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Pathak T, Benson JC, Tang PW, Trebak M, Hempel N. Crosstalk between calcium and reactive oxygen species signaling in cancer revisited. Cell Calcium 2025; 127:103014. [PMID: 40139005 DOI: 10.1016/j.ceca.2025.103014] [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: 01/03/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
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Affiliation(s)
- Trayambak Pathak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - J Cory Benson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Priscilla W Tang
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mohamed Trebak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Nadine Hempel
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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Ayakannu T, Taylor AH, Konje JC. Expression, Distribution and Function of the Transient Receptor Potential Vanilloid Type 1 (TRPV1) in Endometrial Cancer. Int J Mol Sci 2025; 26:3104. [PMID: 40243844 PMCID: PMC11988754 DOI: 10.3390/ijms26073104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 04/18/2025] Open
Abstract
The transient receptor potential vanilloid 1 receptor (TRPV1) is a calcium-sensitive membrane receptor activated by capsaicin and the endocannabinoid, anandamide (AEA). Once activated in vitro, endometrial cancer (EC) cell growth appears to be inhibited through increased apoptosis, but the mechanism remains unclear. Our aim was to investigate the expression and distribution of TRPV1 in normal and cancerous endometria and to determine the precise in vitro mechanism of decreased EC cellular growth. TRPV1 expression in patients with endometrial carcinoma (15 Type 1 EC, six Type 2 EC) and six normal patients (atrophic endometria) was assessed using quantitative RT-PCR and immunohistochemistry (IHC). Additionally, immunohistochemical staining for the proliferation marker Ki-67, the pro-apoptotic marker BAX and the anti-apoptotic marker Bcl-2 were explored. TRPV1 transcript (p = 0.0054) and immunoreactive protein (p < 0.0001) levels were significantly reduced in all EC tissues when compared to control (atrophic) endometria. The almost 50% reduction in TRPV1 transcript levels was mirrored by an almost complete loss of immunoreactive TRPV1 protein. The increased proliferation (Ki-67) of EC tissues correlated with the expression of mutated BAX and inversely correlated to Bcl-2, but only in Type 2 EC samples. In vitro, AEA caused a decrease in Ishikawa cell numbers, whilst capsaicin did not, suggesting the anti-proliferative effect of AEA in EC cells is not via the TRPV1 receptor. In conclusion, the loss of TRPV1 expression in vivo plays a role in the aetiopathogenesis of EC. Activation of cells by AEA also probably promotes EC cell loss through a pro-apoptotic mechanism not involving TRPV1.
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Affiliation(s)
- Thangesweran Ayakannu
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK; (A.H.T.); (J.C.K.)
- Obstetrics & Gynaecology Centre of Excellence, Sunway Medical Centre, Petaling Jaya 47500, Malaysia
- Division of Obstetrics & Gynaecology, Department of Clinical Medicine and Surgery, Sunway University, Petaling Jaya 47500, Malaysia
| | - Anthony H. Taylor
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK; (A.H.T.); (J.C.K.)
- Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Justin C. Konje
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 7RH, UK; (A.H.T.); (J.C.K.)
- Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK
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Trentini F, Agnetti V, Manini M, Giovannetti E, Garajová I. NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes. Front Pharmacol 2024; 15:1499414. [PMID: 39723256 PMCID: PMC11668609 DOI: 10.3389/fphar.2024.1499414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024] Open
Abstract
Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.
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Affiliation(s)
| | - Virginia Agnetti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Martina Manini
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Lab of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Pisa, Italy
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Cancer Pharmacology Iacome Department, San Giuliano Terme, Italy
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
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Xu J, Wang Z, Niu Y, Tang Y, Wang Y, Huang J, Leung ELH. TRP channels in cancer: Therapeutic opportunities and research strategies. Pharmacol Res 2024; 209:107412. [PMID: 39303771 DOI: 10.1016/j.phrs.2024.107412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/11/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024]
Abstract
The influence of gut microbiota on transient receptor potential (TRP) channels has been identified as an important element in the development of gastrointestinal conditions, yet its involvement in cancer progression is not as thoroughly understood. This review explores the multifaceted roles of TRP channels in oncogenesis and emphasizes their significance in cancer progression and therapeutic outcomes. Critical focus was placed on the influence of traditional medicines, such as traditional Chinese medicine (TCM) related aromatic medicines, on TRP channel functions. Moreover, we explored the interplay between the gut microbiota and TRP channels in cancer signaling, highlighting the therapeutic potential of targeting this axis in cancer treatment. The impact of current therapies on TRP channel function was examined, demonstrating the need for a comprehensive understanding of how different modalities affect TRP channels in cancer. Technological advancements, including artificial intelligence (AI) tools and computer-aided drug development (CADD), have been discussed in the context of leveraging TRP channels for innovative cancer therapies. Future directions emphasize the potential applications of TRP channel research in advancing cancer treatment and enhancing patients' well-being.
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Affiliation(s)
- Jiahui Xu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Ziming Wang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Yuqing Niu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Yuping Tang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, China
| | - Yuwei Wang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, China.
| | - Jumin Huang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China.
| | - Elaine Lai-Han Leung
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China; State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, China.
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Yang Y, Gu X, Weng W, Cheng J, Huang O, Pan SJ, Li Y. SUMOylation-induced membrane localization of TRPV1 suppresses proliferation and migration in gastric cancer cells. Cell Commun Signal 2024; 22:465. [PMID: 39350261 PMCID: PMC11441086 DOI: 10.1186/s12964-024-01850-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
Gastric cancer (GC) remains a significant health challenge due to its high mortality rate and the limited efficacy of current targeted therapies. A critical barrier in developing more effective treatments is the lack of understanding of specific mechanisms driving GC progression. This study investigates the role of Transient Receptor Potential Vanilloid 1 (TRPV1), a non-selective cation channel known for its high Ca2+ permeability and tumor-suppressive properties in gastrointestinal cancers. Specifically, we explore the impact of SUMOylation-a dynamic and reversible post-translational modification-on TRPV1's function in GC. We demonstrate that SUMOylation of TRPV1 inhibits cell proliferation and migration in MGC-803 and AGS GC cells. By mutating amino acids near TRPV1's existing SUMO motif (slKpE), we created a bidirectional SUMO motif (EψKψE) that enhances TRPV1 SUMOylation, resulting in further suppression of GC cell proliferation and migration. In vivo studies support these findings, showing that TRPV1 SUMOylation prevents spontaneous tumorigenesis in a mouse GC model. Further investigation reveals that TRPV1 SUMOylation increases the protein's membrane expression by inhibiting its interaction with the adaptor-related protein complex 2 mu 1 subunit (AP2M1). This elevated membrane expression leads to increased intracellular Ca2+ influx, activating the AMP-activated protein kinase (AMPK) pathway, which in turn inhibits the proliferation and migration of GC cells.
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Affiliation(s)
- Yang Yang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China
| | - Xiaokun Gu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China
| | - Weiji Weng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China
| | - Jinke Cheng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China
| | - Ou Huang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200020, China.
| | - Si-Jian Pan
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200020, China.
| | - Yong Li
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
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Ge J, Ge J, Tang G, Xiong D, Zhu D, Ding X, Zhou X, Sang M. Machine learning-based identification of biomarkers and drugs in immunologically cold and hot pancreatic adenocarcinomas. J Transl Med 2024; 22:775. [PMID: 39152432 PMCID: PMC11328457 DOI: 10.1186/s12967-024-05590-0] [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: 03/02/2024] [Accepted: 08/08/2024] [Indexed: 08/19/2024] Open
Abstract
BACKGROUND Pancreatic adenocarcinomas (PAADs) often exhibit a "cold" or immunosuppressive tumor milieu, which is associated with resistance to immune checkpoint blockade therapy; however, the underlying mechanisms are incompletely understood. Here, we aimed to improve our understanding of the molecular mechanisms occurring in the tumor microenvironment and to identify biomarkers, therapeutic targets, and potential drugs to improve PAAD treatment. METHODS Patients were categorized according to immunologically hot or cold PAAD subtypes with distinct disease outcomes. Cox regression and weighted correlation network analysis were performed to construct a novel gene signature, referred to as 'Downregulated in hot tumors, Prognostic, and Immune-Related Genes' (DPIRGs), which was used to develop prognostic models for PAAD via machine learning (ML). The role of DPIRGs in PAAD was comprehensively analyzed, and biomarker genes able to distinguish PAAD immune subtypes and predict prognosis were identified by ML. The expression of biomarkers was verified using public single-cell transcriptomic and proteomic resources. Drug candidates for turning cold tumors hot and corresponding target proteins were identified via molecular docking studies. RESULTS Using the DPIRG signature as input data, a combination of survival random forest and partial least squares regression Cox was selected from 137 ML combinations to construct an optimized PAAD prognostic model. The effects and molecular mechanisms of DPIRGs were investigated by analysis of genetic/epigenetic alterations, immune infiltration, pathway enrichment, and miRNA regulation. Biomarkers and potential therapeutic targets, including PLEC, TRPV1, and ITGB4, among others, were identified, and the cell type-specific expression of the biomarkers was validated. Drug candidates, including thalidomide, SB-431542, and bleomycin A2, were identified based on their ability to modulate DPIRG expression favorably. CONCLUSIONS By combining multiple ML algorithms, we developed a novel prognostic model with excellent performance in PAAD cohorts. ML also proved to be powerful for identifying biomarkers and potential targets for improved PAAD patient stratification and immunotherapy.
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Affiliation(s)
- Jia Ge
- Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, China
| | - Juan Ge
- Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, China
- Department of Respiratory Medicine, Affiliated Nantong Hospital of Shanghai University, Nantong, 226011, China
| | - Gu Tang
- Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, China
| | - Dejun Xiong
- Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, China
| | - Dongyan Zhu
- Department of Rehabilitation, the Second Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Xiaoling Ding
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
| | - Xiaorong Zhou
- Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, China.
| | - Mengmeng Sang
- Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, China.
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Sun Y, Jiang W, Liao X, Wang D. Hallmarks of perineural invasion in pancreatic ductal adenocarcinoma: new biological dimensions. Front Oncol 2024; 14:1421067. [PMID: 39119085 PMCID: PMC11307098 DOI: 10.3389/fonc.2024.1421067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 07/01/2024] [Indexed: 08/10/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor with a high metastatic potential. Perineural invasion (PNI) occurs in the early stages of PDAC with a high incidence rate and is directly associated with a poor prognosis. It involves close interaction among PDAC cells, nerves and the tumor microenvironment. In this review, we detailed discuss PNI-related pain, six specific steps of PNI, and treatment of PDAC with PNI and emphasize the importance of novel technologies for further investigation.
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Affiliation(s)
- Yaquan Sun
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
| | - Wei Jiang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
| | - Xiang Liao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
| | - Dongqing Wang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Zhang Z, Lv ZG, Lu M, Li H, Zhou J. Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications. Biochim Biophys Acta Rev Cancer 2024; 1879:189121. [PMID: 38796026 DOI: 10.1016/j.bbcan.2024.189121] [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: 12/10/2023] [Revised: 04/25/2024] [Accepted: 05/19/2024] [Indexed: 05/28/2024]
Abstract
The autonomic nerve system (ANS) innervates organs and tissues throughout the body and maintains functional balance among various systems. Further investigations have shown that excessive activation of ANS not only causes disruption of homeostasis, but also may promote tumor formation. In addition, the dynamic interaction between nerve and tumor cells in the tumor microenvironment also regulate tumor progression. On the one hand, nerves are passively invaded by tumor cells, that is, perineural invasion (PNI). On the other hand, compared with normal tissues, tumor tissues are subject to more abundant innervation, and nerves can influence tumor progression through regulating tumor proliferation, metastasis and drug resistance. A large number of studies have shown that nerve-tumor crosstalk, including PNI and innervation, is closely related to the prognosis of patients, and contributes to the formation of cancer pain, which significantly deteriorates the quality of life for patients. These findings suggest that nerve-tumor crosstalk represents a potential target for anti-tumor therapies and the management of cancer pain in the future. In this review, we systematically describe the mechanism by which nerve-tumor crosstalk regulates tumorigenesis and progression.
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Affiliation(s)
- Zheng Zhang
- Department of Surgery, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Zhen Gang Lv
- Department of Surgery, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Miao Lu
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Haifeng Li
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Jiahua Zhou
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing 210009, Jiangsu Province, China.
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Wang Y, Zhang Y, Ouyang J, Yi H, Wang S, Liu D, Dai Y, Song K, Pei W, Hong Z, Chen L, Zhang W, Liu Z, Mcleod HL, He Y. TRPV1 inhibition suppresses non-small cell lung cancer progression by inhibiting tumour growth and enhancing the immune response. Cell Oncol (Dordr) 2024; 47:779-791. [PMID: 37902941 DOI: 10.1007/s13402-023-00894-7] [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] [Accepted: 10/20/2023] [Indexed: 11/01/2023] Open
Abstract
PURPOSE TRPV1 is a nonselective Ca2+ channel protein that is widely expressed and plays an important role during the occurrence and development of many cancers. Activation of TRPV1 channels can affect tumour progression by regulating proliferation, apoptosis and migration. Some studies have also shown that activating TRPV1 can affect tumour progression by modulating tumour immunity. However, the effects of TRPV1 on the development of non-small cell lung cancer (NSCLC) have not been explored clearly. METHOD The Cancer Genome Atlas (TCGA) database and spatial transcriptomics datasets from 10 × Genomics were used to analyze TRPV1 expression in various tumour tissues. Cell proliferation and apoptosis were examined by cell counting kit 8 (CCK8), colony formation, and flow cytometry. Immunohistochemistry, qPCR, and western blotting were used to determine the mRNA and protein expression levels of TRPV1 and other related molecules. Tumour xenografts in BALB/C and C57BL/6J mice were used to determine the effects of TRPV1 on NSCLC development in vivo. Neurotransmitter content was examined by LC-MS/MS, ELISA and Immunohistochemistry. Immune cell infiltration was assessed by flow cytometry. RESULTS In this study, we found that TRPV1 expression was significantly upregulated in NSCLC and that patients with high TRPV1 expression had a poor prognosis. TRPV1 knockdown can significantly inhibit NSCLC proliferation and induce cell apoptosis through Ca2+-IGF1R signaling. In addition, TRPV1 knockdown resulted in increased infiltration of CD4+ T cells, CD8+ T cells, GZMB+CD8+ T cells and DCs and decreased infiltration of immunosuppressive MDSCs in NSCLC. In addition, TRPV1 knockout effectively decreased the expression of M2 macrophage markers CD163 and increased the expression of M1-associated, costimulatory markers CD86. Knockdown or knockout of TRPV1 significantly inhibit tumour growth and promoted an antitumour immune response through supressing γ-aminobutyric acid (GABA) secretion in NSCLC. CONCLUSION Our study suggests that TRPV1 acts as a tumour promoter in NSCLC, mediating pro-proliferative and anti-apoptotic effects on NSCLC through IGF1R signaling and regulating GABA release to affect the tumour immune response.
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Affiliation(s)
- Yang Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Yu Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Jing Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Hanying Yi
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Shiyu Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Dongbo Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Yingying Dai
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Kun Song
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Wenwu Pei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Ziyang Hong
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Ling Chen
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Howard L Mcleod
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Center for Precision Medicine, Utah Tech University, St George, UT, USA
| | - Yijing He
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China.
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China.
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Maximiano TKE, Carneiro JA, Fattori V, Verri WA. TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain. Cell Calcium 2024; 119:102870. [PMID: 38531262 DOI: 10.1016/j.ceca.2024.102870] [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: 11/30/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024]
Abstract
In the 1990s, the identification of a non-selective ion channel, especially responsive to capsaicin, revolutionized the studies of somatosensation and pain that were to follow. The TRPV1 channel is expressed mainly in neuronal cells, more specifically, in sensory neurons responsible for the perception of noxious stimuli. However, its presence has also been detected in other non-neuronal cells, such as immune cells, β- pancreatic cells, muscle cells and adipocytes. Activation of the channel occurs in response to a wide range of stimuli, such as noxious heat, low pH, gasses, toxins, endocannabinoids, lipid-derived endovanilloid, and chemical agents, such as capsaicin and resiniferatoxin. This activation results in an influx of cations through the channel pore, especially calcium. Intracellular calcium triggers different responses in sensory neurons. Dephosphorylation of the TRPV1 channel leads to its desensitization, which disrupts its function, while its phosphorylation increases the channel's sensitization and contributes to the channel's rehabilitation after desensitization. Kinases, phosphoinositides, and calmodulin are the main signaling pathways responsible for the channel's regulation. Thus, in this review we provide an overview of TRPV1 discovery, its tissue expression as well as on the mechanisms by which TRPV1 activation (directly or indirectly) induces pain in different disease models.
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Affiliation(s)
- Thaila Kawane Euflazio Maximiano
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina, Paraná, Brazil
| | - Jessica Aparecida Carneiro
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina, Paraná, Brazil
| | - Victor Fattori
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital-Harvard Medical School, Karp Research Building, 300 Longwood Ave, 02115, Boston, Massachusetts, United States.
| | - Waldiceu A Verri
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina, Paraná, Brazil.
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11
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Giri SS, Tripathi AS, Erkekoğlu P, Zaki MEA. Molecular pathway of pancreatic cancer-associated neuropathic pain. J Biochem Mol Toxicol 2024; 38:e23638. [PMID: 38613466 DOI: 10.1002/jbt.23638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 11/29/2023] [Accepted: 12/21/2023] [Indexed: 04/15/2024]
Abstract
The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1β into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.
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Affiliation(s)
| | - Alok Shiomurti Tripathi
- Department of Pharmacology, Era College of Pharmacy, Era University, Lucknow, Uttar Pradesh, India
| | - Pınar Erkekoğlu
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Magdi E A Zaki
- Department of Chemistry, Faculty of Science, Imam Mohammad lbn Saud Islamic University, Riyadh, Saudi Arabia
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12
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Hudhud L, Rozmer K, Kecskés A, Pohóczky K, Bencze N, Buzás K, Szőke É, Helyes Z. Transient Receptor Potential Ankyrin 1 Ion Channel Is Expressed in Osteosarcoma and Its Activation Reduces Viability. Int J Mol Sci 2024; 25:3760. [PMID: 38612571 PMCID: PMC11011947 DOI: 10.3390/ijms25073760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Osteosarcoma is a highly malignant, painful cancer with poor treatment opportunities and a bad prognosis. Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are non-selective cation channels that have been of great interest in cancer, as their expression is increased in some malignancies. In our study we aim to characterize the expression and functionality of the TRPA1 and TRPV1 channels in human and mouse osteosarcoma tissues and in a mouse cell line. TRPA1/Trpa1 and TRPV1/Trpv1 mRNA expressions were demonstrated by PCR gel electrophoresis and RNAscope in situ hybridization. The function of these channels was confirmed by their radioactive 45Ca2+ uptake in response to the TRPA1 agonist, Allyl-isothiocyanate (AITC), and TRPV1 agonist, capsaicin, in K7M2 cells. An ATP-based K2M7 cell viability luminescence assay was used to determine cell viability after AITC or capsaicin treatments. Both TRPA1/Trpa1 and TRPV1/Trpv1 were expressed similarly in human and mouse osteosarcoma tissues, while Trpa1 transcripts were more abundantly present in K7M2 cells. TRPA1 activation with 200 µM AITC induced a significant 45Ca2+ influx into K7M2 cells, and the antagonist attenuated this effect. In accordance with the lower Trpv1 expression, capsaicin induced a moderate 45Ca2+ uptake, which did not reach the level of statistical significance. Both AITC and capsaicin significantly reduced K7M2 cell viability, demonstrating EC50 values of 22 µM and 74 µM. The viability-decreasing effect of AITC was significantly but only partially antagonized by HC-030031, but the action of capsaicin was not affected by the TRPV1 antagonist capsazepine. We provide here the first data on the functional expression of the TRPA1 and TRPV1 ion channels in osteosarcoma, suggesting novel diagnostic and/or therapeutic perspectives.
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Affiliation(s)
- Lina Hudhud
- Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, Medical School, University of Pécs, 7624 Pécs, Hungary (K.R.); (A.K.); (K.P.); (N.B.); (É.S.)
- National Laboratory for Drug Research and Development, 1077 Budapest, Hungary
- Department of Nursing, Faculty of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Katalin Rozmer
- Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, Medical School, University of Pécs, 7624 Pécs, Hungary (K.R.); (A.K.); (K.P.); (N.B.); (É.S.)
- National Laboratory for Drug Research and Development, 1077 Budapest, Hungary
- Department of Pharmaceutical Chemistry, University of Pécs, 7624 Pécs, Hungary
- Hungarian Research Network, Chronic Pain Research Group, 7624 Pécs, Hungary
| | - Angéla Kecskés
- Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, Medical School, University of Pécs, 7624 Pécs, Hungary (K.R.); (A.K.); (K.P.); (N.B.); (É.S.)
- National Laboratory for Drug Research and Development, 1077 Budapest, Hungary
| | - Krisztina Pohóczky
- Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, Medical School, University of Pécs, 7624 Pécs, Hungary (K.R.); (A.K.); (K.P.); (N.B.); (É.S.)
- National Laboratory for Drug Research and Development, 1077 Budapest, Hungary
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, 7624 Pécs, Hungary
| | - Noémi Bencze
- Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, Medical School, University of Pécs, 7624 Pécs, Hungary (K.R.); (A.K.); (K.P.); (N.B.); (É.S.)
- National Laboratory for Drug Research and Development, 1077 Budapest, Hungary
| | - Krisztina Buzás
- Department of Immunology, Albert Szent-Györgyi Medical School, Faculty of Science and Informatics, University of Szeged, 6720 Szeged, Hungary;
- Laboratory of Microscopic Image Analysis and Machine Learning, Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network (ELKH), 6726 Szeged, Hungary
| | - Éva Szőke
- Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, Medical School, University of Pécs, 7624 Pécs, Hungary (K.R.); (A.K.); (K.P.); (N.B.); (É.S.)
- National Laboratory for Drug Research and Development, 1077 Budapest, Hungary
- Hungarian Research Network, Chronic Pain Research Group, 7624 Pécs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, Medical School, University of Pécs, 7624 Pécs, Hungary (K.R.); (A.K.); (K.P.); (N.B.); (É.S.)
- National Laboratory for Drug Research and Development, 1077 Budapest, Hungary
- Hungarian Research Network, Chronic Pain Research Group, 7624 Pécs, Hungary
- PharmInVivo Ltd., 7629 Pécs, Hungary
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13
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Zeng J, Lu Y, Chu H, Lu L, Chen Y, Ji K, Lin Y, Li J, Wang S. Research trends and frontier hotspots of TRPV1 based on bibliometric and visualization analyses. Heliyon 2024; 10:e24153. [PMID: 38293347 PMCID: PMC10827456 DOI: 10.1016/j.heliyon.2024.e24153] [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: 07/11/2023] [Revised: 11/30/2023] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Background Transient receptor potential vanilloid type1 (TRPV1) is a non-selective cation channel with multiple activation mechanisms, which has received increasing attention since it was first cloned in 1997. Methods We used bibliometric and visualization analyses to evaluate the theme trends and knowledge structure of TRPV1 research-papers on TRPV1 from 2002 to 2022 obtained from the Web of Science Core Collection. VOSviewer and CiteSpace were used to analyze authors, institutions, countries, co-cited references, and keywords. Results A total of 7413 papers were included. The main research area of TRPV1 was neuroscience; the most published country was the United States, and the University of California, San Francisco, had the highest centrality. Two major collaborative sub-networks were formed between the authors. The distribution of keywords shows that TRPV1 was initially studied extensively, and the recent studies focused on TRPV1 structure and diseases. "Oxidative stress," "TRPV1 structure," "cancer," and "model" have been the research hotspots in recent years. Conclusions This research provides valuable information for the study of TRPV1. Disease research was focused on pain, cancer, and neurodegenerative diseases. Both agonists and antagonists of TRPV1 are gradually being used in clinical practice, and acupuncture was effective in treating TRPV1-mediated inflammatory pain. TRPV1 is involved in classical endogenous cannabis system signaling, and new signaling pathways continue to be revealed.
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Affiliation(s)
- Jingchun Zeng
- Rehabilitation Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yiqian Lu
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Hui Chu
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Liming Lu
- Clinical Research and Data Center, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuexuan Chen
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Kaisong Ji
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yeze Lin
- Rehabilitation Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jingjing Li
- Bao'an Traditional Chinese Medicine Hospital//Seventh Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, Guangdong, China
| | - Shuxin Wang
- Rehabilitation Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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14
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Shi RJ, Ke BW, Tang YL, Liang XH. Perineural invasion: A potential driver of cancer-induced pain. Biochem Pharmacol 2023; 215:115692. [PMID: 37481133 DOI: 10.1016/j.bcp.2023.115692] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/24/2023]
Abstract
Perineural invasion (PNI) is the process through which tumors invade and interact with nerves. The dynamic changes in the nerves caused by PNI may induce disturbing symptoms. PNI-related cancer pain in neuro-rich tumors has attracted much attention because the occurrence of tumor-induced pain is closely related to the invasion of nerves in the tumor microenvironment. PNI-related pain might indicate the occurrence of PNI, guide the improvement of treatment strategies, and predict the unresectability of tumors and the necessity of palliative care. Although many studies have investigated PNI, its relationship with tumor-induced pain and its common mechanisms have not been summarized thoroughly. Therefore, in this review, we evaluated the relationship between PNI and cancer-associated pain. We showed that PNI is a major cause of cancer-related pain and that this pain can predict the occurrence of PNI. We also elucidated the cellular and molecular mechanisms of PNI-induced pain. Finally, we analyzed the possible targets for alleviating PNI-related pain or combined antitumor and pain management. Our findings might provide new perspectives for improving the treatment of patients with malignant tumors.
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Affiliation(s)
- Rong-Jia Shi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery,West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu 610041, Sichuan, China
| | - Bo-Wen Ke
- Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu 610041, Sichuan, China.
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery,West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu 610041, Sichuan, China.
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15
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The Mechanisms of GPR55 Receptor Functional Selectivity during Apoptosis and Proliferation Regulation in Cancer Cells. Int J Mol Sci 2023; 24:ijms24065524. [PMID: 36982628 PMCID: PMC10054013 DOI: 10.3390/ijms24065524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/15/2023] Open
Abstract
GPR55 is a non-canonical cannabinoid receptor, important for cancer proliferation. Depending on the ligand, it induces either cell proliferation or death. The objective of the study was to establish the mechanisms of this multidirectional signaling. Using the CRISPR-Cas9 system, the GPR55, CB1, CB2, and GPR18 receptor knockouts of the MDA-MB-231 line were obtained. After the CB2 receptor knockout, the pro-apoptotic activity of the pro-apoptotic ligand docosahexaenoyl dopamine (DHA-DA) slightly increased, while the pro-proliferative activity of the most active synthetic ligand of the GPR55 receptor (ML-184) completely disappeared. On the original cell line, the stimulatory effect of ML-184 was removed by the CB2 receptor blocker and by GPR55 receptor knockout. Thus, it can be confidently assumed that when proliferation is stimulated with the participation of the GPR55 receptor, a signal is transmitted from the CB2 receptor to the GPR55 receptor due to the formation of a heterodimer. GPR18 was additionally involved in the implementation of the pro-apoptotic effect of DHA-DA, while the CB1 receptor is not involved. In the implementation of the pro-apoptotic action of DHA-DA, the elimination of Gα13 led to a decrease in cytotoxicity. The obtained data provide novel details to the mechanism of the pro-proliferative action of GPR55.
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16
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Haroun R, Wood JN, Sikandar S. Mechanisms of cancer pain. FRONTIERS IN PAIN RESEARCH 2023; 3:1030899. [PMID: 36688083 PMCID: PMC9845956 DOI: 10.3389/fpain.2022.1030899] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/14/2022] [Indexed: 01/05/2023] Open
Abstract
Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain.
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Affiliation(s)
- Rayan Haroun
- Division of Medicine, Wolfson Institute of Biomedical Research, University College London, London, United Kingdom
| | - John N Wood
- Division of Medicine, Wolfson Institute of Biomedical Research, University College London, London, United Kingdom
| | - Shafaq Sikandar
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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17
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Selvaggi F, Melchiorre E, Casari I, Cinalli S, Cinalli M, Aceto GM, Cotellese R, Garajova I, Falasca M. Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance. Cancers (Basel) 2022; 14:5793. [PMID: 36497277 PMCID: PMC9739544 DOI: 10.3390/cancers14235793] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/26/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most threatening solid malignancies. Molecular and cellular mediators that activate paracrine signalling also regulate the dynamic interaction between pancreatic cancer cells and nerves. This reciprocal interface leads to perineural invasion (PNI), defined as the ability of cancer cells to invade nerves, similar to vascular and lymphatic metastatic cascade. Targeting PNI in pancreatic cancer might help ameliorate prognosis and pain relief. In this review, the modern knowledge of PNI in pancreatic cancer has been analysed and critically presented. We focused on molecular pathways promoting cancer progression, with particular emphasis on neuropathic pain generation, and we reviewed the current knowledge of pharmacological inhibitors of the PNI axis. PNI represents a common hallmark of PDAC and correlates with recurrence, poor prognosis and pain in pancreatic cancer patients. The interaction among pancreatic cancer cells, immune cells and nerves is biologically relevant in each stage of the disease and stimulates great interest, but the real impact of the administration of novel agents in clinical practice is limited. It is still early days for PNI-targeted treatments, and further advanced studies are needed to understand whether they could be effective tools in the clinical setting.
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Affiliation(s)
- Federico Selvaggi
- Unit of Surgery, Renzetti Hospital, ASL2 Lanciano-Vasto-Chieti, 66034 Lanciano, Italy
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University, Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Eugenia Melchiorre
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University, Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Ilaria Casari
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | | | - Massimiliano Cinalli
- Unit of Surgery, Renzetti Hospital, ASL2 Lanciano-Vasto-Chieti, 66034 Lanciano, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University, Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University, Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
- Villa Serena Foundation for Research, 65013 Pescara, Italy
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
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Le TT, Payne SL, Buckwald MN, Hayes LA, Parker SR, Burge CB, Oudin MJ. Sensory nerves enhance triple-negative breast cancer invasion and metastasis via the axon guidance molecule PlexinB3. NPJ Breast Cancer 2022; 8:116. [PMID: 36333352 PMCID: PMC9636220 DOI: 10.1038/s41523-022-00485-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
In breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis, yet the mechanisms by which different types of peripheral nerves drive tumor progression remain poorly understood. In this study, we identified sensory nerves as more abundant in human triple-negative breast cancer (TNBC) tumors. Co-injection of sensory neurons isolated from the dorsal root ganglia (DRG) of adult female mice with human TNBC cells in immunocompromised mice increased the number of lung metastases. Direct in vitro co-culture of human TNBC cells with the dorsal root ganglia (DRG) of adult female mice revealed that TNBC cells adhere to sensory neuron fibers leading to an increase in migration speed. Species-specific RNA sequencing revealed that co-culture of TNBC cells with sensory nerves upregulates the expression of genes associated with cell migration and adhesion in cancer cells. We demonstrated that lack of the semaphorin receptor PlexinB3 in cancer cells attenuate their adhesion to and migration on sensory nerves. Together, our results identify a mechanism by which nerves contribute to breast cancer migration and metastasis by inducing a shift in TNBC cell gene expression and support the rationale for disrupting neuron-cancer cell interactions to target metastasis.
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Affiliation(s)
- Thanh T Le
- Department of Biomedical Engineering, Tufts University, 200 College Avenue, Medford, MA, 02155, USA
| | - Samantha L Payne
- Department of Biomedical Engineering, Tufts University, 200 College Avenue, Medford, MA, 02155, USA
| | - Maia N Buckwald
- Department of Biomedical Engineering, Tufts University, 200 College Avenue, Medford, MA, 02155, USA
| | - Lily A Hayes
- Department of Biomedical Engineering, Tufts University, 200 College Avenue, Medford, MA, 02155, USA
| | - Savannah R Parker
- Department of Biomedical Engineering, Tufts University, 200 College Avenue, Medford, MA, 02155, USA
| | | | - Madeleine J Oudin
- Department of Biomedical Engineering, Tufts University, 200 College Avenue, Medford, MA, 02155, USA.
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TRPV1 Is a Potential Tumor Suppressor for Its Negative Association with Tumor Proliferation and Positive Association with Antitumor Immune Responses in Pan-Cancer. JOURNAL OF ONCOLOGY 2022; 2022:6964550. [PMID: 36304985 PMCID: PMC9596243 DOI: 10.1155/2022/6964550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/16/2022] [Accepted: 10/03/2022] [Indexed: 11/23/2022]
Abstract
Background Although numerous studies have shown that the expression and activation of TRPV1 have an important role in cancer development, a comprehensive exploration of associations between TRPV1 expression and tumor proliferation, microenvironment, and clinical outcomes in pan-cancer remains insufficient. Methods From The Cancer Genome Atlas (TCGA) program, we downloaded multiomics data of ten cancer cohorts and investigated the correlations between TRPV1 expression and immune signatures' enrichment, stromal content, genomic features, oncogenic signaling, and clinical features in these cancer cohorts and pan-cancer. Results Elevated expression of TRPV1 correlated with better clinical outcomes in pan-cancer and diverse cancer types. In multiple cancer types, TRPV1 expression correlated negatively with the expression of tumor proliferation marker genes (MKI67 and RACGAP1), proliferation scores, cell cycle scores, stemness scores, epithelial-mesenchymal transition scores, oncogenic pathways' enrichment, tumor immunosuppressive signals, intratumor heterogeneity, homologous recombination deficiency, tumor mutation burden, and stromal content. Moreover, TRPV1 expression was downregulated in late-stage versus early-stage tumors. In breast cancer, bladder cancer, and low-grade glioma, TRPV1 expression was more inferior in invasive than in noninvasive subtypes. Pathway analysis showed that the enrichment of cancer-associated pathways correlated inversely with TRPV1 expression levels. Conclusion TRPV1 upregulation correlates with decreased tumor proliferation, tumor driver gene expression, genomic instability, and tumor immunosuppressive signals in various cancers. Our results provide new understanding of the role of TRPV1 in both cancer biology and clinical practice.
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20
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Bertozzi MM, Saraiva-Santos T, Zaninelli TH, Pinho-Ribeiro FA, Fattori V, Staurengo-Ferrari L, Ferraz CR, Domiciano TP, Calixto-Campos C, Borghi SM, Zarpelon AC, Cunha TM, Casagrande R, Verri WA. Ehrlich Tumor Induces TRPV1-Dependent Evoked and Non-Evoked Pain-like Behavior in Mice. Brain Sci 2022; 12:brainsci12091247. [PMID: 36138983 PMCID: PMC9496717 DOI: 10.3390/brainsci12091247] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/09/2022] [Accepted: 09/11/2022] [Indexed: 11/16/2022] Open
Abstract
We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) than the saline-injected animals (p < 0.05). We also observed diminished mechanical (electronic von Frey) and thermal (hot plate) hyperalgesia, paw flinching, and normalization of weight distribution imbalance in TRPV1 deficient mice (p < 0.05). On the other hand, TRPV1 deficiency did not alter paw volume or weight, indicating no significant alteration in tumor growth. Intrathecal injection of AMG9810 (TRPV1 antagonist) reduced ongoing Ehrlich tumor-triggered mechanical and thermal hyperalgesia (p < 0.05). Therefore, the contribution of TRPV1 to Ehrlich tumor pain behavior was revealed by genetic and pharmacological approaches, thus, supporting the use of this model to investigate TRPV1-targeting therapies for the treatment of cancer pain.
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Affiliation(s)
- Mariana M. Bertozzi
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Telma Saraiva-Santos
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Tiago H. Zaninelli
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Felipe A. Pinho-Ribeiro
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
- Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Victor Fattori
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Larissa Staurengo-Ferrari
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Camila R. Ferraz
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Talita P. Domiciano
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Cassia Calixto-Campos
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Sergio M. Borghi
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
- Center for Research in Health Sciences, University of Northern Londrina, Londrina 86041-120, PR, Brazil
| | - Ana C. Zarpelon
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
| | - Thiago M. Cunha
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, Ribeirão Preto 14049-900, SP, Brazil
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Center of Health Science, Londrina State University, Londrina 86038-440, PR, Brazil
| | - Waldiceu A. Verri
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil
- Correspondence: or ; Tel.: +55-43-3371-4979; Fax: +55-43-3371-4387
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Anticancer Activity of Natural and Semi-Synthetic Drimane and Coloratane Sesquiterpenoids. Molecules 2022; 27:molecules27082501. [PMID: 35458699 PMCID: PMC9031474 DOI: 10.3390/molecules27082501] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/09/2022] [Accepted: 04/11/2022] [Indexed: 12/12/2022] Open
Abstract
Drimane and coloratane sesquiterpenoids are present in several plants, microorganisms, and marine life. Because of their cytotoxic activity, these sesquiterpenoids have received increasing attention as a source for new anticancer drugs and pharmacophores. Natural drimanes and coloratanes, as well as their semi-synthetic derivatives, showed promising results against cancer cell lines with in vitro activities in the low micro- and nanomolar range. Despite their high potential as novel anticancer agents, the mode of action and structure–activity relationships of drimanes and coloratanes have not been completely enlightened nor systematically reviewed. Our review aims to give an overview of known structures and derivatizations of this class of sesquiterpenoids, as well as their activity against cancer cells and potential modes-of-action. The cytotoxic activities of about 40 natural and 25 semi-synthetic drimanes and coloratanes are discussed. In addition to that, we give a summary about the clinical significance of drimane and coloratane sesquiterpenoids.
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Hladkykh F. Therapeutic potential of modulation of the ion channel activity of vanilloid receptors TRPV1 in oncological practice. УКРАЇНСЬКИЙ РАДІОЛОГІЧНИЙ ТА ОНКОЛОГІЧНИЙ ЖУРНАЛ 2022; 30:67-77. [DOI: 10.46879/ukroj.1.2022.67-77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Background. Type 1 vanilloid receptors (TRPV1 ) play an important role in tumoral genesis and cancer development, because the expression levels of TRPV1 change in a lot of types of cancer cells. At present, the regulation of functional activity and sensitivity of TRPV1 is an object of intensive research. Purpose – to characterize the modern concept of therapeutic potential of modulation of the ion channel activity of vanilloid receptors TRPV1 in oncological practice according to the data from open literature sources.
Materials and methods. The publications were selected from the following databases: PubMed, EBSCO, Clinical Key, etc. In these publications the data on the ion channels of the transistor receptor potential were elucidated, particularly on type 1 vanilloid receptors, their role in tumoral genesis and the therapeutic potential of the modulation of their activity. Results. Binding of exogenous agonists to the TRPV1 receptor is accompanied by the influx of Ca2+ ions from the cytosol to the cell. It is known that Ca2+ ions are one of the main secondary messengers, since they play an important role in lots of fundamental physiological processes, including cell excitability, vitality, apoptosis and transcription. The disbalance of intracellular flow of Ca2+ is associated with characteristics of different types of cancer. The latest studies have shown that Ca2+ also contributes to certain malignant appearances, such as proliferation, invasion, migration and metastasis. Moreover, TRPV1 activation modulates the apoptosis-proliferation balance through the mechanisms beyond Ca2+ signaling, and in some works TRPV1 role in metastasis of cancer cells is mentioned. Conclusions. Selective TRPV1 activation or the increase in its expression has therapeutic potential, conditioned by pleiotropic influence on the apoptosis-proliferation balance in cancer cells. TRPV1 blockage or reduction of its expression can mitigate hyperalgesia caused by the tumor. In addition, TRPV1 act as biomarkers of a range of cancers (invasive breast carcinoma, epithelial ovarian and cervical cancer).
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Li L, Chen C, Xiang Q, Fan S, Xiao T, Chen Y, Zheng D. Transient Receptor Potential Cation Channel Subfamily V Member 1 Expression Promotes Chemoresistance in Non-Small-Cell Lung Cancer. Front Oncol 2022; 12:773654. [PMID: 35402237 PMCID: PMC8990814 DOI: 10.3389/fonc.2022.773654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 03/02/2022] [Indexed: 12/23/2022] Open
Abstract
Approximately 85% of lung cancer cases are non-small-cell lung cancer (NSCLC). Chemoresistance is a leading cause of chemotherapy failure in NSCLC treatment. Transient receptor potential cation channel subfamily V, member 1 (TRPV1), a non-selective cation channel, plays multiple roles in tumorigenesis and tumor development, including tumor cell proliferation, death, and metastasis as well as the response to therapy. In this study, we found TRPV1 expression was increased in NSCLC. TRPV1 overexpression induced cisplatin (DDP) and fluorouracil (5-FU) resistance in A549 cells independent of its channel function. TRPV1 expression was upregulated in A549-DDP/5-FU resistant cells, and DDP/5-FU sensitivity was restored by TRPV1 knockdown. TRPV1 overexpression mediated DDP and 5-FU resistance by upregulation of ABCA5 drug transporter gene expression, thereby increasing drug efflux, enhancing homologous recombination (HR) DNA repair pathway to alleviate apoptosis and activating IL-8 signaling to promote cell survival. These findings demonstrate an essential role of TRPV1 in chemoresistance in NSCLC and implicate TRPV1 as a potential chemotherapeutic target.
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Affiliation(s)
- Li Li
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Cheng Chen
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Qin Xiang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Tian Xiao
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Duo Zheng
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, Shenzhen University, Shenzhen, China
- *Correspondence: Duo Zheng,
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24
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Falasca V, Falasca M. Targeting the Endocannabinoidome in Pancreatic Cancer. Biomolecules 2022; 12:320. [PMID: 35204820 PMCID: PMC8869154 DOI: 10.3390/biom12020320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when the tumour has locally advanced or metastasised. PDAC is resistant to most of the available chemotherapy and radiation therapy treatments, making surgery the most potent curative treatment. The desmoplastic tumour microenvironment contributes to determining PDAC pathophysiology, immune response and therapeutic efficacy. The existing therapeutic approaches such as FDA-approved chemotherapeutics, gemcitabine, abraxane and folfirinox, prolong survival marginally and are accompanied by adverse effects. Several studies suggest the role of cannabinoids as anti-cancer agents. Cannabinoid receptors are known to be expressed in pancreatic cells, with a higher expression reported in pancreatic cancer patients. Therefore, pharmacological targeting of the endocannabinoid system might offer therapeutic benefits in pancreatic cancer. In addition, emerging data suggest that cannabinoids in combination with chemotherapy can increase survival in transgenic pancreatic cancer murine models. This review provides an overview of the regulation of the expanded endocannabinoid system, or endocannabinoidome, in PDAC and will explore the potential of targeting this system for novel anticancer approaches.
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Affiliation(s)
- Valerio Falasca
- School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
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Jiang X, Wang C, Ke Z, Duo L, Wu T, Wang W, Yang Y, Dai Y. The ion channel TRPV1 gain-of-function reprograms the immune microenvironment to facilitate colorectal tumorigenesis. Cancer Lett 2021; 527:95-106. [PMID: 34920021 DOI: 10.1016/j.canlet.2021.12.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 02/06/2023]
Abstract
Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+-permeable ion channel that acts as cellular sensor and is implicated in the tumor microenvironment cross talk. However, the functional role of TRPV1 in colorectal cancer (CRC) is still controversial. By using a TRPV1 gain-of-function model, we previously reported that hyperfunctional TRPV1 exacerbated experimental colitis by modulating mucosal immunity. Here, we found that TRPV1 gain-of-function significantly promoted tumor initiation and progression in colitis-associated cancer, as evidenced by the increase in the number and size of tumor. Systemic TRPV1 hyperactivation fostered a tumor permissive microenvironment through altering macrophage activation status and shifting the Th1/Th2 balance towards Th2 phenotype. Mechanistically, TRPV1 gain-of-function directly potentiated M1 cytokine production in macrophage and enhanced Th2 immune response by promoting Calcineurin/nuclear factor of activated T cells (NFATc2) signaling activation. In patients with CRC, TRPV1 expression was increased in tumor immune infiltrating cells. TRPV1 level was associated with CRC progression and could impact clinical outcome. Our study reveals an important role for TRPV1 in regulating the immune microenvironment during colorectal tumorigenesis. TRPV1 might be a potential target for CRC immunotherapy.
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Affiliation(s)
- Xuehui Jiang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Chaohui Wang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Ziliang Ke
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Lina Duo
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China; Department of Dermatology, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, Sichuan, China; Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Ting Wu
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Weihong Wang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Yong Yang
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China; Peking-Tsinghua Center for Life Sciences, Beijing, China; Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China
| | - Yun Dai
- Department of Gastroenterology, Peking University First Hospital, Beijing, China.
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Iozzo M, Sgrignani G, Comito G, Chiarugi P, Giannoni E. Endocannabinoid System and Tumour Microenvironment: New Intertwined Connections for Anticancer Approaches. Cells 2021; 10:cells10123396. [PMID: 34943903 PMCID: PMC8699381 DOI: 10.3390/cells10123396] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/24/2021] [Accepted: 11/30/2021] [Indexed: 01/01/2023] Open
Abstract
The tumour microenvironment (TME) is now recognised as a hallmark of cancer, since tumour:stroma crosstalk supports the key steps of tumour growth and progression. The dynamic co-evolution of the tumour and stromal compartments may alter the surrounding microenvironment, including the composition in metabolites and signalling mediators. A growing number of evidence reports the involvement of the endocannabinoid system (ECS) in cancer. ECS is composed by a complex network of ligands, receptors, and enzymes, which act in synergy and contribute to several physiological but also pathological processes. Several in vitro and in vivo evidence show that ECS deregulation in cancer cells affects proliferation, migration, invasion, apoptosis, and metastatic potential. Although it is still an evolving research, recent experimental evidence also suggests that ECS can modulate the functional behaviour of several components of the TME, above all the immune cells, endothelial cells and stromal components. However, the role of ECS in the tumour:stroma interplay remains unclear and research in this area is particularly intriguing. This review aims to shed light on the latest relevant findings of the tumour response to ECS modulation, encouraging a more in-depth analysis in this field. Novel discoveries could be promising for novel anti-tumour approaches, targeting the microenvironmental components and the supportive tumour:stroma crosstalk, thereby hindering tumour development.
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Li J, Kang R, Tang D. Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma. Cancer Commun (Lond) 2021; 41:642-660. [PMID: 34264020 PMCID: PMC8360640 DOI: 10.1002/cac2.12188] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/11/2021] [Accepted: 06/18/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.
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Affiliation(s)
- Jingbo Li
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
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28
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de Almeida AS, Bernardes LDB, Trevisan G. TRP channels in cancer pain. Eur J Pharmacol 2021; 904:174185. [PMID: 34015320 DOI: 10.1016/j.ejphar.2021.174185] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 05/06/2021] [Accepted: 05/12/2021] [Indexed: 01/06/2023]
Abstract
Chronic pain is a common symptom experienced during cancer progression. Additionally, some patients experience bone pain caused by cancer metastasis, which further complicates the prognosis. Cancer pain is often treated using opioid-based pharmacotherapy, but these drugs possess several adverse effects. Accordingly, new mechanisms for cancer pain management are being explored, including transient receptor potential channels (TRPs). TRP ion channels are expressed in several tissues and play a key role in pain detection, especially TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1). In the present review, we describe the role of TRPV1 and TRPA1 involved in cancer pain mechanisms. Several studies have revealed that the administration of TRPV1 or TRPA1 agonists/antagonists and TRPV1 or TRPA1 knockdown reduced sensitivity to nociception in cancer pain models. TRPV1 was also found to be involved in various models of cancer-induced bone pain (CIBP), with TRPV1 expression reportedly enhanced in some models. These studies have demonstrated the TRPV1 or TRPA1 association with cancer pain in models induced by tumour cell inoculation into the bone cavity, hind paw, mammary fat pad, and sciatic nerve in mice or rats. To date, only resiniferatoxin, a TRPV1 agonist, has been evaluated in clinical trials for cancer pain and showed preliminary positive results. Thus, TRP channels are potential targets for managing cancer-related pain syndromes.
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Affiliation(s)
- Amanda Spring de Almeida
- Programa de Pós-Graduação Em Farmacologia, Universidade Federal de Santa Maria (UFSM), 97105-900, Santa Maria, RS, Brazil
| | - Laura de Barros Bernardes
- Programa de Pós-Graduação Em Farmacologia, Universidade Federal de Santa Maria (UFSM), 97105-900, Santa Maria, RS, Brazil
| | - Gabriela Trevisan
- Programa de Pós-Graduação Em Farmacologia, Universidade Federal de Santa Maria (UFSM), 97105-900, Santa Maria, RS, Brazil.
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Li L, Chen C, Chiang C, Xiao T, Chen Y, Zhao Y, Zheng D. The Impact of TRPV1 on Cancer Pathogenesis and Therapy: A Systematic Review. Int J Biol Sci 2021; 17:2034-2049. [PMID: 34131404 PMCID: PMC8193258 DOI: 10.7150/ijbs.59918] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/23/2021] [Indexed: 12/27/2022] Open
Abstract
The transient receptor potential cation channel subfamily V member 1 (TRPV1) is a transmembrane protein that can be activated by various physical and chemical stimuli and is associated with pain transduction. In recent years, TRPV1 was discovered to play essential roles in cancer tumorigenesis and development, as TRPV1 expression levels are altered in numerous cancer cell types. Several investigations have discovered direct associations between TRPV1 and cancer cell proliferation, cell death, and metastasis. Furthermore, about two dozen TRPV1 agonists/antagonists are under clinical trial, as TRPV1 is a potential drug target for treating various diseases. Hence, more researchers are focusing on the effects of TRPV1 agonists or antagonists on cancer tumorigenesis and development. However, both agonists and antagonists may reveal anti-cancer effects, and the effect may function via or be independent of TRPV1. In this review, we provide an overview of the impact of TRPV1 on cancer cell proliferation, cell death, and metastasis, as well as on cancer therapy and the tumor microenvironment, and consider the implications of using TRPV1 agonists and antagonists for future research and potential therapeutic approaches.
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Affiliation(s)
- Li Li
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China
| | - Cheng Chen
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China
| | - Chengyao Chiang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China
| | - Tian Xiao
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| | - Yongxiang Zhao
- National Center for International Research of Biological Targeting Diagnosis and Therapy (Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research), Guangxi Medical University, Nanning, China
| | - Duo Zheng
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China
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Mesquita G, Prevarskaya N, Schwab A, Lehen’kyi V. Role of the TRP Channels in Pancreatic Ductal Adenocarcinoma Development and Progression. Cells 2021; 10:cells10051021. [PMID: 33925979 PMCID: PMC8145744 DOI: 10.3390/cells10051021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/18/2021] [Accepted: 04/21/2021] [Indexed: 12/28/2022] Open
Abstract
The transient receptor potential channels (TRPs) have been related to several different physiologies that range from a role in sensory physiology (including thermo- and osmosensation) to a role in some pathologies like cancer. The great diversity of functions performed by these channels is represented by nine sub-families that constitute the TRP channel superfamily. From the mid-2000s, several reports have shown the potential role of the TRP channels in cancers of multiple origin. The pancreatic cancer is one of the deadliest cancers worldwide. Its prevalence is predicted to rise further. Disappointingly, the treatments currently used are ineffective. There is an urgency to find new ways to counter this disease and one of the answers may lie in the ion channels belonging to the superfamily of TRP channels. In this review, we analyse the existing knowledge on the role of TRP channels in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The functions of these channels in other cancers are also considered. This might be of interest for an extrapolation to the pancreatic cancer in an attempt to identify potential therapeutic interventions.
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Affiliation(s)
- Gonçalo Mesquita
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d’Ascq, France; (G.M.); (N.P.)
- PHYCELL—Laboratoire de Physiologie Cellulaire, INSERM U1003, University of Lille, 59655 Villeneuve d’Ascq, France
- Institute of Physiology II, University Münster, 48149 Münster, Germany;
| | - Natalia Prevarskaya
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d’Ascq, France; (G.M.); (N.P.)
- PHYCELL—Laboratoire de Physiologie Cellulaire, INSERM U1003, University of Lille, 59655 Villeneuve d’Ascq, France
| | - Albrecht Schwab
- Institute of Physiology II, University Münster, 48149 Münster, Germany;
| | - V’yacheslav Lehen’kyi
- Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d’Ascq, France; (G.M.); (N.P.)
- PHYCELL—Laboratoire de Physiologie Cellulaire, INSERM U1003, University of Lille, 59655 Villeneuve d’Ascq, France
- Correspondence: ; Tel.: +33-(0)-3-20-33-70-78; Fax: +33-(0)-3-20-43-40-66
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Hofschröer V, Najder K, Rugi M, Bouazzi R, Cozzolino M, Arcangeli A, Panyi G, Schwab A. Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy. Front Pharmacol 2021; 11:586599. [PMID: 33841132 PMCID: PMC8025202 DOI: 10.3389/fphar.2020.586599] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.
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Affiliation(s)
| | - Karolina Najder
- Institute of Physiology II, University of Münster, Münster, Germany
| | - Micol Rugi
- Institute of Physiology II, University of Münster, Münster, Germany
| | - Rayhana Bouazzi
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
| | - Marco Cozzolino
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
| | - Gyorgy Panyi
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Albrecht Schwab
- Institute of Physiology II, University of Münster, Münster, Germany
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32
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Schnipper J, Dhennin-Duthille I, Ahidouch A, Ouadid-Ahidouch H. Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma. Front Pharmacol 2020; 11:568993. [PMID: 33178018 PMCID: PMC7596276 DOI: 10.3389/fphar.2020.568993] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 09/16/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.
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Affiliation(s)
- Julie Schnipper
- Laboratory of Cellular and Molecular Physiology, UR-4667, University of Picardie Jules Verne, Amiens, France
| | - Isabelle Dhennin-Duthille
- Laboratory of Cellular and Molecular Physiology, UR-4667, University of Picardie Jules Verne, Amiens, France
| | - Ahmed Ahidouch
- Laboratory of Cellular and Molecular Physiology, UR-4667, University of Picardie Jules Verne, Amiens, France.,Department of Biology, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco
| | - Halima Ouadid-Ahidouch
- Laboratory of Cellular and Molecular Physiology, UR-4667, University of Picardie Jules Verne, Amiens, France
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Dwivedi S, Krishnan A. Neural invasion: a scenic trail for the nervous tumor and hidden therapeutic opportunity. Am J Cancer Res 2020; 10:2258-2270. [PMID: 32905513 PMCID: PMC7471340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 07/21/2020] [Indexed: 06/11/2023] Open
Abstract
Neural invasion (NI) is the invasion of cancer cells into nerves, influencing the pathological characteristics of malignant tumors. NI promotes metastasis and is associated with reduced survival of affected patients. Although known for decades, its prognostic and therapeutic implications have not been not much appreciated due to the scattered information available on its clinical complications. The use of multiple nomenclatures to describe NI also generated confusions among researchers to understand this pathological process. Here, we discuss the multiple classifications of NI and review its clinical complications. Recent findings of the regulatory roles of nerves on tumor growth have fuelled research in this field, and there has been several attempts to molecularly define the NI interface and the cancer cells involved. Therefore, in this review, we discuss the large datasets available to characterize the cancer cells in NI and also discuss the roles of Schwann cells and macrophages participating in NI.
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Affiliation(s)
- Shubham Dwivedi
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of SaskatchewanSaskatoon, SK, S7N 5E5, Canada
- Cameco MS Neuroscience Research Centre, University of SaskatchewanSaskatoon, SK, S7K 0M7, Canada
| | - Anand Krishnan
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of SaskatchewanSaskatoon, SK, S7N 5E5, Canada
- Cameco MS Neuroscience Research Centre, University of SaskatchewanSaskatoon, SK, S7K 0M7, Canada
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TRPV1 Antagonist DWP05195 Induces ER Stress-Dependent Apoptosis through the ROS-p38-CHOP Pathway in Human Ovarian Cancer Cells. Cancers (Basel) 2020; 12:cancers12061702. [PMID: 32604833 PMCID: PMC7352786 DOI: 10.3390/cancers12061702] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/19/2020] [Accepted: 06/24/2020] [Indexed: 12/25/2022] Open
Abstract
In addition to their analgesic activity, transient receptor potential vanilloid 1 (TRPV1) agonists and antagonists demonstrate profound anti-cancer activities in various human cancers. In the present study, we investigated the anti-cancer activity of a novel TRPV1 antagonist, DWP05195, and evaluated its molecular mechanism in human ovarian cancer cells. DWP05195 demonstrated potent growth inhibitory effects in all five ovarian cancer cell lines examined. DWP05195 induced apoptosis through the activation of caspase-3, -8, and -9. DWP05195 induced C/EBP homologous protein (CHOP) expression and endoplasmic reticulum (ER) stress. Sodium phenylbutyrate (4-PBA), an ER-stress inhibitor, and CHOP knockdown significantly suppressed DWP5195-induced cell death. DWP05195-enhanced CHOP expression stimulated intrinsic and extrinsic apoptotic pathways through the regulation of Bcl2-like11 (BIM), death receptor 4 (DR4), and DR5. DWP05195-induced cell death was associated with increased reactive oxygen species (ROS) levels and p38 pathway activation. Pre-treatment with the antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed DWP05195-induced CHOP expression and p38 activation. Inhibition of NADPH oxidase (NOX) through p47phox knockdown abolished DWP05195-induced CHOP expression and cell death. Taken together, the findings indicate that DWP05195 induces ER stress-induced apoptosis via the ROS-p38-CHOP pathway in human ovarian cancer cells.
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Wei X, He J, Gao B, Han L, Mao Y, Zhao H, Si N, Wang H, Yang J, Bian B. Hellebrigenin anti-pancreatic cancer effects based on apoptosis and autophage. PeerJ 2020; 8:e9011. [PMID: 32426183 PMCID: PMC7213012 DOI: 10.7717/peerj.9011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 03/27/2020] [Indexed: 12/16/2022] Open
Abstract
Hellebrigenin is a natural product found in the toad skin secretions and plants of Urginea, including Hellebores and Kalanchoe genera. It has been shown to be active against Leishmania chagasi promastigotes and Trypanosoma cruzi trypomastigotes and also reported to play an anti-tumor effect on several cancer cell lines in vitro, including pancreatic cancer. This study is aimed to investigate the effects of Hellebrigenin on pancreatic carcinoma cells, SW1990 and BxPC-3 in vitro and its molecular mechanism involved in antitumor activities. Our results showed that Hellebrigenin effectively inhibited the proliferation of SW1990 and BxPC-3 cells in dose- and time-dependent manner. Flow cytometry results showed that Hellebrigenin induced the G0/G1 arrest in both of SW1990 and BxPC-3 cells and promoted cell early apoptosis and autophagy according to morphological observation. Immunofluorescence staining results further confirmed that cell apoptosis and autophagy also increased upon the Hellebrigenin treatment. Moreover, higher dose of Hellebrigenin further increased the cell apoptosis rate while decrease the mitochondrial membrane potential 24 h after treatment. The autophagy rate increased 48 h after treatment with significant difference (P < 0.05). Western blot analysis showed that the expression of caspase 3, 7, cleaved caspase 7, Atg 12, LC3 proteins were increased in SW1990 cell after treatment with Hellebrigenin. In addition, increasing expression of caspase 3, 7, 9, PARP, cleaved caspase 3, 7, 9, PARP, the sub basic protein of the PI3K family, Beclin-1, LC 3, Atg 3, 5, 12, 16 L were also observed after BxPC-3 cells treated with Hellebrigenin. In summary, this study reported for the first time that Hellebrigenin effectively induced autophagy and apoptosis especially the early apoptosis in SW1990 and BxPC-3 cells.
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Affiliation(s)
- Xiaolu Wei
- Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China
| | - Jing He
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, The Key Unit of Exploring Effective Substances of Classical and Famous Prescription of SATCM, Beijing, China
| | - Bo Gao
- China Resources Sanjiu Medical and Pharmaceutical Co. Ltd., Shenzhen, China
| | - Lingyu Han
- Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China
| | - Yingqiu Mao
- Beijing University of Chinese Medicine, Beijing, China
| | - Haiyu Zhao
- Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China
| | - Nan Si
- Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China
| | - Hongjie Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China
| | - Jian Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China
| | - Baolin Bian
- Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China
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36
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The Combination of Transient Receptor Potential Vanilloid Type 1 (TRPV1) and Phosphatase and Tension Homolog (PTEN) is an Effective Prognostic Biomarker in Cervical Cancer. Int J Gynecol Pathol 2020; 40:214-223. [PMID: 32287115 DOI: 10.1097/pgp.0000000000000677] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Transient receptor potential vanilloid type 1 (TRPV1) has been reported to play an important role in human cancers. However, the knowledge about TRPV1 in cervical cancer is sparse. Therefore, we evaluated the expression and clinical significance of TRPV1 in cervical cancer. Immunohistochemical analyses were performed for TRPV1 and phosphatase and tension homolog (PTEN) to delineate clinical significance using 150 cervical cancers, 230 cervical intraepithelial neoplasias, and 312 normal cervical epithelial tissues in a tissue microarray. Furthermore, the role of TRPV1 in cell growth was assessed in a cervical cancer cell line. The TRPV1 expression was significantly higher in cervical cancer tissues than in cervical intraepithelial neoplasias, and normal epithelial tissues (P<0.001). In cervical cancer tissues, TRPV1 expression negatively correlated with PTEN expression (Spearman ρ=-0.121, P=0.009). Multivariate survival analysis revealed high TRPV1 expression (hazard ratio=3.41, 95% confidence interval: 1.25-9.27, P=0.016) as an independent prognostic factor for overall survival. Notably. the high TRPV1/low PTEN expression showed the highest hazard ratio (5.87; 95% confidence interval: 2.18-15.82, P<0.001) for overall survival. In vitro results demonstrated that the overexpression of TRPV1 was associated with increased cell viability and colony formation. Overexpression of TRPV1 could be a good biomarker for the prediction of chemoradiation response. Our result suggested promising potential of high TRPV1/low PTEN as prognostic and survival makers. The possible link between the biologic function of TRPV1 and PTEN in cervical cancer warrants further studies.
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Arenobufagin Inhibits the Phosphatidylinositol 3-kinase/Protein Kinase B/Mammalian Target of Rapamycin Pathway and Induces Apoptosis and Autophagy in Pancreatic Cancer Cells. Pancreas 2020; 49:261-272. [PMID: 32011523 DOI: 10.1097/mpa.0000000000001471] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The aim of the study was to investigate the effects of arenobufagin on pancreatic carcinoma in vitro and in vivo and its molecular mechanism. METHODS The proliferation of pancreatic cancer cells was detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Transmission electron microscopy was used to observe the formation of autophagic vacuoles after arenobufagin treatment. Hoechst 33258 and monodansylcadaverine fluorescence staining were performed to evaluate cell apoptosis and autophagy. Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and JC-1 staining assays were used to evaluate apoptosis-related changes. Reverse-transcription polymerase chain reaction and western blotting were carried out to examine the expression of apoptosis- and autophagy-related markers after arenobufagin treatment. A tumor xenograft nude mouse model was established to evaluate arenobufagin efficacy in vivo. RESULTS Arenobufagin effectively inhibited the proliferation of SW1990 and BxPC3 cells and induced cell arrest, apoptosis, and autophagy. Arenobufagin upregulated the expression of apoptotic- and autophagy-related proteins while downregulated the expression of phosphatidylinositol 3-kinase family proteins. Furthermore, arenobufagin also exerted inhibitory effects on tumor growth in xenograft nude mice. CONCLUSIONS Arenobufagin inhibits tumor growth in vivo and in vitro. The mechanism underlying arenobufagin action may involve induction of autophagy and apoptosis through the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway.
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38
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Huang J, Liu J, Qiu L. Transient receptor potential vanilloid 1 promotes EGFR ubiquitination and modulates EGFR/MAPK signalling in pancreatic cancer cells. Cell Biochem Funct 2020; 38:401-408. [PMID: 31907951 DOI: 10.1002/cbf.3483] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/16/2019] [Accepted: 12/19/2019] [Indexed: 12/12/2022]
Abstract
Transient receptor potential vanilloid-1 (TRPV1) was first identified in sensory neurons, where it was suggested as a therapeutic target for pain relief. Here, we show that TRPV1 is expressed in the pancreatic cancer cell line, PANC-1; that epidermal growth factor receptor (EGFR) expression is downregulated by overexpression or agonist-induced activation of TRPV1; and conversely, that EGFR expression is increased after silencing TRPV1. Furthermore, TRPV1 overexpression inhibits cell proliferation and significantly reduces the mRNA levels of two oncogenes, KRAS and AKT2. More importantly, TRPV1 downregulates EGFR levels by inducing EGFR ubiquitination and degradation, which modulate EGFR/MAPK signalling in pancreatic cancer cells. These results illustrate the regulation and mechanism of TRPV1 on EGFR in pancreatic cancer cells and may provide new ideas for the design of novel antitumor drugs targeting EGFR. SIGNIFICANCE OF THE STUDY: We investigated the effect and mechanism of TRPV1 on EGFR-mediated proliferation and transformation of pancreatic cancer cells, with the aim of providing new ideas and experimental evidence for the application of strategies that promote EGFR degradation to treat pancreatic cancer.
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Affiliation(s)
- Jin Huang
- Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingxue Liu
- Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,College of Pharmacy, The Second Military Medical University, Shanghai, China
| | - Lei Qiu
- College of Pharmacy, The Second Military Medical University, Shanghai, China
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Friedman JR, Richbart SD, Merritt JC, Brown KC, Denning KL, Tirona MT, Valentovic MA, Miles SL, Dasgupta P. Capsaicinoids: Multiple effects on angiogenesis, invasion and metastasis in human cancers. Biomed Pharmacother 2019; 118:109317. [PMID: 31404777 PMCID: PMC6759410 DOI: 10.1016/j.biopha.2019.109317] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer progression is a complex multistep process comprising of angiogenesis of the primary tumor, its invasion into the surrounding stroma and its migration to distant organs to produce metastases. Nutritional compounds of the "capsaicinoid" family regulate angiogenesis, invasion and metastasis of tumors. Capsaicinoids display robust anti-angiogenic activity in both cell culture and mice models. However, conflicting reports exist about the effect of capsaicinoids on invasion of metastasis of cancers. While some published reports have described an anti-invasive and anti-metastatic role for capsaicinoids, others have argued that capsaicinoids stimulate invasion and metastasis of cancers. The present review article summarizes these findings involving the bioactivity of capsaicin in angiogenesis, invasion and metastasis of cancer. A survey of literature indicate that they are several articles summarizing the growth-inhibitory activity of capsaicinoids but few describe its effects on angiogenesis, invasion and metastasis in detail. Our review article fills this gap of knowledge. The discovery of a second generation of natural and synthetic capsaicin analogs (with anti-tumor activity) will pave the way to improved strategies for the treatment of several human cancers.
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Affiliation(s)
- Jamie R Friedman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States
| | - Stephen D Richbart
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States
| | - Justin C Merritt
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States
| | - Kathleen C Brown
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States
| | - Krista L Denning
- Department of Pathology, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States
| | - Maria T Tirona
- Department of Hematology-Oncology, Edwards Cancer Center, Cabell Huntington Hospital, 1400 Hal Greer Boulevard, Huntington, WV 25701, United States
| | - Monica A Valentovic
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States
| | - Sarah L Miles
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States
| | - Piyali Dasgupta
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, WV 25755, United States.
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40
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Ilie MA, Caruntu C, Tampa M, Georgescu SR, Matei C, Negrei C, Ion RM, Constantin C, Neagu M, Boda D. Capsaicin: Physicochemical properties, cutaneous reactions and potential applications in painful and inflammatory conditions. Exp Ther Med 2019; 18:916-925. [PMID: 31384324 PMCID: PMC6639979 DOI: 10.3892/etm.2019.7513] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 09/21/2018] [Indexed: 12/14/2022] Open
Abstract
Capsaicin is a natural protoalkaloid recognized as the main pungent component in hot peppers (Capsicum annuum L.). The capsaicin receptor is highly expressed in the unmyelinated type C nerve fibers originating from small diameter sensory neurons in dorsal root ganglia and cranial nerve ganglia correspondents. Capsaicin and related vanilloids have a variety of effects on primary sensory neurons function, from sensory neuron excitation characterized by local burning sensation and neurogenic inflammation, followed by conduction blockage accompanied by reversible ultrastructural changes of peripheral nociceptive endings (desensitization), going as far as irreversible degenerative changes (neurotoxicity). The main role in capsaicin-induced neurogenic inflammation relies on the capsaicin sensitive, small diameter primary sensory neurons, therefore its evaluation could be used as a diagnostic instrument in functional alterations of cutaneous sensory nerve fibers. Moreover, capsaicin-induced desensitization and neurotoxicity explain the analgesic/anti-nociceptive and anti-inflammatory effects of topical capsaicin and its potential use in the management of painful and inflammatory conditions. In this study, we describe the effects of capsaicin on neurogenic inflammation and nociception, as well as its potential diagnostic value and therapeutic impact in various conditions involving impairment of sensory nerve fibers.
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Affiliation(s)
- Mihaela Adriana Ilie
- Dermatology Research Laboratory, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
- Department of Biochemistry, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
| | - Constantin Caruntu
- Department of Physiology, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
- Department of Dermatology, ‘Prof. N.C. Paulescu’ National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest 020475, Romania
| | - Mircea Tampa
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
| | - Simona-Roxana Georgescu
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
| | - Clara Matei
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
| | - Carolina Negrei
- Department of Toxicology, Faculty of Pharmacy, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020956, Romania
| | - Rodica-Mariana Ion
- The National Institute for Research and Development in Chemistry and Petrochemistry - ICECHIM, Bucharest 060021, Romania
| | - Carolina Constantin
- Department of Immunology, ‘Victor Babes’ National Institute of Pathology, Bucharest 050096, Romania
- Department of Pathology, Colentina Clinical Hospital, 020125 Bucharest, Romania
| | - Monica Neagu
- Department of Immunology, ‘Victor Babes’ National Institute of Pathology, Bucharest 050096, Romania
- Department of Pathology, Colentina Clinical Hospital, 020125 Bucharest, Romania
- Department of Biochemistry, Faculty of Biology, University of Bucharest, Bucharest 020125, Romania
| | - Daniel Boda
- Dermatology Research Laboratory, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020021, Romania
- Department of Dermatology, ‘Prof. N.C. Paulescu’ National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest 020475, Romania
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Friedman JR, Richbart SD, Merritt JC, Perry HE, Brown KC, Akers AT, Nolan NA, Stevenson CD, Hurley JD, Miles SL, Tirona MT, Valentovic MA, Dasgupta P. Capsaicinoids enhance chemosensitivity to chemotherapeutic drugs. Adv Cancer Res 2019; 144:263-298. [PMID: 31349900 DOI: 10.1016/bs.acr.2019.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Cytotoxic chemotherapy is the mainstay of cancer treatment. Conventional chemotherapeutic agents do not distinguish between normal and neoplastic cells. This leads to severe toxic side effects, which may necessitate the discontinuation of treatment in some patients. Recent research has identified key molecular events in the initiation and progression of cancer, promoting the design of targeted therapies to selectively kill tumor cells while sparing normal cells. Although, the side effects of such drugs are typically milder than conventional chemotherapies, some off-target effects still occur. Another serious challenge with all chemotherapies is the acquisition of chemoresistance upon prolonged exposure to the drug. Therefore, identifying supplementary agents that sensitize tumor cells to chemotherapy-induced apoptosis and help minimize drug resistance would be valuable for improving patient tolerance and response to chemotherapy. The use of effective supplementary agents provides a twofold advantage in combination with standard chemotherapy. First, by augmenting the activity of the chemotherapeutic drug it can lower the dose needed to kill tumor cells and decrease the incidence and severity of treatment-limiting side effects. Second, adjuvant therapies that lower the effective dose of chemotherapy may delay/prevent the development of chemoresistance in tumors. Capsaicinoids, a major class of phytochemical compounds isolated from chili peppers, have been shown to improve the efficacy of several anti-cancer drugs in cell culture and animal models. The present chapter summarizes the current knowledge about the chemosensitizing activity of capsaicinoids with conventional and targeted chemotherapeutic drugs, highlighting the potential use of capsaicinoids in novel combination therapies to improve the therapeutic indices of conventional and targeted chemotherapeutic drugs in human cancers.
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Affiliation(s)
- Jamie R Friedman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Stephen D Richbart
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Justin C Merritt
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Haley E Perry
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Kathleen C Brown
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Austin T Akers
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Nicholas A Nolan
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Cathryn D Stevenson
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - John D Hurley
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Sarah L Miles
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Maria T Tirona
- Department of Hematology, Oncology, Edwards Comprehensive Cancer Center, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Monica A Valentovic
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Piyali Dasgupta
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States.
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Sreedharan L, Kumar B, Jewell A, Banim P, Koulouris A, Hart AR. Bridging clinic: The initial medical management of patients with newly diagnosed pancreatic cancer. Frontline Gastroenterol 2019; 10:261-268. [PMID: 31288251 PMCID: PMC6583575 DOI: 10.1136/flgastro-2018-101002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 02/04/2023] Open
Abstract
Pancreatic cancer is the 11th most common cancer in the UK and has the worst prognosis of any tumour with minimal improvements in survival over recent decades. As most patients are either ineligible for surgery or may decline chemotherapy, the emphasis is on control of symptoms and management of complications such as poor nutritional status. The time period between informing the patient of their diagnosis and commencing cancer treatments presents a valuable opportunity to proactively identify and treat symptoms to optimise patients' overall well-being. The 'bridging clinic', delivered by a range of healthcare professionals from gastroenterologists to nurse practitioners, can provide this interface where patients are first informed of their diagnosis and second supportive therapies offered. In this article, we provide a structure for instituting such supportive therapies at the bridging clinic. The components of the clinic are summarised using the mnemonic INDASH (Information/Nutrition/Diabetes and Depression/Analgesia/Stenting/Hereditary) and each is discussed in detail below.
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Affiliation(s)
| | - Bhaskar Kumar
- Upper GI Surgery, Norfolk and Norwich Hospital, Norwich, UK
| | | | - Paul Banim
- James Paget University Hospitals, Great Yarmouth, Norfolk, UK
| | - Andreas Koulouris
- Academic Clinical Fellow in Gastroenterology, Norfolk and Norwich Hospital, Norwich, UK
| | - Andrew R Hart
- Gastroenterology, Norfolk and Norwich Hospital, Norwich, UK
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43
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Gasparini G, Pellegatta M, Crippa S, Lena MS, Belfiori G, Doglioni C, Taveggia C, Falconi M. Nerves and Pancreatic Cancer: New Insights into a Dangerous Relationship. Cancers (Basel) 2019; 11:E893. [PMID: 31248001 PMCID: PMC6678884 DOI: 10.3390/cancers11070893] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer-particularly in pancreatic ductal adenocarcinoma (PDAC)-PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously ("present" or "absent"). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.
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Affiliation(s)
- Giulia Gasparini
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Marta Pellegatta
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Stefano Crippa
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
| | - Marco Schiavo Lena
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Giulio Belfiori
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Claudio Doglioni
- Vita Salute San Raffaele University, 20132 Milan, Italy.
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Carla Taveggia
- Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Massimo Falconi
- Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
- Vita Salute San Raffaele University, 20132 Milan, Italy.
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Bao Z, Dai X, Wang P, Tao Y, Chai D. Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1-dependent and -independent pathways. Cell Cycle 2019; 18:1379-1392. [PMID: 31095448 DOI: 10.1080/15384101.2019.1618119] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
An accumulating body of evidence has shown that capsaicin induces apoptosis in various tumor cells as a mechanism of its anti-tumor activity. However, the effects of capsaicin on osteosarcoma have not been studied extensively. In the current study, we explore the molecular mechanism of capsaicin-mediated tumor suppressive function in osteosarcoma. We found that capsaicin-induced apoptosis and the activation of transient receptor potential receptor vanilloid 1 (TRPV1) in a dose- and time-dependent manner in human osteosarcoma MG63 cells in vitro. Blocking TRPV1 using capsazepine attenuated the capsaicin-induced cytotoxicity, mitochondrial dysfunction, overproduction of reactive oxygen species (ROS) and decrease in superoxide dismutase (SOD) activity. In addition, the results demonstrated that capsaicin induced the activation of adenosine 5'-monophosphate-activated protein kinase (AMPK), p53 and C-jun N-terminal kinase (JNK). In addition, Compound C (antagonist of AMPK) attenuated the activation of p53, which appeared to be TRPV1 independent. Taken together, the present study suggests that capsaicin effectively causes cell death in human osteosarcoma MG63 cells via the activation of TRPV1-dependent (mitochondrial dysfunction, and overproduction of ROS and JNK) and TRPV1-independent (AMPK-p53) pathways. Thus, capsaicin may be a potential anti-osteosarcoma agent.
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Affiliation(s)
- Zhengqi Bao
- a Department of Orthopedics , The First Affiliated Hospital of Bengbu Medical College , Bengbu , China
| | - Xiusong Dai
- a Department of Orthopedics , The First Affiliated Hospital of Bengbu Medical College , Bengbu , China
| | - Peter Wang
- b Department of Biochemistry and Molecular Biology, School of Laboratory Medicine , Bengbu Medical College , Anhui , China
| | - Yisheng Tao
- c Department of Pathology , the First Affiliated Hospital of Bengbu Medical College , Bengbu , China
| | - Damin Chai
- c Department of Pathology , the First Affiliated Hospital of Bengbu Medical College , Bengbu , China
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Effect of polygodial and its direct derivatives on the mammalian Na +/K +-ATPase activity. Eur J Pharmacol 2018; 831:1-8. [PMID: 29715454 DOI: 10.1016/j.ejphar.2018.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 04/06/2018] [Accepted: 04/26/2018] [Indexed: 11/23/2022]
Abstract
The sesquiterpene polygodial is an agonist of the transient receptor potential vanilloid 1 (TRPV1). Our group recently reported the synthesis and anticancer effects of polygodial and its derivatives, and showed that these compounds retain activity against apoptosis- and multidrug-resistant cancer cells. Herein, we tested the inhibitory effect of these compounds on the activity of the enzyme Na+/K+-ATPase (NKA) from kidney (α1 isoform) and brain (α2 and α3 isoforms) guinea pig extracts. Polygodial (1) displayed a dose-dependent inhibition of both kidney and brain purified NKA preparations, with higher sensitivity for the cerebral isoforms. Polygo-11,12-diol (2) and C11,C12-pyridazine derivative (3) proved to be poor inhibitors. Unsaturated ester (4) and 9-epipolygodial (5) inhibited NKA preparations from brain and kidney, with the same inhibitory potency. Nevertheless, they did not achieve maximum inhibition even at higher concentration. Comparing the inhibitory potency in crude homogenates and purified preparations of NKA, compounds 4 and 5 revealed a degree of selectivity toward the renal enzyme. Kinetic studies showed a non-competitive inhibition for Na+ and K+ by compounds 1, 4 and 5 and for ATP by 1 and 4. However, compound 5 presented a competitive inhibition type. Furthermore, K+-activated p-nitrophenylphosphatase activity of these purified preparations was not inhibited by 1, 4 and 5, suggesting that these compounds acted in the initial phase of the enzyme's catalytic cycle. These findings suggest that the antitumor action of polygodial and its analogues may be linked to their NKA inhibitory properties and reinforce that NKA may be an important target for cancer therapy.
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Friedman JR, Nolan NA, Brown KC, Miles SL, Akers AT, Colclough KW, Seidler JM, Rimoldi JM, Valentovic MA, Dasgupta P. Anticancer Activity of Natural and Synthetic Capsaicin Analogs. J Pharmacol Exp Ther 2018; 364:462-473. [PMID: 29246887 PMCID: PMC5803642 DOI: 10.1124/jpet.117.243691] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 12/13/2017] [Indexed: 12/28/2022] Open
Abstract
The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound antineoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps, and burning sensation. This has led to extensive research focused on the identification and rational design of second-generation capsaicin analogs, which possess greater bioactivity than capsaicin. A majority of these natural capsaicinoids and synthetic capsaicin analogs have been studied for their pain-relieving activity. Only a few of these capsaicin analogs have been investigated for their anticancer activity in cell culture and animal models. The present review summarizes the current knowledge of the growth-inhibitory activity of natural capsaicinoids and synthetic capsaicin analogs. Future studies that examine the anticancer activity of a greater number of capsaicin analogs represent novel strategies in the treatment of human cancers.
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Affiliation(s)
- Jamie R Friedman
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Nicholas A Nolan
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Kathleen C Brown
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Sarah L Miles
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Austin T Akers
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Kate W Colclough
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Jessica M Seidler
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - John M Rimoldi
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Monica A Valentovic
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Piyali Dasgupta
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
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Nabissi M, Morelli MB, Arcella A, Cardinali C, Santoni M, Bernardini G, Santoni A, Santoni G, Amantini C. Post-transcriptional regulation of 5'-untranslated regions of human Transient Receptor Potential Vanilloid type-1 (TRPV-1) channels: role in the survival of glioma patients. Oncotarget 2018; 7:81541-81554. [PMID: 27829230 PMCID: PMC5348411 DOI: 10.18632/oncotarget.13132] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/14/2016] [Indexed: 01/02/2023] Open
Abstract
The Transient Receptor Potential Vanilloid type-1 (TRPV1) channel is a non-selective cation channel belonging to the Transient Receptor Potential family; variation of its expression has been correlated to glioma progression. In human, TRPV1 transcripts display a remarkable homogeneity differing only for the 5'-untranslated region (5'UTR) sequence that generates four variants encoding the same protein. Herein, we investigated the role of the 5'UTR sequences in TRPV1 transcripts stability, regulation of translation, expression in glioma cells and tissues. In addition, the expression of 5'UTR TRPV1 variants as prognostic factor in the survival of glioblastoma patients was evaluated. The expression level for each 5'UTR and their stability was evaluated by RT-PCR analysis. The effect of rapamycin and interferon-gamma in 5'UTR-regulating TRPV1 translation was determined by western blot analysis in glioma cell lines. We demonstrated that the 5'UTR influences the stability and translation efficacy of TRPV1 transcripts, and that TRPV1 variant three (TRPV1v3) was the most stable and the only variant expressed in GBM samples and in glioma stem-like cells. Furthermore, we found that TRPV1v3 expression levels correlate with patient's survival, suggesting that it may represent a potential prognostic marker for patients with glioma.
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Affiliation(s)
- Massimo Nabissi
- School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino (MC), Italy
| | | | | | - Claudio Cardinali
- Department of Molecular Medicine, Sapienza University, Rome (RM), Italy
| | - Matteo Santoni
- Department of Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona (AN), Italy
| | - Giovanni Bernardini
- Department of Molecular Medicine, Sapienza University, Rome (RM), Italy.,I.N.M. Neuromed, Pozzilli, Isernia (IS), Italy
| | - Angela Santoni
- Department of Molecular Medicine, Sapienza University, Rome (RM), Italy.,I.N.M. Neuromed, Pozzilli, Isernia (IS), Italy
| | - Giorgio Santoni
- School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino (MC), Italy
| | - Consuelo Amantini
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
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Fazzari J, Linher-Melville K, Singh G. Tumour-Derived Glutamate: Linking Aberrant Cancer Cell Metabolism to Peripheral Sensory Pain Pathways. Curr Neuropharmacol 2018; 15:620-636. [PMID: 27157265 PMCID: PMC5543678 DOI: 10.2174/1570159x14666160509123042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 03/16/2016] [Accepted: 04/17/2016] [Indexed: 01/22/2023] Open
Abstract
Background Chronic pain is a major symptom that develops in cancer patients, most commonly emerging during advanced stages of the disease. The nature of cancer-induced pain is complex, and the efficacy of current therapeutic interventions is restricted by the dose-limiting side-effects that accompany common centrally targeted analgesics. Methods This review focuses on how up-regulated glutamate production and export by the tumour converge at peripheral afferent nerve terminals to transmit nociceptive signals through the transient receptor cation channel, TRPV1, thereby initiating central sensitization in response to peripheral disease-mediated stimuli. Results Cancer cells undergo numerous metabolic changes that include increased glutamine catabolism and over-expression of enzymes involved in glutaminolysis, including glutaminase. This mitochondrial enzyme mediates glutaminolysis, producing large pools of intracellular glutamate. Up-regulation of the plasma membrane cystine/glutamate antiporter, system xc-, promotes aberrant glutamate release from cancer cells. Increased levels of extracellular glutamate have been associated with the progression of cancer-induced pain and we discuss how this can be mediated by activation of TRPV1. Conclusion With a growing population of patients receiving inadequate treatment for intractable pain, new targets need to be considered to better address this largely unmet clinical need for improving their quality of life. A better understanding of the mechanisms that underlie the unique qualities of cancer pain will help to identify novel targets that are able to limit the initiation of pain from a peripheral source–the tumour.
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Affiliation(s)
| | | | - Gurmit Singh
- Department of Pathology and Molecular Medicine; Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON. Canada
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5-Fluorouracil-induced mitochondrial oxidative cytotoxicity and apoptosis are increased in MCF-7 human breast cancer cells by TRPV1 channel activation but not Hypericum perforatum treatment. Mol Cell Biochem 2017; 439:189-198. [PMID: 28795251 DOI: 10.1007/s11010-017-3147-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 08/02/2017] [Indexed: 12/13/2022]
Abstract
5-Fluorouracil (5-FU) is a widely used chemotherapy agent for breast cancer, although drug resistance is a critical issue regarding the use of this agent in the disease. Calcium signaling is a well-known main cause of proliferation and apoptosis in breast cancer cells. Although previous studies have implicated TRPV1 inhibitor, anticancer, and apoptotic roles of Hypericum perforatum (HPer) in several cells, the synergistic inhibition effects of HPer and 5-FU in cancer and the stimulation of ongoing apoptosis have not yet been clarified in MCF-7 cells. Therefore, we investigated the apoptotic and antioxidant properties of 5-FU with/without HPer through activation of TRPV1 in MCF-7 cells. The MCF-7 cells were divided into four groups: the control group, the HPer-treated group (0.3 mM), the 5-FU-treated group (25 μM), and the 5-FU+HPer-treated group. The intracellular free calcium ion concentration ([Ca2+]i) increased with 5-FU treatments, but they decreased with the HPer and HPer+5-FU treatments. The [Ca2+]i is further decreased in the four groups by TRPV1 channel antagonist (capsazepine and 0.01 mM) treatments. However, mitochondrial membrane depolarization and apoptosis levels, and the PARP1, caspase 3, and caspase 9 expression levels were increased by 5-FU treatment, although the values were decreased by the HPer and 5-FU+HPer treatments. Cell viability level was also decreased by 5-FU treatment. In conclusion, antitumor and apoptosis effects of 5-FU are up-regulated by activation of TRPV1 channels, but its action was down-regulated by HPer treatment. It seems that HPer cannot be used for increasing the antitumor effect of 5-FU through modulation of the TRPV1.
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Pain in Patients with Pancreatic Cancer: Prevalence, Mechanisms, Management and Future Developments. Dig Dis Sci 2017; 62:861-870. [PMID: 28229252 DOI: 10.1007/s10620-017-4488-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 02/01/2017] [Indexed: 12/18/2022]
Abstract
Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients' quality of life and survival.
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