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Chen S, Rao Y, Liu W, Yang Q, Wu G, Wu F, Gao Y, Li J, Fu J. Role of TRKC and NT-3 proteins in the progression and prognosis of colorectal cancer. Transl Cancer Res 2025; 14:2457-2469. [PMID: 40386265 PMCID: PMC12079258 DOI: 10.21037/tcr-2025-519] [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] [Received: 03/06/2025] [Accepted: 04/14/2025] [Indexed: 05/20/2025]
Abstract
Background Colorectal cancer (CRC) is a common tumor of the digestive system. In recent years, CRC has had the fourth highest incidence and second highest mortality rate among tumors worldwide. Therefore, it is important to identify new molecular markers, and examine their relationship with the clinicopathological features and prognosis of CRC patients. This study examined the correlation between the expression levels of the tropomyosin receptor kinase C (TRKC) and neurotrophic factor-3 (NT-3) proteins, and the clinicopathological features and prognosis of CRC patients. Methods In total, 141 paraffin-embedded specimens from patients who had undergone radical surgical resection for CRC were analyzed. All CRC diagnoses were confirmed by pathological examination. Corresponding adjacent normal tissues served as controls. Immunohistochemical staining was employed to assess the expression of the TRKC and NT-3 proteins in both the CRC and adjacent normal tissues. A subsequent statistical analysis was conducted to explore the associations between the expression levels of these proteins, and the clinicopathological features and prognostic outcomes of CRC patients. Results The expression level of TRKC was significantly higher in the CRC tissues than the adjacent normal tissues, while the expression level of NT-3 was significantly lower in the CRC tissues than the adjacent normal tissues, and the observed differences were statistically significant (P<0.001). Notably, TRKC expression was significantly correlated with the tumor site (P<0.05), lymph node metastasis (P<0.05), tumor node metastasis (TNM) stage (P<0.01), serum carcinoembryonic antigen (CEA) level (P<0.01), and serum carbohydrate antigen 19-9 (CA199) level (P<0.05). The patients with positive TRKC had significantly shorter overall survival (OS) and progression-free survival (PFS) times than those with negative TRKC expression (P<0.001). Further, NT-3 expression was significantly associated with lymph node metastasis (P<0.05), distant metastasis (P<0.05), TNM stage (P<0.05), and serum CEA level (P<0.05). The patients with positive NT-3 expression had prolonged OS and PFS compared to those with negative NT-3 expression (P<0.01). The Cox proportional hazards regression model revealed that TRKC expression had a hazard ratio (HR) of 2.679 (P<0.01), while NT-3 expression had a HR of 0.433 (P<0.05). Conclusions We found that the TRKC and NT-3 proteins were closely associated with the occurrence, metastasis, invasion, and tumor marker levels of CRC, and can be used as independent predictors of prognosis in patients with CRC. TRKC mainly indicates a poor prognosis in CRC, while NT-3 indicates a good prognosis.
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Affiliation(s)
- Shan Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yao Rao
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Weihui Liu
- Department of Oncology, Dazhou Central Hospital, Dazhou, China
| | - Qian Yang
- Department of Oncology, Dazhou Central Hospital, Dazhou, China
| | - Guirong Wu
- Department of Oncology, Dazhou Central Hospital, Dazhou, China
| | - Fudao Wu
- Department of Oncology, Dazhou Central Hospital, Dazhou, China
| | - Youshu Gao
- Department of Oncology, Dazhou Central Hospital, Dazhou, China
| | - Jie Li
- Department of Clinical Research Center, Dazhou Central Hospital, Dazhou, China
| | - Jiangping Fu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Oncology, Dazhou Central Hospital, Dazhou, China
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Sakyo A, Ryo E, Yoshimoto S, Omura G, Fushimi C, Sakai T, Matsumoto Y, Sakai A, Eguchi K, Suzuki Y, Yokoyama K, Honma Y, Yatabe Y, Matsumoto F, Mori T. EGR1-BDNF-Linking Crosstalk Between Cancer Cells and Nerves for Perineural Invasion in Salivary Duct Carcinoma: Comparison of Salivary Duct Carcinoma De Novo and Ex Pleomorphic Adenoma. J Transl Med 2025; 105:104167. [PMID: 40210168 DOI: 10.1016/j.labinv.2025.104167] [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: 05/20/2024] [Revised: 03/09/2025] [Accepted: 04/01/2025] [Indexed: 04/12/2025] Open
Abstract
Salivary duct carcinoma (SDC) is primarily categorized as de novo (SDCDN) or ex pleomorphic adenoma (SDCXPA). The incidence of HMGA2 and PLAG1 fusion genes has been suggested to be higher in SDCXPA than in SDCDN. Surgical resection remains the main intervention due to limited guidance on new treatment strategies. However, frequent recurrence and challenging management of metastasis highlight the necessity for innovative treatments. This study aimed to investigate SDC characteristics, including perineural invasion (PNI), and elucidate its carcinogenic mechanisms and adverse prognostic factors. We analyzed 52 patients with SDC diagnosed in the National Cancer Center Hospital from 2014 to 2023. To compare gene expression profiles, we performed immunohistochemical staining, including Her2, adrenergic receptor, PLAG1, and HMGA2, followed by human epidermal growth factor receptor 2 (HER2) in situ hybridization and RNA sequencing of 30 cases. Differential analysis identified genes subjected to immunohistochemical staining and statistical analysis. Based on histologic classification using PLAG1 and HMGA2, 52 cases were classified as 26 cases (50%) SDCDN and 26 cases (50%) SDCXPA. Compared with SDCXPA, SDCDN showed higher perineural, venous, and lymphatic invasion rates (P = .0005, .0294, and .0044, respectively). Genetic expression profiling revealed clustering tendencies between these subtypes. Focusing on PNI, gene expression was decreased in early growth response 1 in tumor portions infiltrating perineural tissues, indicating a negative correlation (P < .0001). Additionally, RNA sequencing showed 3 new fusion genes. In conclusion, clinical disparities between SDCDN and SDCXPA based on molecular and pathological features were observed. We found early growth response 1-brain-derived neurotrophic factor-linking crosstalk between cancer cells and nerves for PNI in SDC, offering insights into future treatment and prognostic factors.
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Affiliation(s)
- Airi Sakyo
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan; Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan; Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Eijitsu Ryo
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Seiichi Yoshimoto
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Go Omura
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Chihiro Fushimi
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Toshihiko Sakai
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshifumi Matsumoto
- Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo, Japan; Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Azusa Sakai
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kohtaro Eguchi
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yo Suzuki
- Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Kazuki Yokoyama
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshitaka Honma
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yasushi Yatabe
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan; Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Fumihiko Matsumoto
- Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Taisuke Mori
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan; Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
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Jastrząb P, Car H, Wielgat P. Cell membrane sialome machinery and regulation of receptor tyrosine kinases in gliomas: The functional relevance and therapeutic perspectives. Biomed Pharmacother 2025; 184:117921. [PMID: 39986236 DOI: 10.1016/j.biopha.2025.117921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/24/2025] Open
Abstract
Gliomas are the most common primary brain tumors characterized by high aggressive potential, poor therapeutic response, and significantly reduced overall patient survival. Despite significant progress in the diagnosis and therapy of cancer, gliomas remain a clinical challenge due to the high molecular and cellular heterogeneity, which provides for multiple mechanisms of chemoresistance and adaptive plasticity. A better understanding of cellular regulatory mechanisms of intracellular signal transduction enables the development of targeted drug therapies and clinical application. The increasing evidence confirms the role of sialoglycans in the processing of cell membrane receptors via altered dimerization, activation, and autophosphorylation, which results in changes in cellular signaling and promotes cancer progression. Hence, the modified sialylation patterns, as a hallmark of cancer, have been described as modulators of chemotherapy effectiveness and drug resistance. The receptor tyrosine kinases (RTKs)-mediated signaling in glial tumors control cell growth, survival, migration, and angiogenesis. Here, we focus on the engagement of the sialome machinery in RTKs processing in gliomas and its importance as a suitable therapeutic target. The analysis of the sialylation pattern and its impact on the activity of growth factor receptors provides valuable insights into our understanding of the molecular and cellular complexity of glial tumors. This highlights the novel treatment approaches that could improve prognosis and patients' overall survival.
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Affiliation(s)
- Patrycja Jastrząb
- Department of Clinical Pharmacology, Medical University of Bialystok, ul. Waszyngtona 15A, Bialystok 15-274, Poland
| | - Halina Car
- Department of Clinical Pharmacology, Medical University of Bialystok, ul. Waszyngtona 15A, Bialystok 15-274, Poland; Department of Experimental Pharmacology, Medical University of Bialystok, ul. Szpitalna 37, Bialystok 15-295, Poland
| | - Przemyslaw Wielgat
- Department of Clinical Pharmacology, Medical University of Bialystok, ul. Waszyngtona 15A, Bialystok 15-274, Poland.
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Huang Q, Hu B, Zhang P, Yuan Y, Yue S, Chen X, Liang J, Tang Z, Zhang B. Neuroscience of cancer: unraveling the complex interplay between the nervous system, the tumor and the tumor immune microenvironment. Mol Cancer 2025; 24:24. [PMID: 39825376 PMCID: PMC11740516 DOI: 10.1186/s12943-024-02219-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 12/26/2024] [Indexed: 01/20/2025] Open
Abstract
The study of the multifaceted interactions between neuroscience and cancer is an emerging field with significant implications for understanding tumor biology and the innovation in therapeutic approaches. Increasing evidence suggests that neurological functions are connected with tumorigenesis. In particular, the peripheral and central nervous systems, synapse, neurotransmitters, and neurotrophins affect tumor progression and metastasis through various regulatory approaches and the tumor immune microenvironment. In this review, we summarized the neurological functions that affect tumorigenesis and metastasis, which are controlled by the central and peripheral nervous systems. We also explored the roles of neurotransmitters and neurotrophins in cancer progression. Moreover, we examined the interplay between the nervous system and the tumor immune microenvironment. We have also identified drugs that target the nervous system for cancer treatment. In this review we present the work supporting that therapeutic agent targeting the nervous system could have significant potential to improve cancer therapy.
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Affiliation(s)
- Qibo Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, NHC Key Laboratory of Organ Transplantation, Wuhan, China
| | - Bai Hu
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ye Yuan
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
| | - Shiwei Yue
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, NHC Key Laboratory of Organ Transplantation, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China.
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, NHC Key Laboratory of Organ Transplantation, Wuhan, China.
| | - Junnan Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China.
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, NHC Key Laboratory of Organ Transplantation, Wuhan, China.
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China.
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, NHC Key Laboratory of Organ Transplantation, Wuhan, China.
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Lei M, Liu Q, Nie J, Huang R, Mei Y, Pan D, Chen Y, Liu W. Impact and Mechanisms of Action of BDNF on Neurological Disorders, Cancer, and Cardiovascular Diseases. CNS Neurosci Ther 2024; 30:e70138. [PMID: 39648800 PMCID: PMC11626086 DOI: 10.1111/cns.70138] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/04/2024] [Accepted: 11/10/2024] [Indexed: 12/10/2024] Open
Abstract
Brain-derived neurotrophic factor (BDNF), which is primarily expressed in the brain and nervous tissues, is the most abundant neurotrophic factor in the adult brain. BDNF serves not only as a major neurotrophic signaling agent in the human body but also as a crucial neuromodulator. Widely distributed throughout the central nervous system (CNS), both BDNF and its receptors play a significant role in promoting neuronal survival and growth, thereby exerting neuroprotective effects. It is further considered as a guiding medium for the functionality and structural plasticity of the CNS. Increasingly, research has indicated the critical importance of BDNF in understanding human diseases. Activation of intracellular signaling pathways such as the mitogen-activated protein kinase pathway, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, and phospholipase C γ pathway by BDNF can all potentially enhance the growth, survival, proliferation, and migration of cancer cells, influencing cancer development. The loss of BDNF and its receptor, tropomyosin receptor kinase B, in signaling pathways is also associated with increased susceptibility to brain and heart diseases. Additionally, reduced BDNF levels in both the central and peripheral systems have been closely linked to various neurogenic diseases, including neuropathic pain and psychiatric disorders. As such, this review summarizes and analyzes the impact of BDNF on neurogenic diseases, cancer, and cardiovascular diseases. This study thereby aimed to elucidate its effects on these diseases to provide new insights and approaches for their treatment.
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Affiliation(s)
- Min Lei
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical CollegeHubei University of Science and TechnologyXianningHubeiChina
| | - Qiwen Liu
- School of Basic Medical Sciences, Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical CollegeHubei University of Science and TechnologyXianningHubeiChina
| | - Jinxia Nie
- School of Basic Medical Sciences, Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical CollegeHubei University of Science and TechnologyXianningHubeiChina
| | - Rongyi Huang
- School of Basic Medical Sciences, Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical CollegeHubei University of Science and TechnologyXianningHubeiChina
| | - Yan Mei
- School of Basic Medical Sciences, Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical CollegeHubei University of Science and TechnologyXianningHubeiChina
| | - Dan Pan
- School of Basic Medical Sciences, Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical CollegeHubei University of Science and TechnologyXianningHubeiChina
| | - Yong Chen
- Xianning Central HospitalThe First Affiliated Hospital of Hubei University of Science and TechnologyXianningHubeiChina
| | - Wu Liu
- School of Basic Medical Sciences, Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical CollegeHubei University of Science and TechnologyXianningHubeiChina
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Yildirim GE, Yilmaz E. Developing a novel neutralizing monoclonal antibody against TrkB. 3 Biotech 2024; 14:221. [PMID: 39247456 PMCID: PMC11377376 DOI: 10.1007/s13205-024-04063-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 08/23/2024] [Indexed: 09/10/2024] Open
Abstract
The TrkB receptor, which is highly expressed in various human cancers and considered a pro-oncogene, was targeted to develop neutralizing monoclonal antibodies against its immunoglobulin-like (Ig-like) domains. Recombinant TrkB-IgL peptide, including the Ig-like C2 type 1 (Ig-C2-type 1) and Ig-like C2 type 2 (Ig-C2-type 2) domains, was expressed and purified from E. coli. Mice were immunized with this peptide, and hybridoma clones producing anti-TrkB-IgL antibodies were generated. Among 23 ELISA-positive TrkB-IgL hybridoma clones, four (TrkB-IgL 5.11, 4.11, 4.6, 4.3) showed anti-proliferative effects compared to the control on human breast cancer (MCF-7) and human colon cancer (HCT116) cells, as assessed using the xCELLigence system. Western blot analysis revealed that TrkB-IgL 5.11 and 4.11 significantly suppressed TrkB-mediated signaling pathways compared to the control. Purified TrkB-IgL monoclonal antibodies (mAbs) exhibited anti-proliferative effects compared to both positive and negative controls using the xCELLigence system. The TrkB-IgL 5.11 mAb notably suppressed phosphorylation of TrkB, Akt, and ERK and induced Caspase-3 and Caspase-9 activities in a dose-dependent manner, as determined by Western blotting. Additionally, immunostaining confirmed the localization of these mAbs on the SH-SY5Y cell membrane, which is known for high TrkB expression. In conclusion, the TrkB-IgL 5.11 antibody effectively inhibits cancer cell proliferation and induces apoptosis by suppressing key signaling pathways. These findings demonstrate the potential of this antibody as a therapeutic agent for cancers that overexpress TrkB. Additionally, it is considered a promising candidate for humanization, which would facilitate its application in cancer treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-024-04063-x.
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Affiliation(s)
| | - Erkan Yilmaz
- Biotechnology Institute, Ankara University, Ankara, Türkiye
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Chaldakov GN, Aloe L, Yanev SG, Fiore M, Tonchev AB, Vinciguerra M, Evtimov NT, Ghenev P, Dikranian K. Trackins (Trk-Targeting Drugs): A Novel Therapy for Different Diseases. Pharmaceuticals (Basel) 2024; 17:961. [PMID: 39065809 PMCID: PMC11279958 DOI: 10.3390/ph17070961] [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: 05/27/2024] [Revised: 06/19/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor kinase; pronounced "track"). Indeed, we introduced the word trackins, standing for Trk-targeting drugs, that play an agonistic or antagonistic role in the function of TrkBBDNF, TrkCNT-3, TrkANGF, and TrkApro-NGF receptors. Based on our own published results, supported by those of other authors, we aim to update and enlarge our trackins concept, focusing on (1) agonistic trackins as possible drugs for (1a) neurotrophin-deficiency cardiometabolic disorders (hypertension, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, obesity, diabetic erectile dysfunction and atrial fibrillation) and (1b) neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and multiple sclerosis), and (2) antagonistic trackins, particularly TrkANGF inhibitors for prostate and breast cancer, pain, and arrhythmogenic right-ventricular dysplasia. Altogether, the druggability of TrkANGF, TrkApro-NGF, TrkBBDNF, and TrkCNT-3 receptors via trackins requires a further translational pursuit. This could provide rewards for our patients.
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Affiliation(s)
- George N. Chaldakov
- Departments of Anatomy and Cell Biology and Translational Stem Cell Biology, Research Institute, Medical University, 9002 Varna, Bulgaria
| | - Luigi Aloe
- Fondazione Iret, Tecnopolo R. Levi-Montalcini, Ozzano dell’Emilia, 40064 Bologna, Italy
| | - Stanislav G. Yanev
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, National Research Council, IBBC-CNR, 00185 Rome, Italy
| | - Anton B. Tonchev
- Departments of Anatomy and Cell Biology and Translational Stem Cell Biology, Research Institute, Medical University, 9002 Varna, Bulgaria
| | - Manlio Vinciguerra
- Department of Translational Stem Cell Biology, Research Institute, Medical University, 9002 Varna, Bulgaria
| | - Nikolai T. Evtimov
- Department of Urology, University St Anna Hospital, 9002 Varna, Bulgaria
| | - Peter Ghenev
- Department of General and Clinical Pathology, Medical University, 9002 Varna, Bulgaria
| | - Krikor Dikranian
- Department of Neuroscience, Medical School, Washington University, St. Louis, MO 63110, USA
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Köktürk S, Doğan S, Yılmaz CE, Cetinkol Y, Mutlu O. Expression of brain-derived neurotrophic factor and formation of migrasome increases in the glioma cells induced by the adipokinetic hormone. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2024; 70:e20231337. [PMID: 38775506 PMCID: PMC11110965 DOI: 10.1590/1806-9282.20231337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 01/28/2024] [Indexed: 05/24/2024]
Abstract
OBJECTIVE It has been previously shown that brain-derived neurotrophic factor is linked with various types of cancer. Brain-derived neurotrophic factor is found to be highly expressed in multiple human cancers and associated with tumor growth, invasion, and metastasis. Adipokinetic hormones are functionally related to the vertebrate glucagon, as they have similar functionalities that manage the nutrient-dependent secretion of these two hormones. Migrasomes are new organelles that contain numerous small vesicles, which aid in transmitting signals between the migrating cells. Therefore, the aim of this study was to investigate the effects of Anax imperator adipokinetic hormone on brain-derived neurotrophic factor expression and ultrastructure of cells in the C6 glioma cell line. METHODS The rat C6 glioma cells were treated with concentrations of 5 and 10 Anax imperator adipokinetic hormone for 24 h. The effects of the Anax imperator adipokinetic hormone on the migrasome formation and brain-derived neurotrophic factor expression were analyzed using immunocytochemistry and transmission electron microscope. RESULTS The rat C6 glioma cells of the 5 and 10 μM Anax imperator adipokinetic hormone groups showed significantly high expressions of brain-derived neurotrophic factor and migrasomes numbers, compared with the control group. CONCLUSION A positive correlation was found between the brain-derived neurotrophic factor expression level and the formation of migrasome, which indicates that the increased expression of brain-derived neurotrophic factor and the number of migrasomes may be involved to metastasis of the rat C6 glioma cell line induced by the Anax imperator adipokinetic hormone. Therefore, the expression of brain-derived neurotrophic factor and migrasome formation may be promising targets for preventing tumor proliferation, invasion, and metastasis in glioma.
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Affiliation(s)
- Sibel Köktürk
- Istanbul University, Faculty of Medicine, Department of Histology and Embryology – İstanbul, Turkey
| | - Sibel Doğan
- Istanbul University, Faculty of Medicine, Department of Histology and Embryology – İstanbul, Turkey
| | - Cansu Eda Yılmaz
- Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Pathology – İstanbul, Turkey
| | - Yeliz Cetinkol
- Afyonkarahisar Health Sciences University, Faculty of Medicine, Department of Medical Microbiology – Afyonkarahisar, Turkey
| | - Oğuz Mutlu
- Kocaeli University, Faculty of Medicine, Department of Pharmacology – İzmit, Turkey
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Park H, Lee CH. The contribution of the nervous system in the cancer progression. BMB Rep 2024; 57:167-175. [PMID: 38523371 PMCID: PMC11058356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 02/09/2024] [Accepted: 03/19/2024] [Indexed: 03/26/2024] Open
Abstract
Cancer progression is driven by genetic mutations, environmental factors, and intricate interactions within the tumor microenvironment (TME). The TME comprises of diverse cell types, such as cancer cells, immune cells, stromal cells, and neuronal cells. These cells mutually influence each other through various factors, including cytokines, vascular perfusion, and matrix stiffness. In the initial or developmental stage of cancer, neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor are associated with poor prognosis of various cancers by communicating with cancer cells, immune cells, and peripheral nerves within the TME. Over the past decade, research has been conducted to prevent cancer growth by controlling the activation of neurotrophic factors within tumors, exhibiting a novel attemt in cancer treatment with promising results. More recently, research focusing on controlling cancer growth through regulation of the autonomic nervous system, including the sympathetic and parasympathetic nervous systems, has gained significant attention. Sympathetic signaling predominantly promotes tumor progression, while the role of parasympathetic signaling varies among different cancer types. Neurotransmitters released from these signalings can directly or indirectly affect tumor cells or immune cells within the TME. Additionally, sensory nerve significantly promotes cancer progression. In the advanced stage of cancer, cancer-associated cachexia occurs, characterized by tissue wasting and reduced quality of life. This process involves the pathways via brainstem growth and differentiation factor 15-glial cell line-derived neurotrophic factor receptor alpha-like signaling and hypothalamic proopiomelanocortin neurons. Our review highlights the critical role of neurotrophic factors as well as central nervous system on the progression of cancer, offering promising avenues for targeted therapeutic strategies. [BMB Reports 2024; 57(4): 167-175].
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Affiliation(s)
- Hongryeol Park
- Department of Tissue Morphogenesis, Max-Planck Institute for Molecular Biomedicine, Muenster D-48149, Germany, Chuncheon 24252, Korea
| | - Chan Hee Lee
- Department of Biomedical Science, Hallym University, Chuncheon 24252, Korea
- Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon 24252, Korea
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Moriwaki K, Ayani Y, Kuwabara H, Terada T, Higashino M, Kawata R. Differential expression of TRKB tyrosine kinase in the two histological types of parotid salivary duct carcinoma with cancer aggressiveness. Oral Oncol 2024; 151:106751. [PMID: 38479153 DOI: 10.1016/j.oraloncology.2024.106751] [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: 10/18/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 04/06/2024]
Abstract
Parotid salivary duct carcinoma (SDC) is a rare and aggressive parotid gland carcinoma (PGC). SDC has two origins: de novo and ex pleomorphic adenoma (SDC ex PA); however, because of its rarity, the clinical and molecular features of the two types of SDC are not sufficiently understood. Here, we studied the differences in their clinicopathological and molecular features using clinical specimens while comparing them to those of adenoid cystic carcinoma (AdCC), an intermediate-grade PGC. Clinicopathological analysis of tissues from patients with PGC revealed significant associations between histological types and malignant phenotypes, including nodal metastasis, recurrence, vascular invasion, and neural invasion, and revealed more malignant phenotypes of de novo SDC than of SDC ex PA. The de novo SDC showed a significantly higher frequency of intra-neural invasion (intra-NI) and vascular invasion than AdCC and SDC ex PA. PGCs with high intra-NI were significantly correlated with malignant phenotypes and survival rates. Recently, we observed the overexpression of tropomyosin receptor kinase B (TRKB), a receptor tyrosine kinase, in PGC cells. Here, immunohistochemical and clinicopathological analyses showed that TRKB was highly expressed in SDC cells, particularly de novo SDC cells, and was significantly associated with poor survival and highly malignant phenotypes, including intra-NI and vascular invasion. Collectively, these data show that TRKB expression is significantly elevated in PGC, particularly in de novo SDC, and can be one of the biomarkers of their aggressiveness.
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Affiliation(s)
- Kazumasa Moriwaki
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
| | - Yusuke Ayani
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Hiroko Kuwabara
- Department of Pathology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Tetsuya Terada
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Masaaki Higashino
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Ryo Kawata
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
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11
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Shi J, Yang Z, Zhang Y, Abdelrehem A, Wu Z, Zhang B, Xiao M, Zhang S, Zhang Z, Wang L. Distinctive mesenchymal-like neurofibroma stem cells shape NF1 clinical phenotypes controlled by BDNF microenvironment. Transl Oncol 2024; 40:101852. [PMID: 38042136 PMCID: PMC10716025 DOI: 10.1016/j.tranon.2023.101852] [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: 05/17/2023] [Revised: 10/23/2023] [Accepted: 11/27/2023] [Indexed: 12/04/2023] Open
Abstract
BACKGROUND Neurofibroma type I (NF1) often presents with multiple clinical phenotypes due to mutations of NF1 gene. The aim of this study was to determine the phenotypic and therapeutic relevance of tumor microenvironment in NF1 patients. METHODS Tumor stem cells (TSCs) from NF1 were isolated and cultured using fluorescence activated cell sorting (FACS) and colony formation experiments. Then, flow cytometry was used to detect the surface markers, osteogenic and adipogenic differentiation were performed as well. Its tumorigenesis ability was confirmed by subcutaneous tumorigenesis in nude mice. Immunohistochemical staining was performed on neurofibroma tissues from the head and trunk with different phenotypes. The expression of BDNF in neurofibroma tissues was detected by Elisa and immunohistochemical staining. Western Blotting was used to detect the expression of p38 MAPK pathway in TSCs. The effect of BDNF neutralizing antibody on the tumorigenesis of TSCs was observed. RESULTS Herein, we advocate that NF1 contain a new subgroup of mesenchymal-like neurofibroma stem cells (MNSCs). Such colony-forming MNSCs preserved self-renewal, multiple differentiation and tumorigenic capabilities. More interestingly, the MNSCs isolated from neurofibroma tissues of the same patient with different phenotypes presented site-specific capabilities. Moreover, different levels of brain-derived neurotrophic factor (BDNF) in neurofibroma tissues can impact the MNSCs by activating the TrkB/p38 MAPK pathway. Systemic administration of BDNF neutralizing antibodies inhibited MNSCs' characteristics. CONCLUSIONS We demonstrated that BDNF can modulate MNSCs and thereby controlling different tumor phenotypes between the head and trunk regions. Application of BDNF neutralizing antibodies may inhibit p38 MAPK pathway, therefore providing a promising strategy for managing NF1.
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Affiliation(s)
- Jingcun Shi
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Zihui Yang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shanxi Clinical Research Center for Oral Diseases, Department of Maxillofacial Oncology, School of Stomatology, Air Force Medical University, Xian, China
| | - Yuhan Zhang
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Ahmed Abdelrehem
- Buraidah Central Hospital, Saudi Arabia; Department of Craniomaxillofacial and Plastic Surgery, Faculty of Dentistry, Alexandria University, Alexandria, Egypt
| | - Ziqian Wu
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Bingqing Zhang
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Meng Xiao
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Shijian Zhang
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Zhang
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Wang
- Department of Oral and Maxillofacial Surgery - Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China; Department of Stomatology, Fengcheng Hospital, Fengxian District, Shanghai 201411, China.
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12
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Sasa K, Son R, Oguchi A, Ashizawa K, Hasegawa N, Kubota D, Suehara Y, Takagi T, Okubo T, Akaike K, Sugimoto K, Takahashi M, Sakamoto K, Hashimoto T, Mine S, Fukunaga T, Ishijima M, Hayashi T, Yao T, Murakawa Y, Saito T. NTRK2 expression in gastrointestinal stromal tumors with a special emphasis on the clinicopathological and prognostic impacts. Sci Rep 2024; 14:768. [PMID: 38191907 PMCID: PMC10774370 DOI: 10.1038/s41598-024-51211-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 01/02/2024] [Indexed: 01/10/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin.
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Affiliation(s)
- Keita Sasa
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
| | - Raku Son
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Akiko Oguchi
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Karin Ashizawa
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Nobuhiko Hasegawa
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
| | - Daisuke Kubota
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
| | - Yoshiyuki Suehara
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
| | - Tatsuya Takagi
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
| | - Taketo Okubo
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
| | - Keisuke Akaike
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
- Department of Orthopaedic Surgery, Yamanashi Central Hospital, Yamanashi, Japan
| | - Kiichi Sugimoto
- Department of Coloproctological Surgery, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Makoto Takahashi
- Department of Coloproctological Surgery, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Takashi Hashimoto
- Department of Upper Gastroenterological Surgery, Juntendo University Hospital, Bunkyo-ku, Tokyo, 113-8431, Japan
| | - Shinji Mine
- Department of Upper Gastroenterological Surgery, Juntendo University Hospital, Bunkyo-ku, Tokyo, 113-8431, Japan
| | - Tetsu Fukunaga
- Department of Upper Gastroenterological Surgery, Juntendo University Hospital, Bunkyo-ku, Tokyo, 113-8431, Japan
| | - Muneaki Ishijima
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan
- Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan
| | - Takuo Hayashi
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yasuhiro Murakawa
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
- IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
- Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
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13
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Deng C, Chen H. Brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling in spinal muscular atrophy and amyotrophic lateral sclerosis. Neurobiol Dis 2024; 190:106377. [PMID: 38092270 DOI: 10.1016/j.nbd.2023.106377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/15/2023] [Accepted: 12/10/2023] [Indexed: 12/23/2023] Open
Abstract
Tropomyosin receptor kinase B (TrkB) and its primary ligand brain-derived neurotrophic factor (BDNF) are expressed in the neuromuscular system, where they affect neuronal survival, differentiation, and functions. Changes in BDNF levels and full-length TrkB (TrkB-FL) signaling have been revealed in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), two common forms of motor neuron diseases that are characterized by defective neuromuscular junctions in early disease stages and subsequently progressive muscle weakness. This review summarizes the current understanding of BDNF/TrkB-FL-related research in SMA and ALS, with an emphasis on their alterations in the neuromuscular system and possible BDNF/TrkB-FL-targeting therapeutic strategies. The limitations of current studies and future directions are also discussed, giving the hope of discovering novel and effective treatments.
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Affiliation(s)
- Chunchu Deng
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Chen
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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14
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Khan SU, Fatima K, Malik F, Kalkavan H, Wani A. Cancer metastasis: Molecular mechanisms and clinical perspectives. Pharmacol Ther 2023; 250:108522. [PMID: 37661054 DOI: 10.1016/j.pharmthera.2023.108522] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 08/22/2023] [Accepted: 08/29/2023] [Indexed: 09/05/2023]
Abstract
Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its lethal outcome. The complex molecular events that promote metastasis are a combination of both, the acquired pro-metastatic properties of cancer cells and a metastasis-permissive or -supportive tumor micro-environment (TME). Yet, dissemination is a challenging process for cancer cells that requires a series of events to enable cancer cell survival and growth. Metastatic cancer cells have to initially detach themselves from primary tumors, overcome the challenges of their intravasal journey and colonize distant sites that are suited for their metastases. The implicated obstacles including anoikis and immune surveillance, can be overcome by intricate intra- and extracellular signaling pathways, which we will summarize and discuss in this review. Further, emerging modulators of metastasis, like the immune-microenvironment, microbiome, sublethal cell death engagement, or the nervous system will be integrated into the existing working model of metastasis.
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Affiliation(s)
- Sameer Ullah Khan
- The University of Texas MD Anderson Cancer Center, Division of Genitourinary Medical Oncology, Holcombe Blvd, Houston, TX 77030, USA; Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu and Kashmir, India
| | - Kaneez Fatima
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (ASIR), Ghaziabad 201002, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (ASIR), Ghaziabad 201002, India.
| | - Halime Kalkavan
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
| | - Abubakar Wani
- St. Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105, United States.
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15
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Jetsonen E, Didio G, Winkel F, Llach Pou M, Boj C, Kuczynski-Noyau L, Võikar V, Guirado R, Taira T, Lauri SE, Castrén E, Umemori J. Activation of TrkB in Parvalbumin interneurons is required for the promotion of reversal learning in spatial and fear memory by antidepressants. Neuropsychopharmacology 2023; 48:1021-1030. [PMID: 36944718 PMCID: PMC10209093 DOI: 10.1038/s41386-023-01562-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 02/16/2023] [Accepted: 02/26/2023] [Indexed: 03/23/2023]
Abstract
Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin-positive (PV+) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV+ interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV+ interneurons (PV-TrkB hCKO) in IntelliCage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV+ interneurons. In addition, hippocampal long-term potentiation was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV+ interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV+ interneurons, and here we show that TrkB expression in PV+ interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood.
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Affiliation(s)
- Elias Jetsonen
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Giuliano Didio
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Frederike Winkel
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
- Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Maria Llach Pou
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
- Integrative Neurobiology of Cholinergic Systems, Neuroscience Department, Institut Pasteur, Paris, France
| | - Chloe Boj
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Laura Kuczynski-Noyau
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, F-59000, Lille, France
| | - Vootele Võikar
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Ramon Guirado
- Neurobiology Unit, Department of Cell Biology, Interdisciplinary Research Structure for Biotechnology and Biomedicine (BIOTECMED), Universitat de Valencia, Valencia, Spain
| | - Tomi Taira
- Department of Veterinary Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland
| | - Sari E Lauri
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
| | - Eero Castrén
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland.
| | - Juzoh Umemori
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland.
- Gene and Cell Technology, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
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16
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Di Donato M, Giovannelli P, Migliaccio A, Castoria G. The nerve growth factor-delivered signals in prostate cancer and its associated microenvironment: when the dialogue replaces the monologue. Cell Biosci 2023; 13:60. [PMID: 36941697 PMCID: PMC10029315 DOI: 10.1186/s13578-023-01008-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 03/06/2023] [Indexed: 03/22/2023] Open
Abstract
Prostate cancer (PC) represents the most diagnosed and the second most lethal cancer in men worldwide. Its development and progression occur in concert with alterations in the surrounding tumor microenvironment (TME), made up of stromal cells and extracellular matrix (ECM) that dynamically interact with epithelial PC cells affecting their growth and invasiveness. PC cells, in turn, can functionally sculpt the TME through the secretion of various factors, including neurotrophins. Among them, the nerve growth factor (NGF) that is released by both epithelial PC cells and carcinoma-associated fibroblasts (CAFs) triggers the activation of various intracellular signaling cascades, thereby promoting the acquisition of a metastatic phenotype. After many years of investigation, it is indeed well established that aberrations and/or derangement of NGF signaling are involved not only in neurological disorders, but also in the pathogenesis of human proliferative diseases, including PC. Another key feature of cancer progression is the nerve outgrowth in TME and the concept of nerve dependence related to perineural invasion is currently emerging. NGF released by cancer cells can be a driver of tumor neurogenesis and nerves infiltrated in TME release neurotransmitters, which might stimulate the growth and sustainment of tumor cells.In this review, we aim to provide a snapshot of NGF action in the interactions between TME, nerves and PC cells. Understanding the molecular basis of this dialogue might expand the arsenal of therapeutic strategies against this widespread disease.
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Affiliation(s)
- Marzia Di Donato
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy.
| | - Pia Giovannelli
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy.
| | - Antimo Migliaccio
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy
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17
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Takumi Y, Arai S, Suzuki C, Fukuda K, Nishiyama A, Takeuchi S, Sato H, Matsumoto K, Sugio K, Yano S. MET kinase inhibitor reverses resistance to entrectinib induced by hepatocyte growth factor in tumors with NTRK1 or ROS1 rearrangements. Cancer Med 2023; 12:5809-5820. [PMID: 36416133 PMCID: PMC10028024 DOI: 10.1002/cam4.5342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 07/06/2022] [Accepted: 08/08/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non-small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor-associated fibroblasts, critically affect the sensitivity to targeted drugs. METHODS We investigated whether growth factors that can be produced by the microenvironment affect sensitivity of NTRK1-rearranged colon cancer KM12SM cells and ROS1-rearranged NSCLC HCC78 cells to entrectinib both in vitro and in vivo. RESULTS Among the growth factors assessed, HGF most potently induced entrectinib resistance in KM12SM and HCC78 cells by activating its receptor MET. HGF-induced entrectinib resistance was reversed by the active-HGF-specific macrocyclic peptide HiP-8 and the MET kinase inhibitor capmatinib in vitro. In addition, HGF-producing fibroblasts promoted entrectinib resistance in vitro (culture model) and in vivo (subcutaneous tumor model). The use of capmatinib circumvented entrectinib resistance in a subcutaneous tumor model inoculated with KM12SM and HGF-producing fibroblasts. CONCLUSION Our findings suggest that growth factors in the tumor microenvironment, such as HGF, may induce resistance to entrectinib in tumors with NTRK1 or ROS1 rearrangements. Our results further suggest that optimally co-administering inhibitors of resistance-inducing growth factors may maximize the therapeutic efficacy of entrectinib.
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Affiliation(s)
- Yohei Takumi
- Division of Medical OncologyCancer Research Institute, Kanazawa UniversityKanazawaJapan
- Department of Thoracic and Breast SurgeryFaculty of MedicineOita UniversityYufuJapan
| | - Sachiko Arai
- Division of Medical OncologyCancer Research Institute, Kanazawa UniversityKanazawaJapan
| | - Chiaki Suzuki
- Division of Medical OncologyCancer Research Institute, Kanazawa UniversityKanazawaJapan
| | - Koji Fukuda
- Division of Medical OncologyCancer Research Institute, Kanazawa UniversityKanazawaJapan
| | - Akihiro Nishiyama
- Division of Medical OncologyCancer Research Institute, Kanazawa UniversityKanazawaJapan
| | - Shinji Takeuchi
- Division of Medical OncologyCancer Research Institute, Kanazawa UniversityKanazawaJapan
| | - Hiroki Sato
- Division of Tumor Dynamics and RegulationCancer Research Institute, Kanazawa UniversityKanazawaJapan
| | - Kunio Matsumoto
- Division of Tumor Dynamics and RegulationCancer Research Institute, Kanazawa UniversityKanazawaJapan
| | - Kenji Sugio
- Department of Thoracic and Breast SurgeryFaculty of MedicineOita UniversityYufuJapan
| | - Seiji Yano
- Division of Medical OncologyCancer Research Institute, Kanazawa UniversityKanazawaJapan
- Department of Respiratory MedicineFaculty of MedicineInstitute of Medical, Pharmaceutical, and Health SciencesKanazawaJapan
- WPI‐Nano Life Science Institute (WPI‐Nano LSI)Kanazawa UniversityKanazawaJapan
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18
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Tian J, Cheng H, Wang N, Wang C. SLERT, as a novel biomarker, orchestrates endometrial cancer metastasis via regulation of BDNF/TRKB signaling. World J Surg Oncol 2023; 21:27. [PMID: 36721236 PMCID: PMC9887878 DOI: 10.1186/s12957-022-02821-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 10/29/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Recent evidence suggests that the box H/ACA small nucleolar RNA (snoRNA)-ended long noncoding RNA (lncRNA), SLERT, plays a critical role in gene regulation. However, its role in cancer remains undetermined. Herein, we explored its implication in human endometrial cancer (EC). METHODS EC plasma and tissue samples were collected for the detection of SLERT expression using qRT-PCR method. The functional investigation was tested by CCK-8 and transwell assays. Luciferase reporter, RNA pull-down, and immunoprecipitation (RIP) assays were used to determine the regulatory network involved in SLERT. The in vivo effect of SLERT was tested by caudal vein lung metastasis model. RESULTS Stable knockdown of SLERT significantly inhibited EC cell (KLE and AN3CA) migration and invasion, while it did not affect cell viability. SLERT induced epithelial-mesenchymal transition (EMT) via elevating N-cadherin and Vimentin and downregulating E-cadherin. Further investigation showed that SLERT directly binds to METTL3, increasing the m6A levels of BDNF mRNA; then, the m6A sites were read by IGF2BP1, enhancing BDNF mRNA stability, followed by the activation of BDNF/TRKB signaling, an inducer of EMT. The animal model showed that overexpression of SLERT increased EC cell lung metastasis, and this effect was effectively blocked by BDNF silencing or treatment with TRKB inhibitor k252a. Clinically, EC patients have high levels of SLERT both in tissue or plasma, which might be used as a biomarker of diagnosis and prognosis. CONCLUSION Our findings, for the first time, uncover the metastasis-promoting effect of SLERT in EC via in vitro and in vivo evidence, providing a potential therapeutic target for metastatic EC treatment.
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Affiliation(s)
- Jun Tian
- grid.256922.80000 0000 9139 560XDepartment of Gynaecology, Huaihe Hospital of Henan University, 1 Baogong Hubei Road, Gulou District, Kaifeng City, 475001 Henan Province China
| | - Hailing Cheng
- grid.256922.80000 0000 9139 560XDepartment of Gynaecology, Huaihe Hospital of Henan University, 1 Baogong Hubei Road, Gulou District, Kaifeng City, 475001 Henan Province China
| | - Ning Wang
- grid.256922.80000 0000 9139 560XDepartment of Gynaecology, Huaihe Hospital of Henan University, 1 Baogong Hubei Road, Gulou District, Kaifeng City, 475001 Henan Province China
| | - Chenhui Wang
- grid.256922.80000 0000 9139 560XDepartment of Gynaecology, Huaihe Hospital of Henan University, 1 Baogong Hubei Road, Gulou District, Kaifeng City, 475001 Henan Province China
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Wang J, Meng X, Chen K, Feng J. An autophagy-related four-lncRNA signature helps to predict progression-free survival of neuroblastoma patients. Front Oncol 2022; 12:1014845. [PMID: 36530992 PMCID: PMC9753905 DOI: 10.3389/fonc.2022.1014845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/14/2022] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND This study aimed to identify autophagy-related long non-coding RNAs (lncRNAs) associated with progression of neuroblastoma (NB), and to build an autophagy-related lncRNA signature that helps to predict progression-free survival (PFS) of NB. METHODS Three independent gene expression datasets were utilized in this study. Autophagy-related genes (ARG) associated with PFS of NB patients were firstly identified by univariate Cox survival analysis. lncRNAs correlated with those PFS-related ARGs were then identified. The least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses were performed to select out those lncRNAs with the best prognostic value for PFS. The Receiver Operating Characteristic (ROC) and Area Under Curve (AUC) analyses were performed to assess the prediction accuracy. RESULTS Four autophagy-related lncRNAs (AL356599.1, AC022075.1, AC020928.1 and LINC02076) were found to be with the best prognostic value and integrated into a four-lncRNA risk signature for predicting PFS of NB patients. The four-lncRNA signature significantly stratify NB patients into two risk groups, with high-risk group has significantly poorer PFS than the low-risk group. The prognostic role of the lncRNA signature was independent with other clinical risk factors. The ROC curves revealed that the lncRNA signature has a good performance in predicting PFS (AUC > 0.70). A nomogram based on COG (Children's Oncology Group) risk and the lncRNA risk score was constructed, showing good prediction accuracy (C-index = 0.700). The prognostic ability of the nomogram was better than that of COG risk alone (AUC = 0.790 versus AUC = 0.748). GSEA analyses revealed that multiple autophagy-related gene sets are significantly enriched in the low-risk group. CONCLUSIONS We identified an autophagy-related four-lncRNA signature that could help to predict the PFS of NB patients. Autophagy-related gene sets are significantly enriched in low-risk group, suggesting tumor suppressive roles of autophagy in NB.
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Affiliation(s)
| | | | | | - Jiexiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.
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21
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Assessment of Brain-Derived Neurotrophic Factor (BDNF) Concentration in Children with Idiopathic Nephrotic Syndrome. Int J Mol Sci 2022; 23:ijms232012312. [PMID: 36293164 PMCID: PMC9603999 DOI: 10.3390/ijms232012312] [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] [Received: 09/16/2022] [Revised: 10/07/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
Abstract
Idiopathic nephrotic syndrome (INS) is a chronic disease affecting children in early childhood. It is characterized by proteinuria, hypoalbuminemia, edema and hyperlipidemia. To date, the diagnosis is usually established at an advanced stage of proteinuria. Therefore, new methods of early INS detection are desired. This study was designed to assess brain-derived neurotrophic factor (BDNF) as a potential marker in the early diagnosis of INS. The study group included patients with a diagnosis of idiopathic nephrotic syndrome (n = 30) hospitalized in Clinical Hospital No. 1 in Zabrze, from December 2019 to December 2021. Our study shows that serum BDNF concentration decreased and urine BDNF concentration increased in a group of patients with INS, compared with healthy controls. Such outcomes might be related to loss of the BDNF contribution in podocyte structure maintenance. Moreover, we anticipate the role of BDNF in urine protein concentration increase, which could be used as a direct predictor of urine protein fluctuations in clinical practice. Moreover, the ROC curve has also shown that serum BDNF and urine BDNF levels might be useful as an INS marker.
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22
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Orientation algorithm for PPI networks based on network propagation approach. J Biosci 2022. [DOI: 10.1007/s12038-022-00284-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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23
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Casablanca Y, Wang G, Lankes HA, Tian C, Bateman NW, Miller CR, Chappell NP, Havrilesky LJ, Wallace AH, Ramirez NC, Miller DS, Oliver J, Mitchell D, Litzi T, Blanton BE, Lowery WJ, Risinger JI, Hamilton CA, Phippen NT, Conrads TP, Mutch D, Moxley K, Lee RB, Backes F, Birrer MJ, Darcy KM, Maxwell GL. Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study. Cancers (Basel) 2022; 14:cancers14174070. [PMID: 36077609 PMCID: PMC9454742 DOI: 10.3390/cancers14174070] [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: 06/17/2022] [Revised: 07/29/2022] [Accepted: 08/11/2022] [Indexed: 12/31/2022] Open
Abstract
Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80-0.98) for MS7 compared with 0.69 (0.59-0.80) and 0.71 (0.58-0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival (p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool.
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Affiliation(s)
- Yovanni Casablanca
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
| | - Guisong Wang
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Heather A. Lankes
- Gynecologic Oncology Group Statistical and Data Management Center, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Chunqiao Tian
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Nicholas W. Bateman
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Caela R. Miller
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
| | - Nicole P. Chappell
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
| | | | - Amy Hooks Wallace
- Division of Gynecologic Oncology, Duke University, Durham, NC 27710, USA
| | - Nilsa C. Ramirez
- Gynecologic Oncology Group Tissue Bank, Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - David S. Miller
- Division of Gynecologic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Julie Oliver
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Dave Mitchell
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Tracy Litzi
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Brian E. Blanton
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - William J. Lowery
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
| | - John I. Risinger
- Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick Ave., NE, Grand Rapids, MI 49503, USA
| | - Chad A. Hamilton
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA 22042, USA
| | - Neil T. Phippen
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA 22042, USA
| | - Thomas P. Conrads
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA 22042, USA
| | - David Mutch
- Division of Gynecologic Oncology, Washington University, St. Louis, MO 63110, USA
| | - Katherine Moxley
- Department of OB/GYN, Section of Gyn Oncology, University of Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Roger B. Lee
- Department of GYN/ONC, Tacoma General Hospital, Tacoma, WA 98405, USA
| | - Floor Backes
- Division of Gynecologic Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Michael J. Birrer
- P. Rockefeller Cancer Institute, Women’s Gynecologic Cancer Clinic, Little Rock, AR 72205, USA
| | - Kathleen M. Darcy
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- Correspondence: (K.M.D.); (G.L.M.)
| | - George Larry Maxwell
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
- Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA 22042, USA
- Correspondence: (K.M.D.); (G.L.M.)
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Zhu Z, Fang C, Xu H, Yuan L, Du Y, Ni Y, Xu Y, Shao A, Zhang A, Lou M. Anoikis resistance in diffuse glioma: The potential therapeutic targets in the future. Front Oncol 2022; 12:976557. [PMID: 36046036 PMCID: PMC9423707 DOI: 10.3389/fonc.2022.976557] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 07/25/2022] [Indexed: 11/28/2022] Open
Abstract
Glioma is the most common malignant intracranial tumor and exhibits diffuse metastasis and a high recurrence rate. The invasive property of glioma results from cell detachment. Anoikis is a special form of apoptosis that is activated upon cell detachment. Resistance to anoikis has proven to be a protumor factor. Therefore, it is suggested that anoikis resistance commonly occurs in glioma and promotes diffuse invasion. Several factors, such as integrin, E-cadherin, EGFR, IGFR, Trk, TGF-β, the Hippo pathway, NF-κB, eEF-2 kinase, MOB2, hypoxia, acidosis, ROS, Hsp and protective autophagy, have been shown to induce anoikis resistance in glioma. In our present review, we aim to summarize the underlying mechanism of resistance and the therapeutic potential of these molecules.
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Affiliation(s)
- Zhengyang Zhu
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaoyou Fang
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Houshi Xu
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Yuan
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yichao Du
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunjia Ni
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanzhi Xu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Anwen Shao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Neurosurgery, Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, China
| | - Anke Zhang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Neurosurgery, Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, China
| | - Meiqing Lou
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Upregulation of p75NTR by Histone Deacetylase Inhibitors Sensitizes Human Neuroblastoma Cells to Targeted Immunotoxin-Induced Apoptosis. Int J Mol Sci 2022; 23:ijms23073849. [PMID: 35409209 PMCID: PMC8998832 DOI: 10.3390/ijms23073849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/29/2022] [Accepted: 03/29/2022] [Indexed: 12/22/2022] Open
Abstract
Histone deacetylase (HDAC) inhibitors are novel chemotherapy agents with potential utility in the treatment of neuroblastoma, the most frequent solid tumor of childhood. Previous studies have shown that the exposure of human neuroblastoma cells to some HDAC inhibitors enhanced the expression of the common neurotrophin receptor p75NTR. In the present study we investigated whether the upregulation of p75NTR could be exploited to render neuroblastoma cells susceptible to the cytotoxic action of an anti-p75NTR antibody conjugated to the toxin saporin-S6 (p75IgG-Sap). We found that two well-characterized HDAC inhibitors, valproic acid (VPA) and entinostat, were able to induce a strong expression of p75NTR in different human neuroblastoma cell lines but not in other cells, with entinostat, displaying a greater efficacy than VPA. Cell pretreatment with entinostat enhanced p75NTR internalization and intracellular saporin-S6 delivery following p75IgG-Sap exposure. The addition of p75IgG-Sap had no effect on vehicle-pretreated cells but potentiated the apoptotic cell death that was induced by entinostat. In three-dimensional neuroblastoma cell cultures, the subsequent treatment with p75IgG-Sap enhanced the inhibition of spheroid growth and the impairment of cell viability that was produced by entinostat. In athymic mice bearing neuroblastoma xenografts, chronic treatment with entinostat increased the expression of p75NTR in tumors but not in liver, kidney, heart, and cerebellum. The administration of p75IgG-Sap induced apoptosis only in tumors of mice that were pretreated with entinostat. These findings define a novel experimental strategy to selectively eliminate neuroblastoma cells based on the sequential treatment with entinostat and a toxin-conjugated anti-p75NTR antibody.
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Gohil K, Kazmi MZH, Williams FJ. Structure-activity relationship and bioactivity studies of neurotrophic trans-banglene. Org Biomol Chem 2022; 20:2187-2193. [PMID: 35229853 DOI: 10.1039/d2ob00016d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2024]
Abstract
The synthesis and bioactivity of neurotrophic banglenes and derivatives is described, establishing a structure-activity relationship which enables future mechanistic studies. Neuritogenesis assays indicate that (-) trans-banglene is the active enantiomer. Assays performed with and without NGF protein suggest that neurotrophic activity and potentiation of NGF activity by (-) trans-banglene might be distinct unassociated processes. Interestingly, (-) trans-banglene potentiation of NGF-induced neuritogenesis is unaffected by the presence of Erk1/2, Akt and Pkc inhibitors.
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Affiliation(s)
- Khyati Gohil
- Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada
| | - M Zain H Kazmi
- Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada
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27
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Pan S, Zhang L, Luo X, Nan J, Yang W, Bin H, Li Y, Huang Q, Wang T, Pan Z, Mu B, Wang F, Tian C, Liu Y, Li L, Yang S. Structural Optimization and Structure-Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6 H-pyrimido[5,4- b][1,4]oxazin-7(8 H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants. J Med Chem 2022; 65:2035-2058. [PMID: 35080890 DOI: 10.1021/acs.jmedchem.1c01597] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tropomyosin receptor kinases (TrkA, TrkB, and TrkC) are attractive therapeutic targets for multiple cancers. Two first-generation small-molecule Trks inhibitors, larotrectinib and entrectinib, have just been approved to use clinically. However, the drug-resistance mutations of Trks have already emerged, which calls for new-generation Trks inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of 6,6-dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one derivatives as a new class of pan-Trk inhibitors. The prioritized compound 11g exhibited low nanomolar IC50 values against TrkA, TrkB, and TrkC and various drug-resistant mutants. It also showed good kinase selectivity. 11g displayed excellent in vitro antitumor activity and strongly suppressed Trk-mediated signaling pathways in intact cells. In in vivo studies, compound 11g exhibited good antitumor activity in BaF3-TEL-TrkA and BaF3-TEL-TrkCG623R allograft mouse models without exhibiting apparent toxicity. Collectively, 11g could be a promising lead compound for drug discovery targeting Trks and deserves further investigation.
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Affiliation(s)
- Shulei Pan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Liting Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Xinling Luo
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jinshan Nan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Wei Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Huachao Bin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yang Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Qiao Huang
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Tianqi Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Zhiling Pan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Bo Mu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Falu Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Chenyu Tian
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yang Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Linli Li
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shengyong Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
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Nguyen CD, Yoo J, Hwang SY, Cho SY, Kim M, Jang H, No KO, Shin JC, Kim JH, Lee G. Bee Venom Activates the Nrf2/HO-1 and TrkB/CREB/BDNF Pathways in Neuronal Cell Responses against Oxidative Stress Induced by Aβ 1-42. Int J Mol Sci 2022; 23:ijms23031193. [PMID: 35163115 PMCID: PMC8835940 DOI: 10.3390/ijms23031193] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 02/04/2023] Open
Abstract
Honeybee venom has recently been considered an anti-neurodegenerative agent, primarily due to its anti-inflammatory effects. The natural accumulation of amyloid-beta (Aβ) in the brain is reported to be the natural cause of aging neural ability downfall, and oxidative stress is the main route by which Aβ ignites its neural toxicity. Anti-neural oxidative stress is considered an effective approach for neurodegenerative therapy. To date, it is unclear how bee venom ameliorates neuronal cells in oxidative stress induced by Aβ. Here, we evaluated the neuroprotective effect of bee venom on Aβ-induced neural oxidative stress in both HT22 cells and an animal model. Our results indicate that bee venom protected HT22 cells against apoptosis induced by Aβ1–42. This protective effect was explained by the increased nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2), consequently upregulating the production of heme oxygenase-1 (HO-1), a critical cellular instinct antioxidant enzyme that neutralizes excessive oxidative stress. Furthermore, bee venom treatment activated the tropomyosin-related kinase receptor B (TrkB)/cAMP response element-binding (CREB)/brain-derived neurotrophic factor (BDNF), which is closely related to the promotion of cellular antioxidant defense and neuronal functions. A mouse model with cognitive deficits induced by Aβ1–42 intracerebroventricular (ICV) injections was also used. Bee venom enhanced animal cognitive ability and enhanced neural cell genesis in the hippocampal dentate gyrus region in a dose-dependent manner. Further analysis of animal brain tissue and serum confirmed that bee venom reduced oxidative stress, cholinergic system activity, and intercellular neurotrophic factor regulation, which were all adversely affected by Aβ1–42. Our study demonstrates that bee venom exerts antioxidant and neuroprotective actions against neural oxidative stress caused by Aβ1–42, thereby promoting its use as a therapeutic agent for neurodegenerative disorders.
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Affiliation(s)
- Cong Duc Nguyen
- College of Korean Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (C.D.N.); (S.-Y.H.); (S.-Y.C.); (M.K.); (H.J.); (K.O.N.)
| | - Jaehee Yoo
- Department of Acupuncture and Moxibustion Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (J.Y.); (J.C.S.)
- Dongshin University Gwangju Korean Medicine Hospital, 141 Wolsan-ro Nam-gu, Gwangju 61619, Korea
| | - Sun-Young Hwang
- College of Korean Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (C.D.N.); (S.-Y.H.); (S.-Y.C.); (M.K.); (H.J.); (K.O.N.)
| | - Sung-Young Cho
- College of Korean Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (C.D.N.); (S.-Y.H.); (S.-Y.C.); (M.K.); (H.J.); (K.O.N.)
| | - Myeonghun Kim
- College of Korean Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (C.D.N.); (S.-Y.H.); (S.-Y.C.); (M.K.); (H.J.); (K.O.N.)
| | - Hyemin Jang
- College of Korean Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (C.D.N.); (S.-Y.H.); (S.-Y.C.); (M.K.); (H.J.); (K.O.N.)
| | - Kyoung Ok No
- College of Korean Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (C.D.N.); (S.-Y.H.); (S.-Y.C.); (M.K.); (H.J.); (K.O.N.)
| | - Jeong Cheol Shin
- Department of Acupuncture and Moxibustion Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (J.Y.); (J.C.S.)
- Dongshin University Mokpo Korean Medicine Hospital, 313 Baengnyeon-daero, Mokpo 58665, Korea
| | - Jae-Hong Kim
- Department of Acupuncture and Moxibustion Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (J.Y.); (J.C.S.)
- Dongshin University Gwangju Korean Medicine Hospital, 141 Wolsan-ro Nam-gu, Gwangju 61619, Korea
- Correspondence: (J.-H.K.); (G.L.)
| | - Gihyun Lee
- College of Korean Medicine, Dongshin University, 67 Dongshindae-gil, Naju 58245, Korea; (C.D.N.); (S.-Y.H.); (S.-Y.C.); (M.K.); (H.J.); (K.O.N.)
- Correspondence: (J.-H.K.); (G.L.)
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Silencing of LINC01963 enhances the chemosensitivity of prostate cancer cells to docetaxel by targeting the miR-216b-5p/TrkB axis. J Transl Med 2022; 102:602-612. [PMID: 35152275 PMCID: PMC9162921 DOI: 10.1038/s41374-022-00736-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 01/10/2022] [Accepted: 01/14/2022] [Indexed: 01/12/2023] Open
Abstract
Docetaxel (DTX) treatment effectively prolongs the overall survival of patients with prostate cancer. However, most patients eventually develop resistance to chemotherapy and experience tumor progression or even death. Long noncoding RNAs (lncRNAs) affect docetaxel chemosensitivity. However, the biological role and regulatory mechanisms of lncRNAs in docetaxel-resistant prostate cancer remain unclear. Differences in lncRNAs were evaluated by lncRNA sequencing and evaluated using quantitative real-time polymerase chain reaction, and TrkB expression was measured through western blot analysis. Proliferation was measured using the MTS, while apoptosis and cell cycle were measured using flow cytometry. In addition, migration and invasion were measured using transwell assays. Forty-eight female BALB/c nude mice were used for subcutaneous tumorigenicity and lung metastasis assays. We found that LINC01963 was overexpressed in the PC3-DR cells. LINC01963 silencing enhanced the chemosensitivity of PC3-DR to docetaxel and inhibited tumorigenicity and lung metastasis, while LINC01963 overexpression enhanced the chemoresistance of PC3 cells to docetaxel. It was found that LINC01963 bind to miR-216b-5p. The miR-216b-5p inhibitor reversed the suppressive effect of sh-LINC01963 on PC3-DR cell proliferation, migration, and invasion. Furthermore, miR-216b-5p can bind to the 3'-UTR of NTRK2 and inhibit TrkB protein levels. TrkB enhances docetaxel resistance in prostate cancer and reverses the effects of LINC01963 silencing and miR-216b-5p overexpression. In conclusion, silencing LINC01963 inhibited TrkB protein level to enhance the chemosensitivity of PC3-DR to docetaxel by means of competitively binding to miR-216b-5p. This study illustrates that LINC01963 is a novel therapeutic target for treating prostate cancer patients with DTX resistance.
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Feng Q, Song D, Wang X. Pan-cancer analysis reveals that neurotrophin signaling correlates positively with anti-tumor immunity, clinical outcomes, and response to targeted therapies and immunotherapies in cancer. Life Sci 2021; 282:119848. [PMID: 34293398 DOI: 10.1016/j.lfs.2021.119848] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/11/2021] [Accepted: 07/12/2021] [Indexed: 12/23/2022]
Abstract
AIMS The crosstalk between cancer cells and nerves plays an important role in tumor biology. However, the correlation between the neurotrophin signaling (NS) and anti-tumor immunity and immunotherapy response in cancer remains unexplored. MATERIALS AND METHODS We analyzed associations of NS with anti-tumor immune signatures, tumor immunity-related molecular and genomic features, and clinical features in 33 TCGA cancer types. We also explored the association between NS and the response to immune checkpoint inhibitors (ICIs) in four cancer cohorts. KEY FINDINGS NS scores had significant positive correlations with the enrichment scores of anti-tumor immune signatures, including CD8+ T cells, interferon response, natural killer cells, Toll-like receptor and NOD-like receptor signaling pathways in most cancer types. NS scores were inversely correlated with the scores of DNA damage repair pathways, tumor mutation burden, copy number alterations, intra-tumor heterogeneity, and tumor stemness in diverse cancers. In contrast, NS scores were significantly and positively correlated with the apoptosis pathway's scores in 32 of the 33 cancer types. NS scores were significantly lower in early-stage versus late-stage and in primary versus metastatic tumors in diverse cancers. Higher NS scores were correlated with better survival in pan-cancer and in eight individual cancer types. Moreover, the response rate to ICIs was higher in higher-NS-score than in lower-NS-score tumors in four cancer cohorts. Elevated NS was correlated with increased drug sensitivity for numerous anti-tumor targeted drugs. SIGNIFICANCE NS is a positive biomarker for anti-tumor immune response, prognosis, and the response to targeted and immunotherapeutic drugs in cancer.
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Affiliation(s)
- Qiushi Feng
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China
| | - Dandan Song
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China.
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31
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Dedoni S, Marras L, Olianas MC, Ingianni A, Onali P. Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis. Apoptosis 2021; 25:697-714. [PMID: 32712736 PMCID: PMC7527367 DOI: 10.1007/s10495-020-01626-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The antiepileptic and mood stabilizer agent valproic acid (VPA) has been shown to exert anti-tumour effects and to cause neuronal damage in the developing brain through mechanisms not completely understood. In the present study we show that prolonged exposure of SH-SY5Y and LAN-1 human neuroblastoma cells to clinically relevant concentrations of VPA caused a marked induction of the protein and transcript levels of the common neurotrophin receptor p75NTR and its co-receptor sortilin, two promoters of apoptotic cell death in response to proneurotrophins. VPA induction of p75NTR and sortilin was associated with an increase in plasma membrane expression of the receptor proteins and was mimicked by cell treatment with several histone deacetylase (HDAC) inhibitors. VPA and HDAC1 knockdown decreased the level of EZH2, a core component of the polycomb repressive complex 2, and upregulated the transcription factor CASZ1, a positive regulator of p75NTR. CASZ1 knockdown attenuated VPA-induced p75NTR overexpression. Cell treatment with VPA favoured proNGF-induced p75NTR/sortilin interaction and the exposure to proNGF enhanced JNK activation and apoptotic cell death elicited by VPA. Depletion of p75NTR or addition of the sortilin agonist neurotensin to block proNGF/sortilin interaction reduced the apoptotic response to VPA and proNGF. Exposure of mouse cerebellar granule cells to VPA upregulated p75NTR and sortilin and induced apoptosis which was enhanced by proNGF. These results indicate that VPA upregulates p75NTR apoptotic cell signalling through an epigenetic mechanism involving HDAC inhibition and suggest that this effect may contribute to the anti-neuroblastoma and neurotoxic effects of VPA.
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Affiliation(s)
- Simona Dedoni
- Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, CA, Italy
| | - Luisa Marras
- Section of Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Maria C Olianas
- Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, CA, Italy
| | - Angela Ingianni
- Section of Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Pierluigi Onali
- Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, CA, Italy.
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32
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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33
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Giridharan N, Glitza Oliva IC, O'Brien BJ, Parker Kerrigan BC, Heimberger AB, Ferguson SD. Targeting the Tumor Microenvironment in Brain Metastasis. Neurosurg Clin N Am 2021; 31:641-649. [PMID: 32921358 DOI: 10.1016/j.nec.2020.06.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Dynamic interplay between cancer cells and the surrounding microenvironment is a feature of the metastatic process. Successful metastatic brain colonization requires complex mechanisms that ultimately allow tumor cells to adapt to the unique microenvironment of the central nervous system, evade immune destruction, survive, and grow. Accumulating evidence suggests that components of the brain tumor microenvironment (TME) play a vital role in the metastatic cascade. In this review, the authors summarize the contribution of the TME to the development and progression of brain metastasis. They also highlight opportunities for TME-directed targeted therapy.
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Affiliation(s)
- Nisha Giridharan
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA
| | - Isabella C Glitza Oliva
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 430, Houston, TX 77030, USA
| | - Barbara J O'Brien
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 431, Houston, TX 77030-4009, USA
| | - Brittany C Parker Kerrigan
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA
| | - Amy B Heimberger
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA
| | - Sherise D Ferguson
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA.
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Dahl NA, Donson AM, Sanford B, Wang D, Walker FM, Gilani A, Foreman NK, Tinkle CL, Baker SJ, Hoffman LM, Venkataraman S, Vibhakar R. NTRK Fusions Can Co-Occur With H3K27M Mutations and May Define Druggable Subclones Within Diffuse Midline Gliomas. J Neuropathol Exp Neurol 2021; 80:345-353. [PMID: 33749791 PMCID: PMC7985828 DOI: 10.1093/jnen/nlab016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Diffuse midline gliomas (DMGs) are incurable pediatric tumors with extraordinarily limited treatment options. Decades of clinical trials combining conventional chemotherapies with radiation therapy have failed to improve these outcomes, demonstrating the need to identify and validate druggable biologic targets within this disease. NTRK1/2/3 fusions are found in a broad range of pediatric cancers, including high-grade gliomas and a subset of DMGs. Phase 1/2 studies of TRK inhibitors have demonstrated good tolerability, effective CNS penetration, and promising objective responses across all patients with TRK fusion-positive cancers, but their use has not been explored in TRK fusion-positive DMG. Here, we report 3 cases of NTRK fusions co-occurring within H3K27M-positive pontine diffuse midline gliomas. We employ a combination of single-cell and bulk transcriptome sequencing from TRK fusion-positive DMG to describe the phenotypic consequences of this co-occurring alteration. We then use ex vivo short-culture assays to evaluate the potential response to TRK inhibition in this disease. Together, these data highlight the importance of routine molecular characterization of these highly aggressive tumors and identify a small subset of patients that may benefit from currently available targeted therapies.
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Affiliation(s)
- Nathan A Dahl
- From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
- Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Andrew M Donson
- From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Bridget Sanford
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Dong Wang
- From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Faye M Walker
- From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Ahmed Gilani
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
- Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Nicholas K Foreman
- From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
- Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, Colorado, USA
- Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Christopher L Tinkle
- Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Suzanne J Baker
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Lindsey M Hoffman
- Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, Arizona, USA
| | - Sujatha Venkataraman
- From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Rajeev Vibhakar
- From the Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
- Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, Colorado, USA
- Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, USA
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Serum Levels of BDNF in Patients with Adenoma and Colorectal Cancer. DISEASE MARKERS 2021; 2021:8867368. [PMID: 33628340 PMCID: PMC7895608 DOI: 10.1155/2021/8867368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 01/18/2021] [Accepted: 01/28/2021] [Indexed: 12/11/2022]
Abstract
The present study is aimed at examining the serum levels of brain-derived neurotrophic factor (BDNF) and investigating its role in differential diagnosis of colorectal cancer (CRC). Materials and Methods. In a Chinese population, we conducted a case-control study to compare the diagnostic performance of serum levels of BDNF and carcinoembryonic antigen (CEA) for CRC. We enrolled 61 healthy controls, 31 patients with adenomas, and 81 patients with CRC. We explored the correlation between serum levels of BDNF and several pathological features, such as tumor differentiation and TNM staging. Results. The serum levels of BDNF were significantly (p < 0.0001) higher in patients with CRC (10.64 ± 3.84, n = 81) than in the healthy controls (4.69 ± 1.69 ng/mL, n = 61). Serum BDNF also correlated with tumor size, tumor differentiation, and TNM staging (p < 0.05). For early diagnosis, the combination of BDNF (AUC 0.719; 95% CI, 0.621–0.816) and CEA (AUC 0.733; 95% CI, 0.632–0.909) slightly improved the diagnostic performance for CRC (AUC 0.823; 95% CI, 0.737-0.909). Conclusions. Combined detection of serum BDNF and CEA may thus have the potential to become a new laboratory method for the early clinical diagnosis of CRC.
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Roos BB, Teske JJ, Bhallamudi S, Pabelick CM, Sathish V, Prakash YS. Neurotrophin Regulation and Signaling in Airway Smooth Muscle. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1304:109-121. [PMID: 34019266 PMCID: PMC11042712 DOI: 10.1007/978-3-030-68748-9_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Structural and functional aspects of bronchial airways are key throughout life and play critical roles in diseases such as asthma. Asthma involves functional changes such as airway irritability and hyperreactivity, as well as structural changes such as enhanced cellular proliferation of airway smooth muscle (ASM), epithelium, and fibroblasts, and altered extracellular matrix (ECM) and fibrosis, all modulated by factors such as inflammation. There is now increasing recognition that disease maintenance following initial triggers involves a prominent role for resident nonimmune airway cells that secrete growth factors with pleiotropic autocrine and paracrine effects. The family of neurotrophins may be particularly relevant in this regard. Long recognized in the nervous system, classical neurotrophins such as brain-derived neurotrophic factor (BDNF) and nonclassical ligands such as glial-derived neurotrophic factor (GDNF) are now known to be expressed and functional in non-neuronal systems including lung. However, the sources, targets, regulation, and downstream effects are still under investigation. In this chapter, we discuss current state of knowledge and future directions regarding BDNF and GDNF in airway physiology and on pathophysiological contributions in asthma.
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Affiliation(s)
- Benjamin B Roos
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jacob J Teske
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Sangeeta Bhallamudi
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA
| | - Christina M Pabelick
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Venkatachalem Sathish
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA
| | - Y S Prakash
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
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Ribeiro JT, Thieme S, Zettermann P, Leite AA, Zanella VG, Pilar EFS, Fonseca FP, Mesquita RA, Vargas PA, Dos Santos JN, Martins MD. Immunoexpression of BDNF, TrkB, and p75NTR receptors in peripheral neural lesions of the head and neck. J Oral Pathol Med 2020; 50:492-501. [PMID: 33222311 DOI: 10.1111/jop.13145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 10/20/2020] [Accepted: 11/11/2020] [Indexed: 01/19/2023]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) and neurotrophin receptors have been recognized as fundamental regulators of normal brain development, homeostasis, and plasticity. They have also been studied in the behavior of central nervous system tumors. Here, we studied the pattern of BDNF, TrkB and p75NTR immunoexpression in peripheral benign and malignant neural lesions in head and neck. METHODS This cross-sectional analytical study included 79 cases of head and neck neural lesions. Nineteen cases of traumatic neuromas (TN), 20 cases of granular cell tumors (GCT), 16 cases of neurofibromas (NF), 20 cases of schwannomas (SC), and 4 malignant peripheral nerve sheath tumor (MPNST) were submitted to immunohistochemistry with BDNF, TrkB, and p75NTR antibodies. A semi-quantitative analysis was performed. RESULTS The analysis of BDNF demonstrated a high percentage of positive cells in TN, GCT and SC with a decrease in cases of NF and MPNST. TrkB presented a lower significant immunoexpression in GCT in relation to the TN, NF, SC, and MPNST (P < .0001); and TN showed less percentage of positive cell compared to SC (P = .0017). Regarding p75NTR, the percentage of positive cell was significantly reduced in MPNST compared GCT (P = .009), NF (P = .0138) and SC (P = .0069). Also, a decrease in TN compared to GCT (P = .007) was observed. CONCLUSIONS Our results showed the immunoreactivity of BDNF, TrkB, and p75NTR in head and neck peripheral neural lesions. Reduction of BDNF and p75NTR in MPNST might suggest down-regulation during the acquisition of malignant phenotype.
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Affiliation(s)
- Julia Turra Ribeiro
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Stéfanie Thieme
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Paula Zettermann
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Amanda Almeida Leite
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, SP, Brazil
| | - Virgilio Gonzales Zanella
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Head and Neck Surgery Department, Hospital Santa Rita, Complexo Hospitalar Santa Casa, Porto Alegre, Brazil
| | - Emily Ferreira Salles Pilar
- Experimental Pathology Unit, Clinics Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Felipe Paiva Fonseca
- Department of Oral Surgery and Pathology, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Ricardo Alves Mesquita
- Department of Oral Surgery and Pathology, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Pablo Agustin Vargas
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, SP, Brazil
| | - Jean Nunes Dos Santos
- Department of Oral Pathology, School of Dentistry, Federal University of Bahia, Salvador, Brazil
| | - Manoela Domingues Martins
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Head and Neck Surgery Department, Hospital Santa Rita, Complexo Hospitalar Santa Casa, Porto Alegre, Brazil.,Department of Oral Medicine, Porto Alegre Clinics Hospital (HCPA/UFRGS), Porto Alegre, Brazil
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Zou W, Hu X, Jiang L. Advances in Regulating Tumorigenicity and Metastasis of Cancer Through TrkB Signaling. Curr Cancer Drug Targets 2020; 20:779-788. [PMID: 32748747 DOI: 10.2174/1568009620999200730183631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 06/27/2020] [Accepted: 06/29/2020] [Indexed: 01/12/2023]
Abstract
The clinical pathology of various human malignancies is supported by tropomyosin receptor kinase (Trk) B TrkB which is a specific binding receptor of the brain-derived neurotrophic factor (BDNF). TrkB and TrkB fusion proteins have been observed to be over-expressed in many cancer patients. Moreover, these proteins have been observed in multiple types of cells. A few signaling pathways can be modulated by the abnormal activation of the BDNF/TrkB pathway. These signaling pathways include PI3K/Akt pathway, transactivation of EGFR, phospholipase C-gamma (PLCγ) pathway, Ras-Raf-MEK-ERK pathway, Jak/STAT pathway, and nuclear factor kappalight- chain-enhancer of activated B cells (NF-kB) pathway. The BDNF/TrkB pathway, when overexpressed in tumors, is correlated with reduced clinical prognosis and short survival time of patients. Targeting the BDNF/TrkB pathway and the use of Trk inhibitors, such as entrectinib, larotrectinib, etc. are promising methods for targeted therapy of tumors. The present review provides an overview of the role of the TrkB pathway in the pathogenesis of cancer and its value as a potential therapeutic target.
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Affiliation(s)
- Wujun Zou
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
| | - Xiaoyan Hu
- Department of Pathogenic Biology, School of Basic Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Liang Jiang
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
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39
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Artim SC, Kiyatkin A, Lemmon MA. Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB. Biochem J 2020; 477:4053-4070. [PMID: 33043964 PMCID: PMC7606831 DOI: 10.1042/bcj20200695] [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: 08/27/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 11/17/2022]
Abstract
The tropomyosin-related kinase (Trk) family consists of three receptor tyrosine kinases (RTKs) called TrkA, TrkB, and TrkC. These RTKs are regulated by the neurotrophins, a class of secreted growth factors responsible for the development and function of neurons. The Trks share a high degree of homology and utilize overlapping signaling pathways, yet their signaling is associated with starkly different outcomes in certain cancers. For example, in neuroblastoma, TrkA expression and signaling correlates with a favorable prognosis, whereas TrkB is associated with poor prognoses. To begin to understand how activation of the different Trks can lead to such distinct cellular outcomes, we investigated differences in kinase activity and duration of autophosphorylation for the TrkA and TrkB tyrosine kinase domains (TKDs). We find that the TrkA TKD has a catalytic efficiency that is ∼2-fold higher than that of TrkB, and becomes autophosphorylated in vitro more rapidly than the TrkB TKD. Studies with mutated TKD variants suggest that a crystallographic dimer seen in many TrkA (but not TrkB) TKD crystal structures, which involves the kinase-insert domain, may contribute to this enhanced TrkA autophosphorylation. Consistent with previous studies showing that cellular context determines whether TrkB signaling is sustained (promoting differentiation) or transient (promoting proliferation), we also find that TrkB signaling can be made more transient in PC12 cells by suppressing levels of p75NTR. Our findings shed new light on potential differences between TrkA and TrkB signaling, and suggest that subtle differences in signaling dynamics can lead to substantial shifts in the cellular outcome.
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Affiliation(s)
- Stephen C. Artim
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Present address: Merck Research Laboratories, Merck, South San Francisco, CA 94080, USA
| | - Anatoly Kiyatkin
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Pharmacology and Cancer Biology Institute, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Mark A. Lemmon
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Pharmacology and Cancer Biology Institute, Yale University School of Medicine, New Haven, CT, 06520, USA
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40
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Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. Int J Mol Sci 2020; 21:E7777. [PMID: 33096634 PMCID: PMC7589016 DOI: 10.3390/ijms21207777] [Citation(s) in RCA: 508] [Impact Index Per Article: 101.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 01/10/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively studied neurotrophins in the mammalian brain. BDNF signals through the tropomycin receptor kinase B (TrkB) and the low affinity p75 neurotrophin receptor (p75NTR). BDNF plays an important role in proper growth, development, and plasticity of glutamatergic and GABAergic synapses and through modulation of neuronal differentiation, it influences serotonergic and dopaminergic neurotransmission. BDNF acts as paracrine and autocrine factor, on both pre-synaptic and post-synaptic target sites. It is crucial in the transformation of synaptic activity into long-term synaptic memories. BDNF is considered an instructive mediator of functional and structural plasticity in the central nervous system (CNS), influencing dendritic spines and, at least in the hippocampus, the adult neurogenesis. Changes in the rate of adult neurogenesis and in spine density can influence several forms of learning and memory and can contribute to depression-like behaviors. The possible roles of BDNF in neuronal plasticity highlighted in this review focus on the effect of antidepressant therapies on BDNF-mediated plasticity. Moreover, we will review data that illustrate the role of BDNF as a potent protective factor that is able to confer protection against neurodegeneration, in particular in Alzheimer's disease. Finally, we will give evidence of how the involvement of BDNF in the pathogenesis of brain glioblastoma has emerged, thus opening new avenues for the treatment of this deadly cancer.
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Affiliation(s)
- Luca Colucci-D’Amato
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
- InterUniversity Center for Research in Neurosciences (CIRN), University of Campania "Luigi Vanvitelli", 80131 Naples, Italy
| | - Luisa Speranza
- Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Floriana Volpicelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy;
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41
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McCullough D, Atofanei C, Knight E, Trim SA, Trim CM. Kinome scale profiling of venom effects on cancer cells reveals potential new venom activities. Toxicon 2020; 185:129-146. [PMID: 32682827 DOI: 10.1016/j.toxicon.2020.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/07/2020] [Accepted: 07/12/2020] [Indexed: 02/07/2023]
Abstract
The search for novel and relevant cancer therapeutics is continuous and ongoing. Cancer adaptations, resulting in therapeutic treatment failures, fuel this continuous necessity for new drugs to novel targets. Recently, researchers have started to investigate the effect of venoms and venom components on different types of cancer, investigating their mechanisms of action. Receptor tyrosine kinases (RTKs) comprise a family of highly conserved and functionally important druggable targets for cancer therapy. This research exploits the novelty of complex venom mixtures to affect phosphorylation of the epidermal growth factor receptor (EGFR) and related RTK family members, dually identifying new activities and unexplored avenues for future cancer and venom research. Six whole venoms from diverse species taxa, were evaluated for their ability to illicit changes in the phosphorylated expression of a panel of 49 commonly expressed RTKs. The triple negative breast cancer cell line MDA-MB-468 was treated with optimised venom doses, pre-determined by SDS PAGE and Western blot analysis. The phosphorylated expression levels of 49 RTKs in response to the venoms were assessed with the use of Human Phospho-RTK Arrays and analysed using ImageLab 5.2.1 analysis software (BioRad). Inhibition of EGFR phosphorylation occurred with treatment of venom from Acanthoscurria geniculata (Theraphosidae), Heterometrus swammerdami (Scorpionidae), Crotalus durissus vegrandis (Crotalidae) and Naja naja (Elapidae). Western green mamba Dendroaspis viridis venom increased EGFR phosphorylation. Eph, HGFR and HER were the most affected receptor families by venoms. Whilst the importance of these changes in terms of effect on MDA-MB-468 cells' long-term viability and functionality are still unclear, the findings present exciting opportunities for further investigation as potential drug targets in cancer and as tools to understand better how these pathways interact.
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Affiliation(s)
- Danielle McCullough
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK
| | - Cristina Atofanei
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK
| | - Emily Knight
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK; Life Sciences Industry Liaison laboratory, Canterbury Christ Church University, Discovery Park, Sandwich, Kent, CT13 9FF, UK
| | - Steven A Trim
- Venomtech Ltd., Discovery Park, Sandwich, Kent, CT13 9FF, UK
| | - Carol M Trim
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK.
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Tinaburri L, Valente C, Teson M, Minafò YA, Cordisco S, Guerra L, Dellambra E. The Secretome of Aged Fibroblasts Promotes EMT-Like Phenotype in Primary Keratinocytes from Elderly Donors through BDNF-TrkB Axis. J Invest Dermatol 2020; 141:1052-1062.e12. [PMID: 32931807 DOI: 10.1016/j.jid.2020.08.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 08/11/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023]
Abstract
Age-related changes in the dermis can play a primary role in tumor initiation promoting the unrestrained proliferation of precancerous keratinocytes (KCs) through cytokines and GF secretion. We found a high percentage of epithelial-to-mesenchymal transition-like colonies raising in primary human KC cultures from old subjects after treatment with aged fibroblast supernatants (SPNs). Continuous extracellular signals were required for maintaining these changes. Conversely, the secretome did not induce epithelial-to-mesenchymal transition-like colonies in KCs from young subjects. SPN-treated aged KCs displayed the activation of pathways involved in the disjunction of cell‒cell adhesion, extracellular matrix remodeling, manifestation of a mesenchymal phenotype, and dedifferentiation programs. Moreover, they recovered proliferation and clonogenic ability and showed enhanced migration. We identified an age-related increase of the BDNF secretion from fibroblasts as well as of the expression of its receptor TrkB in KCs. BDNF treatment of aged KCs induced TrkB phosphorylation and recapitulated the modifications promoted by aged fibroblast SPN. Furthermore, the treatment with a specific antibody against BDNF or a TrkB antagonist inhibited the paracrine signaling preventing SPN-mediated morphological and molecular changes. Finally, BDNF induced signs of matrix invasion in a three-dimensional organotypic model. Therefore, we demonstrate that aged fibroblast SPN promotes phenotypic plasticity in KCs from the elderly through BDNF-TrkB axis.
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Affiliation(s)
| | | | - Massimo Teson
- Molecular and Cell Laboratory, IDI-IRCCS, Rome, Italy
| | | | - Sonia Cordisco
- Molecular and Cell Laboratory, IDI-IRCCS, Rome, Italy; Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
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43
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Thomaz A, Jaeger M, Brunetto AL, Brunetto AT, Gregianin L, de Farias CB, Ramaswamy V, Nör C, Taylor MD, Roesler R. Neurotrophin Signaling in Medulloblastoma. Cancers (Basel) 2020; 12:E2542. [PMID: 32906676 PMCID: PMC7564905 DOI: 10.3390/cancers12092542] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/04/2020] [Accepted: 09/06/2020] [Indexed: 12/11/2022] Open
Abstract
Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.
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Affiliation(s)
- Amanda Thomaz
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (A.T.); (M.J.); (A.L.B.); (A.T.B.); (L.G.); (C.B.d.F.)
- Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90050-170, RS, Brazil
| | - Mariane Jaeger
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (A.T.); (M.J.); (A.L.B.); (A.T.B.); (L.G.); (C.B.d.F.)
- Children’s Cancer Institute, Porto Alegre 90620-110, RS, Brazil
| | - Algemir L. Brunetto
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (A.T.); (M.J.); (A.L.B.); (A.T.B.); (L.G.); (C.B.d.F.)
- Children’s Cancer Institute, Porto Alegre 90620-110, RS, Brazil
| | - André T. Brunetto
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (A.T.); (M.J.); (A.L.B.); (A.T.B.); (L.G.); (C.B.d.F.)
- Children’s Cancer Institute, Porto Alegre 90620-110, RS, Brazil
| | - Lauro Gregianin
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (A.T.); (M.J.); (A.L.B.); (A.T.B.); (L.G.); (C.B.d.F.)
- Department of Pediatrics, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
- Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
| | - Caroline Brunetto de Farias
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (A.T.); (M.J.); (A.L.B.); (A.T.B.); (L.G.); (C.B.d.F.)
- Children’s Cancer Institute, Porto Alegre 90620-110, RS, Brazil
| | - Vijay Ramaswamy
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON 17-9702, Canada; (V.R.); (C.N.); (M.D.T.)
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Carolina Nör
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON 17-9702, Canada; (V.R.); (C.N.); (M.D.T.)
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Michael D. Taylor
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON 17-9702, Canada; (V.R.); (C.N.); (M.D.T.)
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada
- Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Rafael Roesler
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil; (A.T.); (M.J.); (A.L.B.); (A.T.B.); (L.G.); (C.B.d.F.)
- Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90050-170, RS, Brazil
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44
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Pinheiro KV, Thomaz A, Souza BK, Metcalfe VA, Freire NH, Brunetto AT, de Farias CB, Jaeger M, Bambini V, Smith CGS, Shaw L, Roesler R. Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma. Mol Biol Rep 2020; 47:6817-6828. [PMID: 32862352 DOI: 10.1007/s11033-020-05739-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 08/25/2020] [Indexed: 02/08/2023]
Abstract
A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM. Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments. Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM.
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Affiliation(s)
- Kelly V Pinheiro
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Porto Alegre, RS, 90050-170, Brazil
| | - Amanda Thomaz
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Porto Alegre, RS, 90050-170, Brazil.,Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA 4YG, UK
| | - Bárbara Kunzler Souza
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Porto Alegre, RS, 90050-170, Brazil.,Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Victoria Anne Metcalfe
- Faculty of Clinical and Biomedical Sciences, School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire, PR1 2HE, UK
| | - Natália Hogetop Freire
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
| | - André Tesainer Brunetto
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.,Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Caroline Brunetto de Farias
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.,Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Mariane Jaeger
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.,Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil
| | - Victorio Bambini
- Faculty of Clinical and Biomedical Sciences, School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire, PR1 2HE, UK
| | - Christopher G S Smith
- Faculty of Clinical and Biomedical Sciences, School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire, PR1 2HE, UK
| | - Lisa Shaw
- Faculty of Clinical and Biomedical Sciences, School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire, PR1 2HE, UK
| | - Rafael Roesler
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil. .,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Porto Alegre, RS, 90050-170, Brazil.
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45
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Mallepalli S, Gupta MK, Vadde R. Neuroblastoma: An Updated Review on Biology and Treatment. Curr Drug Metab 2020; 20:1014-1022. [PMID: 31878853 DOI: 10.2174/1389200221666191226102231] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 08/20/2019] [Accepted: 08/23/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Neuroblastoma (NB) is the second leading extracranial solid tumors of early childhood and clinically characterized by the presence of round, small, monomorphic cells with excess nuclear pigmentation (hyperchromasia).Owing to a lack of definitive treatment against NB and less survival rate in high-risk patients, there is an urgent requirement to understand molecular mechanisms associated with NB in a better way, which in turn can be utilized for developing drugs towards the treatment of NB in human. OBJECTIVES In this review, an approach was adopted to understand major risk factors, pathophysiology, the molecular mechanism associated with NB, and various therapeutic agents that can serve as drugs towards the treatment of NB in humans. CONCLUSION Numerous genetic (e.g., MYCN amplification), perinatal, and gestational factors are responsible for developing NB. However, no definite environmental or parental exposures responsible for causing NB have been confirmed to date. Though intensive multimodal treatment approaches, namely, chemotherapy, surgery & radiation, may help in improving the survival rate in children, these approaches have several side effects and do not work efficiently in high-risk patients. However, recent studies suggested that numerous phytochemicals, namely, vincristine, and matrine have a minimal side effect in the human body and may serve as a therapeutic drug during the treatment of NB. Most of these phytochemicals work in a dose-dependent manner and hence must be prescribed very cautiously. The information discussed in the present review will be useful in the drug discovery process as well as treatment and prevention on NB in humans.
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Affiliation(s)
- Suresh Mallepalli
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa-516003, A.P., India
| | - Manoj Kumar Gupta
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa-516003, A.P., India
| | - Ramakrishna Vadde
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa-516003, A.P., India
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Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, García-Acevez SJ. Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduct Target Ther 2020; 5:99. [PMID: 32555170 PMCID: PMC7303203 DOI: 10.1038/s41392-020-0205-z] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 05/15/2020] [Accepted: 05/24/2020] [Indexed: 12/11/2022] Open
Abstract
Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1β, CCL2, PGE2, among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.
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Affiliation(s)
- Rodolfo Daniel Cervantes-Villagrana
- Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), 07360, Mexico City, Mexico.
| | - Damaris Albores-García
- Department of Environmental Health Sciences, Florida International University (FIU), Miami, Florida, 33199, USA
| | - Alberto Rafael Cervantes-Villagrana
- Laboratorio de investigación en Terapéutica Experimental, Unidad Académica de Ciencias Químicas, Área de Ciencias de la Salud, Universidad Autónoma de Zacatecas (UAZ), Zacatecas, México
| | - Sara Judit García-Acevez
- Dirección de Proyectos e Investigación, Grupo Diagnóstico Médico Proa, 06400 CDMX, Cuauhtémoc, México
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Prasad PK, Mahajan P, Hawkins DS, Mostoufi-Moab S, Venkatramani R. Management of pediatric differentiated thyroid cancer: An overview for the pediatric oncologist. Pediatr Blood Cancer 2020; 67:e28141. [PMID: 32275118 DOI: 10.1002/pbc.28141] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 11/11/2019] [Accepted: 12/09/2019] [Indexed: 02/03/2023]
Abstract
Differentiated thyroid cancer (DTC) is the most common childhood thyroid malignancy. The standard of care for pediatric DTC is total thyroidectomy followed by radioactive iodine (RAI) treatment when indicated. Molecular changes and potential therapeutic targets have been recently described in pediatric thyroid cancer. Pediatric oncologists are increasingly involved in the evaluation of thyroid nodules in childhood cancer survivors and in the management of advanced thyroid cancer. In 2015, the American Thyroid Association published management guidelines for children with DTC. We provide an overview of the current standard of care and highlight available targeted therapies for progressive or RAI refractory DTC.
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Affiliation(s)
- Pinki K Prasad
- Louisiana State University Health Sciences Center, Children's Hospital of New Orleans, New Orleans, Louisiana
| | - Priya Mahajan
- Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
| | - Douglas S Hawkins
- Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington
| | - Sogol Mostoufi-Moab
- Divisions of Endocrinology and Hematology/Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Rajkumar Venkatramani
- Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
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Meng X, Fang E, Zhao X, Feng J. Identification of prognostic long noncoding RNAs associated with spontaneous regression of neuroblastoma. Cancer Med 2020; 9:3800-3815. [PMID: 32216054 PMCID: PMC7286466 DOI: 10.1002/cam4.3022] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/25/2020] [Accepted: 03/12/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The association between long noncoding RNAs (lncRNAs) and spontaneous regression of neuroblastoma (NB) has rarely been investigated and remains unknown. OBJECTIVE To identify prognostic lncRNAs involved in the spontaneous regression of NB. METHODS Differential expression analyses were performed between those samples with an outcome of death in stage 4 NB group and those samples with an outcome of survival in stage 4S NB group in two independent public datasets, respectively. Univariate Cox proportional hazard regression survival analysis was performed in each of the entire cohort to identify those lncRNAs significantly associated with overall survival (OS). Those lncRNAs independently associated with OS were then identified by multivariate Cox survival analysis and used to construct an lncRNA risk score. RESULTS A total of 20 differentially expressed and survival-related lncRNAs were identified sharing between the two independent cohorts. The expression of each of these 20 lncRNAs was significantly correlated with the expression of NTRK1, which is a well-known factor involved in NB spontaneous regression. Four lncRNAs (LNC00839, FIRRE, LOC283177, and LOC101928100) were identified to be significantly associated with survival independent with each other and a four-lncRNA signature risk score was constructed. Patients with high lncRNA signature risk score had a significantly poorer OS and event-free survival than those with low lncRNA signature risk score. The four-lncRNA signature has a good performance in predicting survival independent with MYCN amplification (nonamplified vs amplified), age status (<18 months vs ≥18 months), risk status (low risk vs high risk), and International Neuroblastoma Staging System (INSS) stage (INSS 1/2/3/4S vs INSS 4). CONCLUSIONS We identified 20 survival-related lncRNAs that might be associated with the spontaneous regression of NB and developed a four-lncRNA signature risk score. The four-lncRNA signature is an independent prognostic factor for survival of NB patients.
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Affiliation(s)
- Xinyao Meng
- Department of Pediatric SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Erhu Fang
- Department of Pediatric SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiang Zhao
- Department of Pediatric SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jiexiong Feng
- Department of Pediatric SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Li T, Yu Y, Song Y, Li X, Lan D, Zhang P, Xiao Y, Xing Y. Activation of BDNF/TrkB pathway promotes prostate cancer progression via induction of epithelial-mesenchymal transition and anoikis resistance. FASEB J 2020; 34:9087-9101. [PMID: 32390303 DOI: 10.1096/fj.201802159rrr] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 04/07/2020] [Accepted: 04/20/2020] [Indexed: 12/30/2022]
Abstract
Prostate cancer (PCa) is one of the most common malignant diseases in male worldwide, yet, the molecular mechanisms involved in PCa progression are still poorly understood. This study aimed to investigate the roles of the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) pathway in PCa progression. It was demonstrated by immunohistochemical analysis that both BDNF and TrkB were overexpressed in PCa tissues and elevated TrkB expression was tightly related with lymph node metastasis and advanced stage of PCa. In vitro studies showed that stimulation with rhBDNF or overexpression of TrkB in PCa cells promoted cell migration, invasion, and anoikis resistance. Overexpression of TrkB also resulted in epithelial-mesenchymal transition (EMT)-like transformation in cell morphology, whereas RNA interference-mediated TrkB depletion caused reversion of EMT. Further investigation demonstrated that protein kinase B (AKT) was responsible for BDNF/TrkB signaling-induced pro-migratory and pro-invasive effects, EMT, and anoikis resistance. Finally, in vivo studies confirmed that enhanced TrkB expression facilitated tumor growth, whereas downregulation of TrkB suppressed tumor growth. Our findings illustrate that BDNF/TrkB pathway is crucial for PCa progression, which may provide a novel therapeutic strategy for the treatment of advanced PCa.
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Affiliation(s)
- Tao Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Yu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yarong Song
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuechao Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongyang Lan
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajun Xiao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yifei Xing
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ryall S, Tabori U, Hawkins C. Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol Commun 2020; 8:30. [PMID: 32164789 PMCID: PMC7066826 DOI: 10.1186/s40478-020-00902-z] [Citation(s) in RCA: 222] [Impact Index Per Article: 44.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 02/21/2020] [Indexed: 12/17/2022] Open
Abstract
Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior – in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS–mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.
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