and inflammatory cytokine production against TEM8-expressing tumor and stromal cell lines. The increased activation translated to superior NK cell killing of TEM8-expressing tumor spheroids. cam1615TEM8 selectively stimulated NK cell but not T cell proliferation in vitro and enhanced NK cell proliferation, survival, and tumor infiltration in vivo. Finally, cam1615TEM8 stimulated NK cell killing of tumor and tumor endothelial cells in vivo. CONCLUSIONS Our findings indicate that the cam1615TEM8 TriKE is a novel anti-tumor, anti-stroma, and anti-angiogenic cancer therapy for patients with solid tumors. This multifunctional molecule works by selectively targeting and activating NK cells by costimulation with IL-15, and then targeting that activity to TEM8+ tumor cells and TEM8+ tumor stroma.
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Affiliation(s)
- Michael F Kaminski
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Laura Bendzick
- Obstetrics, Gynecology and Women's Health, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Rachel Hopps
- Obstetrics, Gynecology and Women's Health, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Marissa Kauffman
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Behiye Kodal
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Yvette Soignier
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Peter Hinderlie
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Joshua T Walker
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Todd R Lenvik
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Melissa A Geller
- Obstetrics, Gynecology and Women's Health, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Jeffrey S Miller
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Martin Felices
- Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
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26
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Jin T, Zhang Z, Han Y, Li D, Liu J, Jiang M, Kurita R, Nakamura Y, Hu F, Fang X, Huang S, Sun Z. ANTXR1 Regulates Erythroid Cell Proliferation and Differentiation through wnt/ β-Catenin Signaling Pathway In Vitro and in Hematopoietic Stem Cell. DISEASE MARKERS 2022; 2022:1226697. [PMID: 36065334 PMCID: PMC9440811 DOI: 10.1155/2022/1226697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/21/2022] [Accepted: 07/29/2022] [Indexed: 11/18/2022]
Abstract
Erythropoiesis is a highly complex and sophisticated multistage process regulated by many transcription factors, as well as noncoding RNAs. Anthrax toxin receptor 1 (ANTXR1) is a type I transmembrane protein that binds the anthrax toxin ligands and mediates the entry of its toxic part into cells. It also functions as a receptor for the Protective antigen (PA) of anthrax toxin, and mediates the entry of Edema factor (EF) and Lethal factor (LF) into the cytoplasm of target cells and exerts their toxicity. Previous research has shown that ANTXR1 inhibits the expression of γ-globin during the differentiation of erythroid cells. However, the effect on erythropoiesis from a cellular perspective has not been fully determined. This study examined the role of ANTXR1 on erythropoiesis using K562 and HUDEP-2 cell lines as well as cord blood CD34+ cells. Our study has shown that overexpression of ANTXR1 can positively regulate erythrocyte proliferation, as well as inhibit GATA1 and ALAS2 expression, differentiation, and apoptosis in K562 cells and hematopoietic stem cells. ANTXR1 knockdown inhibited proliferation, promoted GATA1 and ALAS2 expression, accelerated erythrocyte differentiation and apoptosis, and promoted erythrocyte maturation. Our study also showed that ANTXR1 may regulate the proliferation and differentiation of hematopoietic cells, though the Wnt/β-catenin pathway, which may help to establish a possible therapeutic target for the treatment of blood disorders.
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Affiliation(s)
- Tingting Jin
- School of Medicine, Guizhou University, Guiyang, Guizhou 550025, China
- Prenatal Diagnosis Center, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Zhaojun Zhang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yuanyuan Han
- School of Medicine, Guizhou University, Guiyang, Guizhou 550025, China
- Prenatal Diagnosis Center, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Di Li
- Prenatal Diagnosis Center, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Juan Liu
- School of Medicine, Guizhou University, Guiyang, Guizhou 550025, China
| | - Minmin Jiang
- Prenatal Diagnosis Center, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Ryo Kurita
- Cell Engineering Division, RIKEN Bio Resource Center, Tsukuba, Ibaraki 305-0074, Japan
| | - Yukio Nakamura
- Cell Engineering Division, RIKEN Bio Resource Center, Tsukuba, Ibaraki 305-0074, Japan
| | - Fangfang Hu
- Department of Laboratory, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Xiangdong Fang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Shengwen Huang
- School of Medicine, Guizhou University, Guiyang, Guizhou 550025, China
- Prenatal Diagnosis Center, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Zhaolin Sun
- School of Medicine, Guizhou University, Guiyang, Guizhou 550025, China
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
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27
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Corbett V, Hallenbeck P, Rychahou P, Chauhan A. Evolving role of seneca valley virus and its biomarker TEM8/ANTXR1 in cancer therapeutics. Front Mol Biosci 2022; 9:930207. [PMID: 36090051 PMCID: PMC9458967 DOI: 10.3389/fmolb.2022.930207] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
Oncolytic viruses have made a significant inroad in cancer drug development. Numerous clinical trials are currently investigating oncolytic viruses both as single agents or in combination with various immunomodulators. Oncolytic viruses (OV) are an integral pillar of immuno-oncology and hold potential for not only delivering durable anti-tumor responses but also converting “cold” tumors to “hot” tumors. In this review we will discuss one such promising oncolytic virus called Seneca Valley Virus (SVV-001) and its therapeutic implications. SVV development has seen seismic evolution over the past decade and now boasts of being the only OV with a practically applicable biomarker for viral tropism. We discuss relevant preclinical and clinical data involving SVV and how bio-selecting for TEM8/ANTXR1, a negative tumor prognosticator can lead to first of its kind biomarker driven oncolytic viral cancer therapy.
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Affiliation(s)
- Virginia Corbett
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | | | - Piotr Rychahou
- Department of Surgery, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Aman Chauhan
- Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- *Correspondence: Aman Chauhan,
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28
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Nikoo M, Rudiansyah M, Bokov DO, Jainakbaev N, Suksatan W, Ansari MJ, Thangavelu L, Chupradit S, Zamani A, Adili A, Shomali N, Akbari M. Potential of chimeric antigen receptor (CAR)-redirected immune cells in breast cancer therapies: Recent advances. J Cell Mol Med 2022; 26:4137-4156. [PMID: 35762299 PMCID: PMC9344815 DOI: 10.1111/jcmm.17465] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/16/2022] [Accepted: 05/28/2022] [Indexed: 11/29/2022] Open
Abstract
Despite substantial developments in conventional treatments such as surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular-targeted therapy, breast cancer remains the leading cause of cancer mortality in women. Currently, chimeric antigen receptor (CAR)-redirected immune cell therapy has emerged as an innovative immunotherapeutic approach to ameliorate survival rates of breast cancer patients by eliciting cytotoxic activity against cognate tumour-associated antigens expressing tumour cells. As a crucial component of adaptive immunity, T cells and NK cells, as the central innate immune cells, are two types of pivotal candidates for CAR engineering in treating solid malignancies. However, the biological distinctions between NK cells- and T cells lead to differences in cancer immunotherapy outcomes. Likewise, optimal breast cancer removal via CAR-redirected immune cells requires detecting safe target antigens, improving CAR structure for ideal immune cell functions, promoting CAR-redirected immune cells filtration to the tumour microenvironment (TME), and increasing the ability of these engineered cells to persist and retain within the immunosuppressive TME. This review provides a concise overview of breast cancer pathogenesis and its hostile TME. We focus on the CAR-T and CAR-NK cells and discuss their significant differences. Finally, we deliver a summary based on recent advancements in the therapeutic capability of CAR-T and CAR-NK cells in treating breast cancer.
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Affiliation(s)
- Marzieh Nikoo
- Department of Immunology, School of MedicineKermanshah University of Medical SciencesKermanshahIran
| | - Mohammad Rudiansyah
- Division of Nephrology & Hypertension, Department of Internal Medicine, Faculty of MedicineUniversitas Lambung Mangkurat / Ulin HospitalBanjarmasinIndonesia
| | - Dmitry Olegovich Bokov
- Institute of PharmacySechenov First Moscow State Medical UniversityMoscowRussian Federation
- Laboratory of Food ChemistryFederal Research Center of Nutrition, Biotechnology and Food SafetyMoscowRussian Federation
| | | | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical ScienceChulabhorn Royal AcademyBangkokThailand
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of PharmacyPrince Sattam Bin Abdulaziz UniversityAl‐kharjSaudi Arabia
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical ScienceSaveetha UniversityChennaiIndia
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical SciencesChiang Mai UniversityChiang MaiThailand
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina HospitalShiraz University of Medical SciencesShirazIran
| | - Ali Adili
- Department of OncologyTabriz University of Medical SciencesTabrizIran
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South FloridaTampaFloridaUSA
| | - Navid Shomali
- Department of ImmunologyTabriz University of Medical SciencesTabrizIran
| | - Morteza Akbari
- Department of ImmunologyTabriz University of Medical SciencesTabrizIran
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Bae E, Huang P, Müller-Greven G, Hambardzumyan D, Sloan AE, Nowacki AS, Marko N, Carlin CR, Gladson CL. Integrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis. Nat Commun 2022; 13:4268. [PMID: 35879332 PMCID: PMC9314429 DOI: 10.1038/s41467-022-31981-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 07/12/2022] [Indexed: 12/13/2022] Open
Abstract
Therapeutic targeting of angiogenesis in glioblastoma has yielded mixed outcomes. Investigation of tumor-associated angiogenesis has focused on the factors that stimulate the sprouting, migration, and hyperproliferation of the endothelial cells. However, little is known regarding the processes underlying the formation of the tumor-associated vessels. To address this issue, we investigated vessel formation in CD31+ cells isolated from human glioblastoma tumors. The results indicate that overexpression of integrin α3β1 plays a central role in the promotion of tube formation in the tumor-associated endothelial cells in glioblastoma. Blocking α3β1 function reduced sprout and tube formation in the tumor-associated endothelial cells and vessel density in organotypic cultures of glioblastoma. The data further suggest a mechanistic model in which integrin α3β1-promoted calcium influx stimulates macropinocytosis and directed maturation of the macropinosomes in a manner that promotes lysosomal exocytosis during nascent lumen formation. Altogether, our data indicate that integrin α3β1 may be a therapeutic target on the glioblastoma vasculature.
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Affiliation(s)
- Eunnyung Bae
- Department of Cancer Biology, Cleveland, Clinic, Cleveland, OH, USA
| | - Ping Huang
- Department of Cancer Biology, Cleveland, Clinic, Cleveland, OH, USA
| | | | - Dolores Hambardzumyan
- Departments of Oncological Sciences and Neurosurgery, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Andrew Edward Sloan
- Department of Neurosurgery, Seidman Cancer Center, Cleveland, OH, USA
- University Hospital-Cleveland Medical Center and the Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
| | - Amy S Nowacki
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - Nicholas Marko
- Department of Neurosurgery, LewisGale Medical Center, Salem, VA, USA
| | - Cathleen R Carlin
- University Hospital-Cleveland Medical Center and the Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
| | - Candece L Gladson
- Department of Cancer Biology, Cleveland, Clinic, Cleveland, OH, USA.
- University Hospital-Cleveland Medical Center and the Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, OH, USA.
- The Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA.
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30
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Matikonda SS, McLaughlin R, Shrestha P, Lipshultz C, Schnermann MJ. Structure-Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold. Bioconjug Chem 2022; 33:1241-1253. [PMID: 35801843 DOI: 10.1021/acs.bioconjchem.2c00177] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Antibody-drug conjugates (ADCs) are a rapidly growing class of cancer therapeutics that seek to overcome the low therapeutic index of conventional cytotoxic agents. However, realizing this goal has been a significant challenge. ADCs comprise several independently modifiable components, including the antibody, payload, linker, and bioconjugation method. Many approaches have been developed to improve the physical properties, potency, and selectivity of ADCs. The anti-HER-2 antibody trastuzumab, first approved in 1998, has emerged as an exceptional targeting agent for ADCs, as well as a broadly used platform for testing new technologies. The extensive work in this area enables the comparison of various linker strategies, payloads, drug-to-antibody ratios (DAR), and mode of attachment. In this review, these conjugates, ranging from the first clinically approved trastuzumab ADC, ado-trastuzumab emtansine (Kadcyla), to the latest variants are described with the goal of providing a broad overview, as well as enabling the comparison of existing and emerging conjugate technologies.
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Affiliation(s)
- Siddharth S Matikonda
- Chemical Biology Laboratory, NIH/NCI/CCR, 376 Boyles Street, Frederick, Maryland 21702, United States
| | - Ryan McLaughlin
- Chemical Biology Laboratory, NIH/NCI/CCR, 376 Boyles Street, Frederick, Maryland 21702, United States
| | - Pradeep Shrestha
- Chemical Biology Laboratory, NIH/NCI/CCR, 376 Boyles Street, Frederick, Maryland 21702, United States
| | - Carol Lipshultz
- Chemical Biology Laboratory, NIH/NCI/CCR, 376 Boyles Street, Frederick, Maryland 21702, United States
| | - Martin J Schnermann
- Chemical Biology Laboratory, NIH/NCI/CCR, 376 Boyles Street, Frederick, Maryland 21702, United States
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31
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Ning WJ, Liu X, Zeng HY, An ZQ, Luo WX, Xia NS. Recent progress in antibody-based therapeutics for triple-negative breast cancer. Expert Opin Drug Deliv 2022; 19:815-832. [PMID: 35738312 DOI: 10.1080/17425247.2022.2093853] [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] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is a subtype of severely aggressive breast cancer that lacks the expression of oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2) and is highly metastatic and related to a poor prognosis. Current standard treatments are still limited to systemic chemotherapy, radiotherapy, and surgical resection. More effective treatments are urgently needed. AREAS COVERED The immunogenicity of TNBC has provided opportunities for the development of targeted immunotherapy. In this review, we focus on the recent development in antibody-based drug modalities, including angiogenesis inhibitors, immune checkpoint inhibitors, antibody-drug conjugates, immunoconjugates, T cell-redirecting bispecific antibodies and CAR-T cells, and their mechanisms of action in TNBC. EXPERT OPINION At present, the treatment of TNBC is still a major challenge that needs to be addressed. Novel immunotherapies are promising opportunities for improving the management of this aggressive disease.
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Affiliation(s)
- Wen-Jing Ning
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Hong-Ye Zeng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Zhi-Qiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wen-Xin Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Ning-Shao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
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32
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Alnefaie A, Albogami S, Asiri Y, Ahmad T, Alotaibi SS, Al-Sanea MM, Althobaiti H. Chimeric Antigen Receptor T-Cells: An Overview of Concepts, Applications, Limitations, and Proposed Solutions. Front Bioeng Biotechnol 2022; 10:797440. [PMID: 35814023 PMCID: PMC9256991 DOI: 10.3389/fbioe.2022.797440] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open
Abstract
Adaptive immunity, orchestrated by B-cells and T-cells, plays a crucial role in protecting the body from pathogenic invaders and can be used as tools to enhance the body's defense mechanisms against cancer by genetically engineering these immune cells. Several strategies have been identified for cancer treatment and evaluated for their efficacy against other diseases such as autoimmune and infectious diseases. One of the most advanced technologies is chimeric antigen receptor (CAR) T-cell therapy, a pioneering therapy in the oncology field. Successful clinical trials have resulted in the approval of six CAR-T cell products by the Food and Drug Administration for the treatment of hematological malignancies. However, there have been various obstacles that limit the use of CAR T-cell therapy as the first line of defense mechanism against cancer. Various innovative CAR-T cell therapeutic designs have been evaluated in preclinical and clinical trial settings and have demonstrated much potential for development. Such trials testing the suitability of CARs against solid tumors and HIV are showing promising results. In addition, new solutions have been proposed to overcome the limitations of this therapy. This review provides an overview of the current knowledge regarding this novel technology, including CAR T-cell structure, different applications, limitations, and proposed solutions.
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Affiliation(s)
- Alaa Alnefaie
- Department of Medical Services, King Faisal Medical Complex, Taif, Saudi Arabia
| | - Sarah Albogami
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Yousif Asiri
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Tanveer Ahmad
- Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, New Delhi, India
| | - Saqer S. Alotaibi
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Mohammad M. Al-Sanea
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Hisham Althobaiti
- Chief of Medical Department, King Faisal Medical Complex (KFMC), Taif, Saudi Arabia
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33
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Cheng H, Jin S, Huang S, Hu T, Zhao M, Li D, Wu B. Serum Proteomic Analysis by Tandem Mass Tag-Based Quantitative Proteomics in Pediatric Obstructive Sleep Apnea. Front Mol Biosci 2022; 9:762336. [PMID: 35480887 PMCID: PMC9035643 DOI: 10.3389/fmolb.2022.762336] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 03/04/2022] [Indexed: 12/02/2022] Open
Abstract
Pediatric obstructive sleep apnea (OSA) is a frequent respiratory disorder with an estimated prevalence of 3–6% in the general population. However, the underlying pathophysiology of OSA remains unclear. Recently, proteomic analysis using high-resolution and high-throughput mass spectrometry has been widely used in the field of medical sciences. In the present study, tandem mass tag (TMT)-based proteomic analysis was performed in the serum of patients with OSA. The proteomic analysis revealed a set of differentially expressed proteins that may be associated with the pathophysiology of OSA. The differentially expressed proteins in patients with OSA were enriched in pathways including phagosome and glycan synthesis/degradation, immune response, and the hedgehog signaling pathway, indicating that such functions are key targets of OSA. Moreover, the experimental validation studies revealed that four proteins including ANTXR1, COLEC10, NCAM1, and VNN1 were reduced in the serum from patients with moderate and severe OSA, while MAN1A1 and CSPG4 protein levels were elevated in the serum from patients with severe OSA. The protein levels of ANTXR1, COLEC10, NCAM1, and VNN1 were inversely correlated with apnea-hypopnea index (AHI) in the recruited subjects, while the protein level of MAN1A1 was positively correlated with AHI, and no significant correlation was detected between CSPG4 protein and AHI. In summary, the present study for the first time identified differentially expressed proteins in the serum from OSA patients with different severities by using TMT-based proteomic analysis. The functional enrichment studies suggested that several signaling pathways may be associated with the pathophysiology of OSA. The experimental validation results indicated that six proteins including ANTXR1, COLEC10, NCAM1, VNN1, CGPG4, and MAN1A1 may play important roles in the pathophysiology of OSA, which requires further mechanistic investigation.
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Affiliation(s)
- Hanrong Cheng
- Institute of Respiratory Diseases, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Shoumei Jin
- Longgang ENT Hospital, Institute of ENT and Shenzhen Key Laboratory of ENT, Shenzhen, China
| | - Simin Huang
- Longgang ENT Hospital, Institute of ENT and Shenzhen Key Laboratory of ENT, Shenzhen, China
| | - Tianyong Hu
- Longgang ENT Hospital, Institute of ENT and Shenzhen Key Laboratory of ENT, Shenzhen, China
| | - Miao Zhao
- Longgang ENT Hospital, Institute of ENT and Shenzhen Key Laboratory of ENT, Shenzhen, China
| | - Dongcai Li
- Longgang ENT Hospital, Institute of ENT and Shenzhen Key Laboratory of ENT, Shenzhen, China
- *Correspondence: Dongcai Li, ; Benqing Wu,
| | - Benqing Wu
- Department of Neonatology, University of Chinese Academy of Science-Shenzhen Hospital, Shenzhen, China
- *Correspondence: Dongcai Li, ; Benqing Wu,
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34
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Luo D, Wang H, Wang Q, Liang W, Liu B, Xue D, Yang Y, Ma B. Senecavirus A as an Oncolytic Virus: Prospects, Challenges and Development Directions. Front Oncol 2022; 12:839536. [PMID: 35371972 PMCID: PMC8968071 DOI: 10.3389/fonc.2022.839536] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Oncolytic viruses have the capacity to selectively kill infected tumor cells and trigger protective immunity. As such, oncolytic virotherapy has become a promising immunotherapy strategy against cancer. A variety of viruses from different families have been proven to have oncolytic potential. Senecavirus A (SVA) was the first picornavirus to be tested in humans for its oncolytic potential and was shown to penetrate solid tumors through the vascular system. SVA displays several properties that make it a suitable model, such as its inability to integrate into human genome DNA and the absence of any viral-encoded oncogenes. In addition, genetic engineering of SVA based on the manipulation of infectious clones facilitates the development of recombinant viruses with improved therapeutic indexes to satisfy the criteria of safety and efficacy regulations. This review summarizes the current knowledge and strategies of genetic engineering for SVA, and addresses the current challenges and future directions of SVA as an oncolytic agent.
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Affiliation(s)
- Dankun Luo
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Haiwei Wang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Qiang Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenping Liang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bo Liu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Yang
- Departments of Biochemistry and Molecular Biology and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Biao Ma
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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35
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Corti C, Venetis K, Sajjadi E, Zattoni L, Curigliano G, Fusco N. CAR-T cell therapy for triple-negative breast cancer and other solid tumors: preclinical and clinical progress. Expert Opin Investig Drugs 2022; 31:593-605. [PMID: 35311430 DOI: 10.1080/13543784.2022.2054326] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Most breast cancer-related deaths arise from triple-negative breast cancer (TNBC). Molecular heterogeneity, aggressiveness and the lack of effective therapies are major hurdles to therapeutic progress. Chimeric antigen receptor (CAR)-T cells have emerged as a promising immunotherapeutic strategy in TNBC. This approach combines the antigen specificity of an antibody with the effector function of T cells. AREAS COVERED This review examines the opportunities provided by CAR-T cell therapies in solid tumors. Emerging targets, ongoing clinical trials, and prospective clinical implications in TNBC are considered later. An emphasis is placed on the key challenges and possible solutions for this therapeutic approach. EXPERT OPINION A challenge for CAR-T cell therapy is the selection of the optimal targets to minimize on-target/off-tumor toxicity. Tumor escape via antigen loss and intrinsic heterogeneity is a further hurdle. TROP2, GD2, ROR1, MUC1 and EpCAM are promising targets. Persistence and trafficking to tumor cells may be enhanced by the implementation of CARs with a chemokine receptor and/or constitutively activated interleukin receptors. Fourth-generation CARs (TRUCKs) may redirect T-cells for universal cytokine-mediated killing. Combinatorial approaches and the application of CARs to other immune cells could revert the suppressive immune environment that characterizes solid neoplasms.
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Affiliation(s)
- Chiara Corti
- Division of New Drugs and Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | | | - Elham Sajjadi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Lorenzo Zattoni
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.,Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
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36
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Cryan LM, Tsang TM, Stiles J, Bazinet L, Lee SL, Garrard S, Madrian E, Roberts C, Payne J, Jensen A, Frankel AE, Ackroyd PC, Christensen KA, Rogers MS. Capillary morphogenesis gene 2 (CMG2) mediates growth factor-induced angiogenesis by regulating endothelial cell chemotaxis. Angiogenesis 2022; 25:397-410. [PMID: 35212873 PMCID: PMC9250616 DOI: 10.1007/s10456-022-09833-w] [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: 10/06/2021] [Accepted: 02/06/2022] [Indexed: 11/28/2022]
Abstract
Anthrax protective antigen (PA) is a potent inhibitor of pathological angiogenesis with an unknown mechanism. In anthrax intoxication, PA interacts with capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8). Here, we show that CMG2 mediates the antiangiogenic effects of PA and is required for growth-factor-induced chemotaxis. Using specific inhibitors of CMG2 and TEM8 interaction with natural ligand, as well as mice with the CMG2 or TEM8 transmembrane and intracellular domains disrupted, we demonstrate that inhibiting CMG2, but not TEM8 reduces growth-factor-induced angiogenesis in the cornea. Furthermore, the antiangiogenic effect of PA was abolished when the CMG2, but not the TEM8, gene was disrupted. Binding experiments demonstrated a broad ligand specificity for CMG2 among extracellular matrix (ECM) proteins. Ex vivo experiments demonstrated that CMG2 (but not TEM8) is required for PA activity in human dermal microvascular endothelial cell (HMVEC-d) network formation assays. Remarkably, blocking CMG2-ligand binding with PA or CRISPR knockout abolishes endothelial cell chemotaxis but not chemokinesis in microfluidic migration assays. These effects are phenocopied by Rho inhibition. Because CMG2 mediates the chemotactic response of endothelial cells to peptide growth factors in an ECM-dependent fashion, CMG2 is well-placed to integrate growth factor and ECM signals. Thus, CMG2 targeting is a novel way to inhibit angiogenesis.
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Affiliation(s)
- Lorna M Cryan
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, 11.211 Karp Family Research Bldg., 300 Longwood Ave., Boston, MA, 02115, USA
| | - Tsz-Ming Tsang
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Jessica Stiles
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, 11.211 Karp Family Research Bldg., 300 Longwood Ave., Boston, MA, 02115, USA
| | - Lauren Bazinet
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, 11.211 Karp Family Research Bldg., 300 Longwood Ave., Boston, MA, 02115, USA
| | - Sai Lun Lee
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Samuel Garrard
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.,Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, 11.211 Karp Family Research Bldg., 300 Longwood Ave., Boston, MA, 02115, USA
| | - Erika Madrian
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, 11.211 Karp Family Research Bldg., 300 Longwood Ave., Boston, MA, 02115, USA
| | - Cody Roberts
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Jessie Payne
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Andrew Jensen
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Arthur E Frankel
- Department of Medicine, West Palm Beach VA Medical Center, 7305 N Military Trail, West Palm Beach, FL, 33410, USA
| | - P Christine Ackroyd
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Kenneth A Christensen
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Michael S Rogers
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, 11.211 Karp Family Research Bldg., 300 Longwood Ave., Boston, MA, 02115, USA.
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Andrea AE, Chiron A, Mallah S, Bessoles S, Sarrabayrouse G, Hacein-Bey-Abina S. Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment. Front Immunol 2022; 13:830292. [PMID: 35211124 PMCID: PMC8861853 DOI: 10.3389/fimmu.2022.830292] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/18/2022] [Indexed: 12/15/2022] Open
Abstract
During this last decade, adoptive transfer of T lymphocytes genetically modified to express chimeric antigen receptors (CARs) emerged as a valuable therapeutic strategy in hematological cancers. However, this immunotherapy has demonstrated limited efficacy in solid tumors. The main obstacle encountered by CAR-T cells in solid malignancies is the immunosuppressive tumor microenvironment (TME). The TME impedes tumor trafficking and penetration of T lymphocytes and installs an immunosuppressive milieu by producing suppressive soluble factors and by overexpressing negative immune checkpoints. In order to overcome these hurdles, new CAR-T cells engineering strategies were designed, to potentiate tumor recognition and infiltration and anti-cancer activity in the hostile TME. In this review, we provide an overview of the major mechanisms used by tumor cells to evade immune defenses and we critically expose the most optimistic engineering strategies to make CAR-T cell therapy a solid option for solid tumors.
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Affiliation(s)
- Alain E. Andrea
- Laboratoire de Biochimie et Thérapies Moléculaires, Faculté de Pharmacie, Université Saint Joseph de Beyrouth, Beirut, Lebanon
| | - Andrada Chiron
- Université de Paris, CNRS, INSERM, UTCBS, Unité des technologies Chimiques et Biologiques pour la Santé, Paris, France
- Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Le-Kremlin-Bicêtre, France
| | - Sarah Mallah
- Faculty of Arts and Sciences, Lebanese American University, Beirut, Lebanon
| | - Stéphanie Bessoles
- Université de Paris, CNRS, INSERM, UTCBS, Unité des technologies Chimiques et Biologiques pour la Santé, Paris, France
| | - Guillaume Sarrabayrouse
- Université de Paris, CNRS, INSERM, UTCBS, Unité des technologies Chimiques et Biologiques pour la Santé, Paris, France
| | - Salima Hacein-Bey-Abina
- Université de Paris, CNRS, INSERM, UTCBS, Unité des technologies Chimiques et Biologiques pour la Santé, Paris, France
- Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Le-Kremlin-Bicêtre, France
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38
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Shan Y, Ni Q, Zhang Q, Zhang M, Wei B, Cheng L, Zhong C, Wang X, Wang Q, Liu J, Zhang J, Wu J, Wang G, Zhou F. Targeting tumor endothelial hyperglycolysis enhances immunotherapy through remodeling tumor microenvironment. Acta Pharm Sin B 2022; 12:1825-1839. [PMID: 35847509 PMCID: PMC9279856 DOI: 10.1016/j.apsb.2022.02.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/17/2021] [Accepted: 01/20/2022] [Indexed: 12/20/2022] Open
Abstract
Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion. Targeting the abnormal metabolism of tumor endothelial cells (TECs) may provide an opportunity to improve the outcome of immunotherapy. Here, in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer (CRC), TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Then an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in TECs. Low-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor, which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of GAPDH. Moreover, osimertinib and anti-PD-1 blockade synergistically retarded tumor growth. This study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.
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39
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Dai C, Waduge P, Ji L, Huang C, He Y, Tian H, Zuniga-Sanchez E, Bhatt A, Pang IH, Su G, Webster KA, Li W. Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy. Cell Mol Life Sci 2022; 79:63. [PMID: 35006382 PMCID: PMC9007175 DOI: 10.1007/s00018-021-04111-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/29/2021] [Accepted: 12/17/2021] [Indexed: 01/12/2023]
Abstract
Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.
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Affiliation(s)
- Chang Dai
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Prabuddha Waduge
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Liyang Ji
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Chengchi Huang
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Ye He
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Hong Tian
- Everglades Biopharma, LLC, Houston, TX, USA
| | | | - Amit Bhatt
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Texas Children Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Iok-Hou Pang
- Department of Pharmaceutical Sciences, North Texas Eye Research Institute, University of North Texas, Fort Worth, TX, USA
| | - Guanfang Su
- Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, Jilin, China
| | - Keith A Webster
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
- Everglades Biopharma, LLC, Houston, TX, USA
| | - Wei Li
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA.
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Zhang S, Zhang H, Shi L, Li Y, Tuerhong M, Abudukeremu M, Cui J, Li Y, Jin DQ, Xu J, Guo Y. Structure features, selenylation modification, and improved anti-tumor activity of a polysaccharide from Eriobotrya japonica. Carbohydr Polym 2021; 273:118496. [PMID: 34560937 DOI: 10.1016/j.carbpol.2021.118496] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/02/2021] [Accepted: 07/21/2021] [Indexed: 12/16/2022]
Abstract
A homogeneous polysaccharide, EJP90-1, was isolated from the leaves of E. japonica by hot water extraction in this study. EJP90-1 (7702 Da) was a heteropolysaccharide mainly consisting of →5)-linked-α-L-Araf-(1→, →4)-linked-β-D-Manp-(1→, →2,4)-linked-α-L-Rhap-(1→, →4)-linked-α-D-Xylp-(1→, →4)-linked-β-D-Galp-(1→, →2)-linked-β-D-Galp-(1→, →6)-linked-β-D-Glcp-(1→, α-D-Glcp-(4→, and t-linked-α-L-Araf. EJP90-1 was found to show moderate anti-tumor activity at the cellular level. In order to improve the anti-tumor activity and the potential applications of EJP90-1, a typical sodium selenite-nitric acid (Na2SeO3-HNO3) modification on EJP90-1 was carried out. X-ray photoelectron spectroscopy (XPS) and energy dispersive spectrometer (EDS) analysis confirmed that Se was successfully introduced into the polymer chain of EJP90-1. The subsequent in vitro cytotoxicity evaluation showed the selenylation modification derivative (EJP90-1-Se) possessed significant antiproliferative activity against cancer cells (HepG2 and A549 cells) through inducing cell apoptosis. The anti-tumor activity of EJP90-1-Se was further confirmed by zebrafish models, which inhibited the proliferation and migration of HepG2 cells and the angiogenesis.
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Affiliation(s)
- Shaojie Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, and Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300350, People's Republic of China
| | - Han Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, and Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300350, People's Republic of China
| | - Lijuan Shi
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, and Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300350, People's Republic of China
| | - Ying Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, and Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300350, People's Republic of China
| | - Muhetaer Tuerhong
- College of Chemistry and Environmental Sciences, Laboratory of Xinjiang Native Medicinal and Edible Plant Resources Chemistry, Kashgar University, Kashgar 844000, People's Republic of China
| | - Munira Abudukeremu
- College of Chemistry and Environmental Sciences, Laboratory of Xinjiang Native Medicinal and Edible Plant Resources Chemistry, Kashgar University, Kashgar 844000, People's Republic of China
| | - Jianlin Cui
- School of Medicine, Nankai University, Tianjin 300071, People's Republic of China
| | - Yuhao Li
- School of Medicine, Nankai University, Tianjin 300071, People's Republic of China
| | - Da-Qing Jin
- School of Medicine, Nankai University, Tianjin 300071, People's Republic of China
| | - Jing Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, and Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300350, People's Republic of China.
| | - Yuanqiang Guo
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, and Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300350, People's Republic of China.
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Si T, Ning X, Chen H, Hu Z, Dun L, Zheng N, Huang P, Yang L, Yi P. ANTXR1 as a potential prognostic biomarker for hepatitis B virus-related hepatocellular carcinoma identified by a weighted gene correlation network analysis. J Gastrointest Oncol 2021; 12:3079-3092. [PMID: 35070431 PMCID: PMC8748048 DOI: 10.21037/jgo-21-764] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/17/2021] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND With high incidence and mortality rates, hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Chronic hepatitis B virus (HBV) infection is a leading cause of HCC, especially for Asians and blacks. However, the molecular mechanisms underlying HBV-related HCC are unclear. This study sought to identify novel prognostic biomarkers and explore the potential pathogenesis of HBV-related HCC. METHODS The gene expression profiles and corresponding clinical information of HCC from The Cancer Genome Atlas Liver Hepatocellular Carcinoma data set were analyzed by a weighted gene co-expression network analysis. Correlations between the co-expression modules and clinical traits were calculated. Next, key modules associated with HBV infection were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted for the genes in the key modules. The hub genes were identified based on the protein-protein interaction (PPI) network via the Cytoscape. Finally, an overall survival (OS) analysis was performed. RESULTS The two modules (i.e., the brown and yellow modules) most relevant to HBV infection were constructed. A functional enrichment analysis revealed that the genes in the two modules were mainly enriched in HCC-related pathways, such as the phosphatidylinositol-3-kinase and protein kinase B signaling pathway, focal adhesion, human papillomavirus infection, the Rap1 signaling pathway, and the cyclic guanosine monophosphate-dependent protein kinase (cGMP-PKG) signaling pathway. Ten hub genes [i.e., COL3A1, ANTXR1, COL14A1, THBS2, ADAMTS2, AEBP1, PRELP, EMILIN1, DCN and PODN] in the brown module, and 10 hub genes [i.e., USP34, SEC24C, ZNF770, STAG1, TSTD2, PKD1P6, CCNK, GFT2I, NT5C2 and SMG6] in the yellow module were identified. Among the hub genes, ANTXR1 (Anthrax-toxin receptor 1) was significantly correlated with HBV-related HCC patients' OS. CONCLUSIONS ANTXR1 represents a potential therapeutic target for HBV-related HCC. This study offers novel insights into the molecular mechanisms of HBV-induced tumorigenesis, which needs to be further validated by basic experiments and large-scale cohort studies.
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Affiliation(s)
- Tao Si
- Department of Oncology, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Xuejian Ning
- Department of Oncology, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Haihui Chen
- Department of Oncology, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Zhengguo Hu
- Department of Oncology, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Linglu Dun
- Department of Neurology Laboratory, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Na Zheng
- Department of Neurology Laboratory, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Ping Huang
- Department of Oncology, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Liu Yang
- Department of Oncology, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
| | - Ping Yi
- Department of Neurology Laboratory, Liuzhou Traditional Chinese Medical Hospital, Liuzhou, China
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Howell LM, Forbes NS. Bacteria-based immune therapies for cancer treatment. Semin Cancer Biol 2021; 86:1163-1178. [PMID: 34547442 DOI: 10.1016/j.semcancer.2021.09.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/03/2021] [Accepted: 09/12/2021] [Indexed: 12/23/2022]
Abstract
Engineered bacterial therapies that target the tumor immune landscape offer a new class of cancer immunotherapy. Salmonella enterica and Listeria monocytogenes are two species of bacteria that have been engineered to specifically target tumors and serve as delivery vessels for immunotherapies. Therapeutic bacteria have been engineered to deliver cytokines, gene silencing shRNA, and tumor associated antigens that increase immune activation. Bacterial therapies stimulate both the innate and adaptive immune system, change the immune dynamics of the tumor microenvironment, and offer unique strategies for targeting tumors. Bacteria have innate adjuvant properties, which enable both the delivered molecules and the bacteria themselves to stimulate immune responses. Bacterial immunotherapies that deliver cytokines and tumor-associated antigens have demonstrated clinical efficacy. Harnessing the diverse set of mechanisms that Salmonella and Listeria use to alter the tumor-immune landscape has the potential to generate many new and effective immunotherapies.
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Affiliation(s)
- Lars M Howell
- Department of Chemical Engineering, University of Massachusetts, Amherst, United States
| | - Neil S Forbes
- Department of Chemical Engineering, University of Massachusetts, Amherst, United States.
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Li M, Fang L, Kwantwi LB, He G, Luo W, Yang L, Huang Y, Yin S, Cai Y, Ma W, Zhan H, Tong Z, Zhang L, Liang C, Yin Y. N-Myc promotes angiogenesis and therapeutic resistance of prostate cancer by TEM8. Med Oncol 2021; 38:127. [PMID: 34523032 PMCID: PMC8440287 DOI: 10.1007/s12032-021-01575-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/01/2021] [Indexed: 11/24/2022]
Abstract
Although patients with early localized prostate cancer can survive longer, castration-resistant prostate cancer (CRPC) has gradually emerged with the use of androgen deprivation therapy (ADT). N-Myc and TEM8 play a vital role in the progression of several cancer types. However, the underlying mechanism of how N-Myc and TEM8 promote the progression of prostate cancer remains unclear. In this study, the expression of N-Myc and TEM8 was detected in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissues by immunohistochemistry (IHC). LNCaP cell lines were maintained in RPMI 1640 medium supplemented with 10% charcoal-stripped fetal bovine serum. Subsequently, R language software was used to verify our results. Tubule formation assay of human umbilical vein endothelial cell (HUVEC) was conducted to examine the effect of N-Myc and TEM8 overexpression on angiogenesis in prostate cancer cells. IHC results showed a positive correlation between the expression of N-Myc and TEM8 in prostate cancer tissues. Further analysis showed that N-Myc and TEM8 were associated with clinicopathological features and poor prognosis in prostate cancer patients. Moreover, the overexpression of N-Myc and TEM8 promoted proliferation of prostate cancer cells and angiogenesis. Additionally, N-Myc and TEM8 overexpression was associated with therapeutic resistance. We further found that N-Myc promoted angiogenesis and therapeutic resistance in prostate cancer via TEM8. Hence, targeting N-Myc/TEM8 pathway in prostate cancer would be a novel therapeutic strategy to enhance the treatment of prostate cancer patients.
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Affiliation(s)
- Mingfeng Li
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Linna Fang
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Louis Boafo Kwantwi
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Guifang He
- Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Wenwu Luo
- Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Lijie Yang
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Yuhang Huang
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Shiyuan Yin
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Yongping Cai
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China.,Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Wei Ma
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China.,Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Heqin Zhan
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China.,Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Zhuting Tong
- Department of Radiotherapy, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Li Zhang
- Department of Urology, First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China
| | - Chaozhao Liang
- Department of Urology, First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China.
| | - Yu Yin
- Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China. .,Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.
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Zam W, Assaad A. Chimeric antigen receptor T-cells (CARs) in cancer treatment. Curr Mol Pharmacol 2021; 15:532-546. [PMID: 34382510 DOI: 10.2174/1874467214666210811150255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/27/2021] [Accepted: 05/17/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer is one of the leading causes of death worldwide. Chemotherapy, radiation therapy, and stem cell transplantation were the main cancer treatment approaches for several years but due to their limited effectiveness, there was a constant search for new therapeutic approaches. Cancer immunotherapy that utilizes and enhances the normal capacity of the patient's immune system was used to fight against cancer. Genetically engineered T-cells that express chimeric antigen receptors (CARs) showed remarkable anti-tumor activity against hematologic malignancies and is now being investigated in a variety of solid tumors. The use of this therapy in the last few years has been successful, achieving a great success in improving the quality of life and prolonging the survival time of patients with a reduction in remission rates. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. <P> Objective: This review summarizes various experimental approaches towards the use of CAR T-cells in hematologic malignancies and solid tumors. <P> Conclusion: Finally, we address the challenges posed by CAR T-cells and discuss strategies for improving the performance of these T cells in fighting cancers.
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Affiliation(s)
- Wissam Zam
- Department of Analytical and Food Chemistry, Faculty of Pharmacy, Al-Wadi International University, Homs. Syrian Arab Republic
| | - Amany Assaad
- 2. Department of Analytical and Food Chemistry, Faculty of Pharmacy,Tartous University, Tartous. Syrian Arab Republic
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Xu J, Yang X, Deng Q, Yang C, Wang D, Jiang G, Yao X, He X, Ding J, Qiang J, Tu J, Zhang R, Lei QY, Shao ZM, Bian X, Hu R, Zhang L, Liu S. TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer. Nat Commun 2021; 12:4413. [PMID: 34285210 PMCID: PMC8292527 DOI: 10.1038/s41467-021-24703-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 07/01/2021] [Indexed: 12/12/2022] Open
Abstract
Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously. Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis
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Affiliation(s)
- Jiahui Xu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoli Yang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Qiaodan Deng
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Cong Yang
- School of Medicine, Guizhou University, Guiyang, Guizhou, China
| | - Dong Wang
- WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan
| | - Guojuan Jiang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaohong Yao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University); Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Xueyan He
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiajun Ding
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiankun Qiang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Juchuanli Tu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Rui Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Qun-Ying Lei
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhi-Min Shao
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University); Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
| | - Ronggui Hu
- State Key Laboratory of Molecular Biology; CAS Center for Excellence in Molecular Cell Science; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
| | - Lixing Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China.
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College, Fudan University, Shanghai, China.
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The genomic architecture of metastasis in breast cancer: focus on mechanistic aspects, signalling pathways and therapeutic strategies. Med Oncol 2021; 38:95. [PMID: 34268641 DOI: 10.1007/s12032-021-01547-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/03/2021] [Indexed: 12/13/2022]
Abstract
Breast cancer is a multifactorial, heterogeneous disease and the second most frequent cancer amongst women worldwide. Metastasis is one of the most leading causes of death in these patients. Early-stage or locally advanced breast cancer is limited to the breast or nearby lymph nodes. When breast cancer spreads to farther tissues/organs from its original site, it is referred to as metastatic or stage IV breast cancer. Normal breast development is regulated by specific genes and signalling pathways controlling cell proliferation, cell death, cell differentiation and cell motility. Dysregulation of genes involved in various signalling pathways not only leads to the formation of primary tumour but also to the metastasis as well. The metastatic cascade is represented by a multi-step process including invasion of the local tumour cell followed by its entry into the vasculature, exit of malignant cells from the circulation and ultimately their colonization at the distant sites. These stages are referred to as formation of primary tumour, angiogenesis, invasion, intravasation and extravasation, respectively. The major sites of metastasis of breast cancer are the lymph nodes, bone, brain and lung. Only about 28% five-year survival rate has been reported for stage IV breast cancer. Metastasis is a serious concern for breast cancer and therefore, various therapeutic strategies such as tyrosine kinase inhibitors have been developed to target specific dysregulated genes and various signalling pathways involved in different steps of metastasis. In addition, other therapies like hyperbaric oxygen therapy, RNA interference and CRISPR/Cas9 are also being explored as novel strategies to cure the stage IV/metastatic breast cancer. Therefore, the current review has been compiled with an aim to evaluate the genetic basis of stage IV breast cancer with a focus on the molecular mechanisms. In addition, the therapeutic strategies targeting these dysregulated genes involved in various signalling pathways have also been discussed. Genome editing technologies that can target specific genes in the affected areas by making knock-in and knock-out alternations and thereby bring significant treatment outcomes in breast cancer have also been summarized.
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Li Y, Wang Q, Wang D, Fu W. KLF7 Promotes Gastric Carcinogenesis Through Regulation of ANTXR1. Cancer Manag Res 2021; 13:5547-5557. [PMID: 34285576 PMCID: PMC8285236 DOI: 10.2147/cmar.s308071] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 06/05/2021] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Elucidating the mechanism of gastric cancer progression is of great importance for the discovery of new therapy targets against gastric cancer. In this study, we investigated the function of Kruppel-like factor 7 (KLF7) in gastric cancer. METHODS qPCR and Western blot were performed to determine the expression of ANTXR1 after KLF7 inhibition. CCK-8, colony formation, apoptosis analysis, cell cycle analysis and transwell assay were performed to determine KLF7 functions in cellular proliferation, migration, apoptosis and cell cycle. Tumour xenograft experiments were performed to examine cell growth in vivo. RESULTS The results showed that KLF7 was upregulated in gastric cancer. The proliferation and migration of gastric cancer cells were suppressed by depletion of KLF7. In vivo tumour progression was also attenuated following the downregulation of KLF7. Meanwhile, overexpression of KLF7 promoted the proliferation and migration of gastric cancer cells. The results of the mechanistic analysis showed that KLF7 promoted gastric carcinogenesis via upregulation of ANTXR cell adhesion molecule 1 (ANTXR1). CONCLUSION Therefore, this study may provide a theoretical foundation for further clinical therapy of gastric cancer.
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Affiliation(s)
- Yuanchun Li
- Department of General Surgery, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang Province, People’s Republic of China
| | - Qingdong Wang
- Department of Anesthesiology, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| | - DongWei Wang
- Department of Anesthesiology, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China,Correspondence: DongWei Wang Department of Anesthesiology, First Affiliated Hospital of Jiamusi University, No. 348, Dexiang Street, Jiamusi, Heilongjiang Province, 154002, People’s Republic of ChinaTel +86-0454-8605850 Email
| | - Weihua Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China,Weihua Fu Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, People’s Republic of ChinaTel +022-60363901 Email
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Gong Q, Deng J, Zhang L, Zhou C, Fu C, Wang X, Zhuang L. Targeted silencing of TEM8 suppresses non‑small cell lung cancer tumor growth via the ERK/Bcl‑2 signaling pathway. Mol Med Rep 2021; 24:595. [PMID: 34165155 PMCID: PMC8240451 DOI: 10.3892/mmr.2021.12234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 05/24/2021] [Indexed: 12/04/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common malignancies with high rates of mortality. Although great progress has been made with the development of novel immunotherapies and targeted therapeutic strategies, the 5-year total survival rate of lung cancer has remained unchanged over the past few decades. Therefore, more effective therapeutics are urgently needed. Tumor endothelial marker 8 (TEM8) is an integrin-like cell surface transmembrane protein that has been demonstrated to be upregulated in numerous cancer types and previously showed promise for targeted cancer therapy. However, the role of TEM8 in NSCLC remains poorly understood. The present study aimed to investigate the effects of silencing TEM8 on expression and regulation of extracellular signal-regulated kinase (ERK)1/2 signaling pathways in NSCLC. In the present study, a lentiviral vector that encoded a short hairpin RNA targeting TEM8 was designed and transfected into Xuanwei Lung Cancer (XWLC)-05 lung cancer cells to silence TEM8 expression. Male BALB/c-nu/nu mice were then given subcutaneous injections in the right dorsal flank with XWLC-05 cells. Microvessel density was measured using an anti-CD34 antibody. The mRNA and protein levels of ERK1/2 and Bcl-2 in XWLC-05 cells or xenograft tumor tissues were detected by reverse transcription-quantitative polymerase chain reaction and western blotting. TEM8 knockdown was found to significantly inhibit tumor growth and conferred an anti-angiogenic ability in vivo. Furthermore, TEM8 knockdown suppressed the expression of Bcl-2 mediated by ERK1/2 activity in XWLC-05 cells or tissues from mice with NSCLC. To conclude, these results suggest that the targeted silencing of TEM8 may serve as an effective method of treating NSCLC.
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Affiliation(s)
- Quan Gong
- Department of Palliative Medicine, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Jing Deng
- Department of Palliative Medicine, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Lijuan Zhang
- Department of Palliative Medicine, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Chunyan Zhou
- Department of Palliative Medicine, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Chaojiang Fu
- Department of Critical Care Medicine, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Xicai Wang
- Department of Tumor Research Institute, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Li Zhuang
- Department of Palliative Medicine, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
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Zhou H, Sun F, Ou M, Zhang Y, Lin M, Song L, Yu Y, Liao H, Fan W, Xing H, Li M, Zhao K, Wu X, Sun Y, Liang C, Cai Y, Cui L. Prior nasal delivery of antagomiR-122 prevents radiation-induced brain injury. Mol Ther 2021; 29:3465-3483. [PMID: 34174438 DOI: 10.1016/j.ymthe.2021.06.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 04/24/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023] Open
Abstract
Radiation-induced brain injury is a major adverse event in head and neck tumor treatment, influencing the quality of life for the more than 50% of patients who undergo radiation therapy and experience long-term survival. However, no effective treatments are available for these patients, and preventative drugs and effective drug-delivery methods must be developed. Based on our results, miR-122-5p was upregulated in the mouse radiation-induced brain injury (RBI) model and patients with nasopharyngeal carcinoma (NPC) who received radiation therapy. Intranasal administration of a single antagomiR-122-5p dose before irradiation effectively alleviated radiation-induced cognitive impairment, neuronal injury, and neuroinflammation in the mouse RBI model. Results further indicated that miR-122-5p inhibition in microglia reduced the levels of proinflammatory cytokines and enhanced the phagocytic function to protect against radiation-induced neuronal injury in cell models. Further, we profiled transcriptome data and verified that Tensin 1 (TNS1) may be the target of miR-122-5p in RBI. In summary, our results reveal a distinct role for miR-122-5p in regulating neuroinflammation in RBI, indicating that a non-invasive strategy for intranasal miR-122-5p administration may be an attractive therapeutic target in RBI, providing new insights for clinical trials. Further systematic safety assessment, optimization of drug administration, and clarity of mechanism will accelerate the process into clinical practice.
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Affiliation(s)
- Haihong Zhou
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Furong Sun
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Mingqian Ou
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Guangdong Medical University Affiliated Luoding People's Hospital, Luoding 527200, China
| | - Yu Zhang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Meijun Lin
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Guangdong Medical University Affiliated Zhanjiang Central People's Hospital, Zhanjiang 524037, China
| | - Liqin Song
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Yangsheng Yu
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Southern Medical University Affiliated Puning People's Hospital, Jieyang 522000, China
| | - Haojie Liao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Southern Medical University Affiliated Shenzhen Baoan Hospital, Shenzhen 518000, China
| | - Weihao Fan
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Shantou University Affiliated Yuebei People's Hospital, Shaoguan 512000, China
| | - Huaijie Xing
- Department of Neurology, The Second Affiliated Hospital of Hainan Medical College, Haikou 571000, China
| | - Minhua Li
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Kui Zhao
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Xiaolian Wu
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Yuanhong Sun
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Chunmei Liang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Yujie Cai
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China.
| | - Lili Cui
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China.
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