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Tang W, Li X, Liu H, Xu C, Deng S. The role of macrophages in chronic pain. Cytokine 2025; 185:156813. [PMID: 39577336 DOI: 10.1016/j.cyto.2024.156813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 11/24/2024]
Abstract
Chronic pain typically lasts or recurs for more than three months and is an unpleasant sensory and emotional experience, including neuropathic pain, long-term tissue damage, tumors, and viral or bacterial infections.The unpleasantness associated with pain affects the basic life of patients and has become a truly global problem. Macrophages, a powerful immune effector cell whose functional plasticity leads to polarization into different subtypes and opposite effects in different environments, are also indispensable in the development of pain.In recent years, there has been an increasing number of studies on the effects of macrophages on pain, and there are multiple pathways that regulate macrophage polarization, including lipopolysaccharide induction and IL-4/IL-13 stimulation.In addition, pathways involving macrophages and macrophage polarization have been found to have an exacerbating or mitigating role in the progression of chronic pain, with M1 macrophages generally exacerbating pain progression and M2 macrophages mitigating pain progression.Therefore, modulating macrophage polarization holds great promise as an intervention in chronic pain. In this paper, we synthesize multiple macrophage pathways as well as mechanisms affecting their pain processes in the context of different types of chronic pain, providing new avenues for chronic pain relief.
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Affiliation(s)
- Weikang Tang
- School of Medicine, Tarim University, Alaer, 843300 Xinjiang, China
| | - Xuan Li
- School of Medicine, Tarim University, Alaer, 843300 Xinjiang, China
| | - Huixia Liu
- School of Medicine, Tarim University, Alaer, 843300 Xinjiang, China
| | - Chunyan Xu
- School of Medicine, Tarim University, Alaer, 843300 Xinjiang, China
| | - Siyao Deng
- School of Medicine, Tarim University, Alaer, 843300 Xinjiang, 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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Lee FS, Nguyen UN, Munns EJ, Wachs RA. Identification of compounds that cause axonal dieback without cytotoxicity in dorsal root ganglia explants and intervertebral disc cells with potential to treat pain via denervation. PLoS One 2024; 19:e0300254. [PMID: 38696450 PMCID: PMC11065314 DOI: 10.1371/journal.pone.0300254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 02/23/2024] [Indexed: 05/04/2024] Open
Abstract
Low back pain, knee osteoarthritis, and cancer patients suffer from chronic pain. Aberrant nerve growth into intervertebral disc, knee, and tumors, are common pathologies that lead to these chronic pain conditions. Axonal dieback induced by capsaicin (Caps) denervation has been FDA-approved to treat painful neuropathies and knee osteoarthritis but with short-term efficacy and discomfort. Herein, we propose to evaluate pyridoxine (Pyr), vincristine sulfate (Vcr) and ionomycin (Imy) as axonal dieback compounds for denervation with potential to alleviate pain. Previous literature suggests Pyr, Vcr, and Imy can cause undesired axonal degeneration, but no previous work has evaluated axonal dieback and cytotoxicity on adult rat dorsal root ganglia (DRG) explants. Thus, we performed axonal dieback screening using adult rat DRG explants in vitro with Caps as a positive control and assessed cytotoxicity. Imy inhibited axonal outgrowth and slowed axonal dieback, while Pyr and Vcr at high concentrations produced significant reduction in axon length and robust axonal dieback within three days. DRGs treated with Caps, Vcr, or Imy had increased DRG cytotoxicity compared to matched controls, but overall cytotoxicity was minimal and at least 88% lower compared to lysed DRGs. Pyr did not lead to any DRG cytotoxicity. Further, neither Pyr nor Vcr triggered intervertebral disc cell death or affected cellular metabolic activity after three days of incubation in vitro. Overall, our findings suggest Pyr and Vcr are not toxic to DRGs and intervertebral disc cells, and there is potential for repurposing these compounds for axonal dieback compounds to cause local denervation and alleviate pain.
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Affiliation(s)
- Fei San Lee
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska United States of America
| | - Uyen N. Nguyen
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska United States of America
| | - Eliza J. Munns
- Department of Electrical, Computer, and Biomedical Engineering, Union College, Schenectady, New York, United States of America
| | - Rebecca A. Wachs
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska United States of America
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Muñoz-Islas E, Santiago-SanMartin ED, Mendoza-Sánchez E, Torres-Rodríguez HF, Ramírez-Quintanilla LY, Peters CM, Jiménez-Andrade JM. Long-term effects of gestational diabetes mellitus on the pancreas of female mouse offspring. World J Diabetes 2024; 15:758-768. [PMID: 38680692 PMCID: PMC11045410 DOI: 10.4239/wjd.v15.i4.758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/29/2024] [Accepted: 03/11/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Prolonged fetal exposure to hyperglycemia may increase the risk of developing abnormal glucose metabolism and type-2 diabetes during childhood, adolescence, and adulthood; however, the mechanisms by which gestational diabetes mellitus (GDM) predisposes offspring to metabolic disorders remain unknown. AIM To quantify the nerve axons, macrophages, and vasculature in the pancreas from adult offspring born from mouse dams with GDM. METHODS GDM was induced by i.p. administration of streptozotocin (STZ) in ICR mouse dams. At 12 wk old, fasting blood glucose levels were determined in offspring. At 15 wk old, female offspring born from dams with and without GDM were sacrificed and pancreata were processed for immunohistochemistry. We quantified the density of sensory [calcitonin gene-related peptide (CGRP)] and tyrosine hydroxylase (TH) axons, blood vessels (endomucin), and macro-phages (CD68) in the splenic pancreas using confocal microscopy. RESULTS Offspring mice born from STZ-treated dams had similar body weight and blood glucose values compared to offspring born from vehicle-treated dams. However, the density of CGRP+ and TH+ axons, endomucin+ blood vessels, and CD68+ macrophages in the exocrine pancreas was significantly greater in offspring from mothers with GDM vs control offspring. Likewise, the microvasculature in the islets was significantly greater, but not the number of macrophages within the islets of offspring born from dams with GDM compared to control mice. CONCLUSION GDM induces neuronal, vascular, and inflammatory changes in the pancreas of adult progeny, which may partially explain the higher propensity for offspring of mothers with GDM to develop metabolic diseases.
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Affiliation(s)
- Enriqueta Muñoz-Islas
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Edgar David Santiago-SanMartin
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Eduardo Mendoza-Sánchez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Héctor Fabián Torres-Rodríguez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | | | - Christopher Michael Peters
- Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, NC 27101, United States
| | - Juan Miguel Jiménez-Andrade
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
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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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Wang Y, Liu Z, Tian Y, Zhao H, Fu X. Periampullary cancer and neurological interactions: current understanding and future research directions. Front Oncol 2024; 14:1370111. [PMID: 38567163 PMCID: PMC10985190 DOI: 10.3389/fonc.2024.1370111] [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: 01/13/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Periampullary cancer is a malignant tumor occurring around the ampullary region of the liver and pancreas, encompassing a variety of tissue types and sharing numerous biological characteristics, including interactions with the nervous system. The nervous system plays a crucial role in regulating organ development, maintaining physiological equilibrium, and ensuring life process plasticity, a role that is equally pivotal in oncology. Investigations into nerve-tumor interactions have unveiled their key part in controlling cancer progression, inhibiting anti-tumor immune responses, facilitating invasion and metastasis, and triggering neuropathic pain. Despite many mechanisms by which nerve fibers contribute to cancer advancement still being incompletely understood, the growing emphasis on the significance of nerves within the tumor microenvironment in recent years has set the stage for the development of groundbreaking therapies. This includes combining current neuroactive medications with established therapeutic protocols. This review centers on the mechanisms of Periampullary cancer's interactions with nerves, the influence of various types of nerve innervation on cancer evolution, and outlines the horizons for ongoing and forthcoming research.
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Affiliation(s)
- Yuchen Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Zi’ang Liu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yanzhang Tian
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- General Surgery Department , Shanxi Bethune Hospital/General Surgery Department, Third Hospital of Shanxi Medical University, Taiyuan, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haoliang Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- General Surgery Department , Shanxi Bethune Hospital/General Surgery Department, Third Hospital of Shanxi Medical University, Taiyuan, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xifeng Fu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- General Surgery Department , Shanxi Bethune Hospital/General Surgery Department, Third Hospital of Shanxi Medical University, Taiyuan, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Mardelle U, Bretaud N, Daher C, Feuillet V. From pain to tumor immunity: influence of peripheral sensory neurons in cancer. Front Immunol 2024; 15:1335387. [PMID: 38433844 PMCID: PMC10905387 DOI: 10.3389/fimmu.2024.1335387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/29/2024] [Indexed: 03/05/2024] Open
Abstract
The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated anti-tumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it.
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Affiliation(s)
- Ugo Mardelle
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Ninon Bretaud
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Clara Daher
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Vincent Feuillet
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
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Zhu M, Luo F, Xu B, Xu J. Research Progress of Neural Invasion in Pancreatic Cancer. Curr Cancer Drug Targets 2024; 24:397-410. [PMID: 37592782 DOI: 10.2174/1568009623666230817105221] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/13/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023]
Abstract
Pancreatic cancer is one of the highly malignant gastrointestinal tumors in humans, and patients suffer from cancer pain in the process of cancer. Most patients suffer from severe pain in the later stages of the disease. The latest studies have shown that the main cause of pain in patients with pancreatic cancer is neuroinflammation caused by tumor cells invading nerves and triggering neuropathic pain on this basis, which is believed to be the result of nerve invasion. Peripheral nerve invasion (PNI), defined as the presence of cancer cells along the nerve or in the epineurial, perineural, and endoneurial spaces of the nerve sheath, is a special way for cancer to spread to distant sites. However, due to limited clinical materials, the research on the mechanism of pancreatic cancer nerve invasion has not been carried out in depth. In addition, perineural invasion is considered to be one of the underlying causes of recurrence and metastasis after pancreatectomy and an independent predictor of prognosis. This article systematically reviewed the neural invasion of pancreatic cancer through bioinformatics analysis, clinical manifestations and literature reviews.
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Affiliation(s)
- Mengying Zhu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China
| | - Feng Luo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, China
| | - Bin Xu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, P.R. China
| | - Jian Xu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China
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Huang FF, Cui WH, Ma LY, Chen Q, Liu Y. Crosstalk of nervous and immune systems in pancreatic cancer. Front Cell Dev Biol 2023; 11:1309738. [PMID: 38099290 PMCID: PMC10720593 DOI: 10.3389/fcell.2023.1309738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 11/20/2023] [Indexed: 12/17/2023] Open
Abstract
Pancreatic cancer is a highly malignant tumor known for its extremely low survival rate. The combination of genetic disorders within pancreatic cells and the tumor microenvironment contributes to the emergence and progression of this devastating disease. Extensive research has shed light on the nature of the microenvironmental cells surrounding the pancreatic cancer, including peripheral nerves and immune cells. Peripheral nerves release neuropeptides that directly target pancreatic cancer cells in a paracrine manner, while immune cells play a crucial role in eliminating cancer cells that have not evaded the immune response. Recent studies have revealed the intricate interplay between the nervous and immune systems in homeostatic condition as well as in cancer development. In this review, we aim to summarize the function of nerves in pancreatic cancer, emphasizing the significance to investigate the neural-immune crosstalk during the advancement of this malignant cancer.
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Affiliation(s)
- Fei-Fei Huang
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Wen-Hui Cui
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Lan-Yue Ma
- Center for Cell Lineage and Development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qi Chen
- Center for Cell Lineage and Development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
| | - Yang Liu
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
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Lu F, Wang X, Tian J, Li X. Early versus delayed computed tomography-guided celiac plexus neurolysis for palliative pain management in patients with advanced pancreatic cancer: a retrospective cohort study. Front Neurol 2023; 14:1292758. [PMID: 38020651 PMCID: PMC10661893 DOI: 10.3389/fneur.2023.1292758] [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: 09/12/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Abdominal and back pain is the most frequent symptom in patients with pancreatic cancer, with pain management being extremely challenging. This study aimed to evaluate pain control, opioid consumption, pain-interfered quality of life, and survival after early and delayed computed tomography (CT)-guided celiac plexus neurolysis (CPN). Methods A retrospective analysis of pancreatic cancer patients receiving CPN for pain (n = 56) between June 2018 and June 2021 was done. The patients were grouped as early group (n = 22) and delayed group (n = 34) on the basis of the presence of persistent refractory pain according to expert consensus on refractory cancer pain. Results Both groups were comparable in demographic characteristics and baseline pain conditions measured using the numeric rating scale (5.77 ± 1.23 vs. 6.27 ± 1.21; p = 0.141). The pain scores were significantly reduced in both groups; early CPN resulted in significantly lower scores from 3 to 5 months. The opioid consumption gradually decreased to a minimum at 2 weeks but increased at 1 month (35.56 ± 30.14 mg and 50.48 ± 47.90 mg, respectively); significantly larger consumption from 2 to 4 months was seen in the delayed group. The total pain interference was lower than baseline in all patients, with significant improvement after early CPN in sleep, appetite, enjoyment of life, and mood. The average survival time of the two groups was comparable. Conclusion Early application of CT-guided CPN for patients with advanced pancreatic cancer may help reduce pain exacerbation and opioids consumption, without influencing the survival.
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Affiliation(s)
- Fan Lu
- Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaojia Wang
- Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Tian
- Department of Anesthesiology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xuehan Li
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
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11
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Ni B, Yin Y, Li Z, Wang J, Wang X, Wang K. Crosstalk Between Peripheral Innervation and Pancreatic Ductal Adenocarcinoma. Neurosci Bull 2023; 39:1717-1731. [PMID: 37347365 PMCID: PMC10603023 DOI: 10.1007/s12264-023-01082-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/04/2023] [Indexed: 06/23/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.
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Affiliation(s)
- Bo Ni
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yiqing Yin
- Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zekun Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Junjin Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xiuchao Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Kaiyuan Wang
- Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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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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13
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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: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [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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14
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Atherton MA, Park S, Horan NL, Nicholson S, Dolan JC, Schmidt BL, Scheff NN. Sympathetic modulation of tumor necrosis factor alpha-induced nociception in the presence of oral squamous cell carcinoma. Pain 2023; 164:27-42. [PMID: 35714327 PMCID: PMC9582047 DOI: 10.1097/j.pain.0000000000002655] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/08/2022] [Indexed: 01/09/2023]
Abstract
ABSTRACT Head and neck squamous cell carcinoma (HNSCC) causes more severe pain and psychological stress than other types of cancer. Despite clinical evidence linking pain, stress, and cancer progression, the underlying relationship between pain and sympathetic neurotransmission in oral cancer is unknown. We found that human HNSCC tumors and mouse tumor tissue are innervated by peripheral sympathetic and sensory nerves. Moreover, β-adrenergic 1 and 2 receptors (β-ARs) are overexpressed in human oral cancer cell lines, and norepinephrine treatment increased β-AR2 protein expression as well as cancer cell proliferation in vitro. We have recently demonstrated that inhibition of tumor necrosis factor alpha (TNFα) signaling reduces oral cancer-induced nociceptive behavior. Norepinephrine-treated cancer cell lines secrete more TNFα which, when applied to tongue-innervating trigeminal neurons, evoked a larger Ca 2+ transient; TNF-TNFR inhibitor blocked the increase in the evoked Ca 2+ transient. Using an orthotopic xenograft oral cancer model, we found that mice demonstrated significantly less orofacial cancer-induced nociceptive behavior during systemic β-adrenergic inhibitory treatment with propranolol. Furthermore, chemical sympathectomy using guanethidine led to a significant reduction in tumor size and nociceptive behavior. We infer from these results that sympathetic signaling modulates oral cancer pain through TNFα secretion and tumorigenesis. Further investigation of the role of neurocancer communication in cancer progression and pain is warranted.
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Affiliation(s)
- Megan A Atherton
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Stella Park
- Bluestone Center for Clinical Research, DDS Program, College of Dentistry, New York University, New York, NY, United States
| | - Nicole L Horan
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Samuel Nicholson
- Bluestone Center for Clinical Research, DDS Program, College of Dentistry, New York University, New York, NY, United States
| | - John C Dolan
- Bluestone Center for Clinical Research, DDS Program, College of Dentistry, New York University, New York, NY, United States
| | - Brian L Schmidt
- Bluestone Center for Clinical Research, DDS Program, College of Dentistry, New York University, New York, NY, United States
| | - Nicole N Scheff
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
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15
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Cascella M, Racca E, Nappi A, Coluccia S, Maione S, Luongo L, Guida F, Avallone A, Cuomo A. Bayesian Network Analysis for Prediction of Unplanned Hospital Readmissions of Cancer Patients with Breakthrough Cancer Pain and Complex Care Needs. Healthcare (Basel) 2022; 10:1853. [PMID: 36292299 PMCID: PMC9601725 DOI: 10.3390/healthcare10101853] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Unplanned hospital readmissions (HRAs) are very common in cancer patients. These events can potentially impair the patients' health-related quality of life and increase cancer care costs. In this study, data-driven prediction models were developed for identifying patients at a higher risk for HRA. METHODS A large dataset on cancer pain and additional data from clinical registries were used for conducting a Bayesian network analysis. A cohort of gastrointestinal cancer patients was selected. Logical and clinical relationships were a priori established to define and associate the considered variables including cancer type, body mass index (BMI), bone metastasis, serum albumin, nutritional support, breakthrough cancer pain (BTcP), and radiotherapy. RESULTS The best model (Bayesian Information Criterion) demonstrated that, in the investigated setting, unplanned HRAs are directly related to nutritional support (p = 0.05) and radiotherapy. On the contrary, BTcP did not significantly affect HRAs. Nevertheless, the correlation between variables showed that when BMI ≥ 25 kg/m2, the spontaneous BTcP is more predictive for HRAs. CONCLUSIONS Whilst not without limitations, a Bayesian model, combined with a careful selection of clinical variables, can represent a valid strategy for predicting unexpected HRA events in cancer patients. These findings could be useful for calibrating care interventions and implementing processes of resource allocation.
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Affiliation(s)
- Marco Cascella
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Napoli, Italy
- DIETI, University Federico II, 80100 Naples, Italy
| | - Emanuela Racca
- Clinical Sperimental Abdominal Oncology Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Napoli, Italy
| | - Anna Nappi
- Clinical Sperimental Abdominal Oncology Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Napoli, Italy
| | - Sergio Coluccia
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Napoli, Italy
| | - Sabatino Maione
- Department of Experimental Medicine, Division of Pharmacology, University of Campania Naples, 80138 Naples, Italy
- Neuromed, IRCCS Pozzilli, 86077 Pozzilli, Italy
| | - Livio Luongo
- Department of Experimental Medicine, Division of Pharmacology, University of Campania Naples, 80138 Naples, Italy
- Neuromed, IRCCS Pozzilli, 86077 Pozzilli, Italy
| | - Francesca Guida
- Department of Experimental Medicine, Division of Pharmacology, University of Campania Naples, 80138 Naples, Italy
| | - Antonio Avallone
- Clinical Sperimental Abdominal Oncology Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Napoli, Italy
| | - Arturo Cuomo
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Napoli, Italy
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16
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Yuan ZL, Liu XD, Zhang ZX, Li S, Tian Y, Xi K, Cai J, Yang XM, Liu M, Xing GG. Activation of GDNF-ERK-Runx1 signaling contributes to P2X3R gene transcription and bone cancer pain. iScience 2022; 25:104936. [PMID: 36072549 PMCID: PMC9441333 DOI: 10.1016/j.isci.2022.104936] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/15/2022] [Accepted: 08/10/2022] [Indexed: 11/24/2022] Open
Abstract
Bone cancer pain is a common symptom in cancer patients with bone metastases and its underlying mechanisms remain unknown. Here, we report that Runx1 directly upregulates the transcriptional activity of P2X3 receptor (P2X3R) gene promoter in PC12 cells. Knocking down Runx1 in dorsal root ganglion (DRG) neurons suppresses the functional upregulation of P2X3R, attenuates neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats, whereas overexpressing Runx1 promotes P2X3R gene transcription in DRG neurons, induces neuronal hyperexcitability and pain hypersensitivity in naïve rats. Activation of GDNF-GFRα1-Ret-ERK signaling is required for Runx1-mediated P2X3R gene transcription in DRG neurons, and contributes to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. These findings indicate that the Runx1-mediated P2X3R gene transcription resulted from activation of GDNF-GFRα1-Ret-ERK signaling contributes to the sensitization of DRG neurons and pathogenesis of bone cancer pain. Our findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients.
Runx1 directly upregulates the transcriptional activity of P2X3R gene promoter Upregulation of Runx1-mediated P2X3R gene transcription underlies bone cancer pain Involvement of GDNF-Ret-ERK signaling in Runx1-mediated P2X3R gene transcription
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17
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Qin T, Xiao Y, Qian W, Wang X, Gong M, Wang Q, An R, Han L, Duan W, Ma Q, Wang Z. HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis. Cell Death Dis 2022; 13:387. [PMID: 35449152 PMCID: PMC9023560 DOI: 10.1038/s41419-022-04799-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/22/2022] [Accepted: 03/30/2022] [Indexed: 12/13/2022]
Abstract
Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. However, the molecular mechanism of PNI remains unclear. The present study aimed to investigate the mechanism that HGF/c-Met pathway facilitates the PNI of pancreatic cancer. In this study, we confirmed that c-Met expression was correlated with PNI in pancreatic cancer tissues. Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI. Activating the HGF/c-Met signaling pathway also enhanced the migration and invasion ability of cancer cells to facilitate cancer cells invading nerves. Mechanistically, HGF/c-Met signaling pathway can active the mTOR/NGF axis to promote the PNI of pancreatic cancer. Additionally, we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo. Taken together, our findings suggest a supportive mechanism of the HGF/c-Met signaling pathway in promoting PNI by activating the mTOR/NGF axis in pancreatic cancer. Blocking the HGF/c-Met signaling pathway may be an effective target for the treatment of PNI.
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Affiliation(s)
- Tao Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xueni Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengyuan Gong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qiqi Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rui An
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Centre for Pancreatic Diseases of Xi'an Jiaotong University, Xi'an, China
| | - Wanxing Duan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Centre for Pancreatic Diseases of Xi'an Jiaotong University, Xi'an, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Centre for Pancreatic Diseases of Xi'an Jiaotong University, Xi'an, China.
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, China.
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Centre for Pancreatic Diseases of Xi'an Jiaotong University, Xi'an, China.
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, China.
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18
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Baraldi JH, Martyn GV, Shurin GV, Shurin MR. Tumor Innervation: History, Methodologies, and Significance. Cancers (Basel) 2022; 14:1979. [PMID: 35454883 PMCID: PMC9029781 DOI: 10.3390/cancers14081979] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/01/2022] [Accepted: 04/08/2022] [Indexed: 12/11/2022] Open
Abstract
The role of the nervous system in cancer development and progression has been under experimental and clinical investigation since nineteenth-century observations in solid tumor anatomy and histology. For the first half of the twentieth century, methodological limitations and opaque mechanistic concepts resulted in ambiguous evidence of tumor innervation. Differential spatial distribution of viable or disintegrated nerve tissue colocalized with neoplastic tissue led investigators to conclude that solid tumors either are or are not innervated. Subsequent work in electrophysiology, immunohistochemistry, pathway enrichment analysis, neuroimmunology, and neuroimmunooncology have bolstered the conclusion that solid tumors are innervated. Regulatory mechanisms for cancer-related neurogenesis, as well as specific operational definitions of perineural invasion and axonogenesis, have helped to explain the consensus observation of nerves at the periphery of the tumor signifying a functional role of nerves, neurons, neurites, and glia in tumor development.
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Affiliation(s)
- James H. Baraldi
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA;
| | - German V. Martyn
- Biomedical Studies Program, Chatham University, Pittsburgh, PA 15232, USA;
| | - Galina V. Shurin
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA;
| | - Michael R. Shurin
- Department of Pathology and Immunology, Division of Clinical Immunopathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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19
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Schmitd LB, Perez‐Pacheco C, D'Silva NJ. Nerve density in cancer: Less is better. FASEB Bioadv 2021; 3:773-786. [PMID: 34632313 PMCID: PMC8493966 DOI: 10.1096/fba.2021-00046] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
The density of nerves in cancer is emerging as a relevant clinical parameter for patient survival. Nerves in the tumor microenvironment have been associated with poor survival and recurrence, particularly if involved in perineural invasion. However, usually only a few nerves inside a tumor are affected by perineural invasion, while most nerves are not. Mechanistic studies have shown nerve-secreted factors promote tumor growth and invasion thereby making tumors more aggressive. Therefore, the overall number of nerves in the tumor microenvironment should be more representative of the nerve-tumor biological interaction than perineural invasion. This review summarizes the available clinical information about nerve density as a measure of clinical outcome in cancer and explores the mechanisms underlying nerve density in cancer, specifically, neurogenesis, axonogenesis, and neurotropism.
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Affiliation(s)
- Ligia B. Schmitd
- Department of Periodontics and Oral MedicineUniversity of Michigan School of DentistryAnn ArborMIUSA
| | - Cindy Perez‐Pacheco
- Department of Periodontics and Oral MedicineUniversity of Michigan School of DentistryAnn ArborMIUSA
| | - Nisha J. D'Silva
- Department of Periodontics and Oral MedicineUniversity of Michigan School of DentistryAnn ArborMIUSA
- Department of PathologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Rogel Cancer CenterUniversity of MichiganAnn ArborMIUSA
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20
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De Logu F, Marini M, Landini L, Souza Monteiro de Araujo D, Bartalucci N, Trevisan G, Bruno G, Marangoni M, Schmidt BL, Bunnett NW, Geppetti P, Nassini R. Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain. Cancer Res 2021; 81:3387-3401. [PMID: 33771895 DOI: 10.1158/0008-5472.can-20-3326] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 02/13/2021] [Accepted: 03/22/2021] [Indexed: 12/16/2022]
Abstract
Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3387/F1.large.jpg.
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Affiliation(s)
- Francesco De Logu
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
| | - Matilde Marini
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
| | - Lorenzo Landini
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
| | | | - Niccolò Bartalucci
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Gabriela Trevisan
- Graduated Program in Pharmacology, Federal University of Santa Maria (UFSM), Avenida Roraima, Santa Maria, Brazil
| | - Gennaro Bruno
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.,Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy
| | - Martina Marangoni
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
| | - Brian L Schmidt
- Department of Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, New York
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, College of Dentistry, Department of Neuroscience and Physiology, and Neuroscience Institute, School of Medicine, New York University, New York
| | - Pierangelo Geppetti
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.
| | - Romina Nassini
- Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy
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21
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Andriessen AS, Donnelly CR, Ji RR. Reciprocal interactions between osteoclasts and nociceptive sensory neurons in bone cancer pain. Pain Rep 2021; 6:e867. [PMID: 33981921 PMCID: PMC8108580 DOI: 10.1097/pr9.0000000000000867] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/10/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023] Open
Abstract
Many common cancers such as breast, prostate, and lung cancer metastasize to bones at advanced stages, producing severe pain and functional impairment. At present, the current pharmacotherapies available for bone cancer pain are insufficient to provide safe and efficacious pain relief. In this narrative review, we discuss the mechanisms used by cancer cells within the bone tumor microenvironment (TME) to drive bone cancer pain. In particular, we highlight the reciprocal interactions between tumor cells, bone-resorbing osteoclasts, and pain-sensing sensory neurons (nociceptors), which drive bone cancer pain. We discuss how tumor cells present within the bone TME accelerate osteoclast differentiation (osteoclastogenesis) and alter osteoclast activity and function. Furthermore, we highlight how this perturbed state of osteoclast overactivation contributes to bone cancer pain through (1) direct mechanisms, through their production of pronociceptive factors that act directly on sensory afferents; and (2) by indirect mechanisms, wherein osteoclasts drive bone resorption that weakens tumor-bearing bones and predisposes them to skeletal-related events, thereby driving bone cancer pain and functional impairment. Finally, we discuss some potential therapeutic agents, such as denosumab, bisphosphonates, and nivolumab, and discuss their respective effects on bone cancer pain, osteoclast overactivation, and tumor growth within the bone TME.
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Affiliation(s)
- Amanda S. Andriessen
- Department of Anesthesiology, Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC, USA
| | - Christopher R. Donnelly
- Department of Anesthesiology, Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC, USA
| | - Ru-Rong Ji
- Department of Anesthesiology, Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC, USA
- Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
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22
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Pineda-Farias JB, Saloman JL, Scheff NN. Animal Models of Cancer-Related Pain: Current Perspectives in Translation. Front Pharmacol 2021; 11:610894. [PMID: 33381048 PMCID: PMC7768910 DOI: 10.3389/fphar.2020.610894] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 10/30/2020] [Indexed: 01/15/2023] Open
Abstract
The incidence of pain in cancer patients during diagnosis and treatment is exceedingly high. Although advances in cancer detection and therapy have improved patient prognosis, cancer and its treatment-associated pain have gained clinical prominence. The biological mechanisms involved in cancer-related pain are multifactorial; different processes for pain may be responsible depending on the type and anatomic location of cancer. Animal models of cancer-related pain have provided mechanistic insights into the development and process of pain under a dynamic molecular environment. However, while cancer-evoked nociceptive responses in animals reflect some of the patients’ symptoms, the current models have failed to address the complexity of interactions within the natural disease state. Although there has been a recent convergence of the investigation of carcinogenesis and pain neurobiology, identification of new targets for novel therapies to treat cancer-related pain requires standardization of methodologies within the cancer pain field as well as across disciplines. Limited success of translation from preclinical studies to the clinic may be due to our poor understanding of the crosstalk between cancer cells and their microenvironment (e.g., sensory neurons, infiltrating immune cells, stromal cells etc.). This relatively new line of inquiry also highlights the broader limitations in translatability and interpretation of basic cancer pain research. The goal of this review is to summarize recent findings in cancer pain based on preclinical animal models, discuss the translational benefit of these discoveries, and propose considerations for future translational models of cancer pain.
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Affiliation(s)
- Jorge B Pineda-Farias
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Jami L Saloman
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Nicole N Scheff
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Hillman Cancer Center, University of Pittsburgh Medicine Center, Pittsburgh, PA, United States
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23
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Abboud C, Duveau A, Bouali-Benazzouz R, Massé K, Mattar J, Brochoire L, Fossat P, Boué-Grabot E, Hleihel W, Landry M. Animal models of pain: Diversity and benefits. J Neurosci Methods 2020; 348:108997. [PMID: 33188801 DOI: 10.1016/j.jneumeth.2020.108997] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 11/03/2020] [Accepted: 11/08/2020] [Indexed: 12/15/2022]
Abstract
Chronic pain is a maladaptive neurological disease that remains a major health problem. A deepening of our knowledge on mechanisms that cause pain is a prerequisite to developing novel treatments. A large variety of animal models of pain has been developed that recapitulate the diverse symptoms of different pain pathologies. These models reproduce different pain phenotypes and remain necessary to examine the multidimensional aspects of pain and understand the cellular and molecular basis underlying pain conditions. In this review, we propose an overview of animal models, from simple organisms to rodents and non-human primates and the specific traits of pain pathologies they model. We present the main behavioral tests for assessing pain and investing the underpinning mechanisms of chronic pathological pain. The validity of animal models is analysed based on their ability to mimic human clinical diseases and to predict treatment outcomes. Refine characterization of pathological phenotypes also requires to consider pain globally using specific procedures dedicated to study emotional comorbidities of pain. We discuss the limitations of pain models when research findings fail to be translated from animal models to human clinics. But we also point to some recent successes in analgesic drug development that highlight strategies for improving the predictive validity of animal models of pain. Finally, we emphasize the importance of using assortments of preclinical pain models to identify pain subtype mechanisms, and to foster the development of better analgesics.
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Affiliation(s)
- Cynthia Abboud
- Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France; Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France; Faculty of Arts and Sciences, Holy Spirit University of Kaslik (USEK), Lebanon
| | - Alexia Duveau
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Rabia Bouali-Benazzouz
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Karine Massé
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Joseph Mattar
- School of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Lebanon
| | - Louison Brochoire
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Pascal Fossat
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Eric Boué-Grabot
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Walid Hleihel
- School of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Lebanon; Faculty of Arts and Sciences, Holy Spirit University of Kaslik (USEK), Lebanon
| | - Marc Landry
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France.
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Bhattacharya A, Janal MN, Veeramachaneni R, Dolgalev I, Dubeykovskaya Z, Tu NH, Kim H, Zhang S, Wu AK, Hagiwara M, Kerr AR, DeLacure MD, Schmidt BL, Albertson DG. Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes. Sci Rep 2020; 10:14724. [PMID: 32895418 PMCID: PMC7477576 DOI: 10.1038/s41598-020-71298-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 08/10/2020] [Indexed: 12/11/2022] Open
Abstract
Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.
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Affiliation(s)
- Aditi Bhattacharya
- Bluestone Center for Clinical Research, New York University College of Dentistry, 421 First Avenue, Room 233W, New York, NY, 10010, USA.,Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, 10010, USA
| | - Malvin N Janal
- Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, NY, 10010, USA
| | - Ratna Veeramachaneni
- Bluestone Center for Clinical Research, New York University College of Dentistry, 421 First Avenue, Room 233W, New York, NY, 10010, USA.,Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, 10010, USA
| | - Igor Dolgalev
- Applied Bioinformatics Laboratories, New York University Langone Medical Center, New York, NY, 10016, USA
| | - Zinaida Dubeykovskaya
- Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, 10010, USA
| | - Nguyen Huu Tu
- Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, 10010, USA
| | - Hyesung Kim
- New York University College of Dentistry, New York, NY, 10010, USA
| | - Susanna Zhang
- New York University College of Dentistry, New York, NY, 10010, USA
| | - Angie K Wu
- Bluestone Center for Clinical Research, New York University College of Dentistry, 421 First Avenue, Room 233W, New York, NY, 10010, USA
| | - Mari Hagiwara
- Department of Radiology, New York University School of Medicine, New York, NY, 10016, USA
| | - A Ross Kerr
- Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University, New York, NY, 10010, USA
| | - Mark D DeLacure
- Division of Head and Neck Surgery and Oncology, New York University School of Medicine, New York, NY, 10016, USA
| | - Brian L Schmidt
- Bluestone Center for Clinical Research, New York University College of Dentistry, 421 First Avenue, Room 233W, New York, NY, 10010, USA.,Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, 10010, USA
| | - Donna G Albertson
- Bluestone Center for Clinical Research, New York University College of Dentistry, 421 First Avenue, Room 233W, New York, NY, 10010, USA. .,Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY, 10010, USA.
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25
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Nasrollahzadeh E, Razi S, Keshavarz-Fathi M, Mazzone M, Rezaei N. Pro-tumorigenic functions of macrophages at the primary, invasive and metastatic tumor site. Cancer Immunol Immunother 2020; 69:1673-1697. [PMID: 32500231 DOI: 10.1007/s00262-020-02616-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 05/16/2020] [Indexed: 12/19/2022]
Abstract
The tumor microenvironment (TME) not only facilitates cancer progression from the early formation to distant metastasis, but also it differs itself from time to time alongside the tumor evolution. Tumor-associated macrophages (TAMs), whether as pre-existing tissue-resident macrophages or recruited monocytes, are an inseparable part of this microenvironment. As their parents are broadly classified into a dichotomic, simplistic M1 and M2 subtypes, TAMs also exert paradoxical and diverse phenotypes as they are settled in different regions of TME and receive different microenvironmental signals. Briefly, M1 macrophages induce an inflammatory precancerous niche and flame the early oncogenic mutations, whereas their M2 counterparts are reprogrammed to release various growth factors and providing an immunosuppressive state in TME as long as abetting hypoxic cancer cells to set up a new vasculature. Further, they mediate stromal micro-invasion and co-migrate with invasive cancer cells to invade the vascular wall and neural sheath, while another subtype of TAMs prepares suitable niches much earlier than metastatic cells arrive at the target tissues. Accordingly, at the neoplastic transformation, during the benign-to-malignant transition and through the metastatic cascade, macrophages are involved in shaping the primary, micro-invasive and pre-metastatic TMEs. Whether their behavioral plasticity is derived from distinct genotypes or is fueled by microenvironmental cues, it could define these cells as remarkably interesting therapeutic targets.
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Affiliation(s)
- Elaheh Nasrollahzadeh
- School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Keshavarz-Fathi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, VIB, KU Leuven, Louvain, B3000, Belgium
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, 14194, Tehran, Iran. .,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. .,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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26
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Lohse I, Brothers SP. Pathogenesis and Treatment of Pancreatic Cancer Related Pain. Anticancer Res 2020; 40:1789-1796. [PMID: 32234867 DOI: 10.21873/anticanres.14133] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/18/2020] [Accepted: 02/19/2020] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer is often diagnosed due to the patient seeking medical attention for abdominal pain. It is among the most painful cancers, with pain severity strongly correlating with prognosis. Perineural invasion is a prominent feature of pancreatic cancer and often the first route of metastasis resulting in neuropathic pain. While surgical pain is present, it is generally short-lived; chemo- and radio-therapy associated side effect pain is often longer lasting and more difficult to manage. Treatment-induced mucositis in response to chemotherapy occurs throughout the GI tract resulting in infection-prone ulcers on the lip, buccal mucosa, palate or tongue. Cisplatin treatment is associated with axonal neuropathy in the dorsal root ganglion, although other large sensory fibers can be affected. Opioid-induced hyperalgesia can also emerge in patients. Along with traditional means to address pain, neurolytic celiac plexus block of afferent nociceptive fibers has been reported to be effective in 74% of patients. Moreover, as cancer treatments become more effective and result in improved survival, treatment-related side effects become more prevalent. Here, pancreatic cancer and treatment associated pain are reviewed along with current treatment strategies. Potential future therapeutic strategies to target the pathophysiology underlying pancreatic cancer and pain induction are also presented.
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Affiliation(s)
- Ines Lohse
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, U.S.A.,Department of Psychiatry and Behavioral Sciences, University of Miami, FL, U.S.A.,Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, FL, U.S.A
| | - Shaun P Brothers
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, U.S.A. .,Department of Psychiatry and Behavioral Sciences, University of Miami, FL, U.S.A.,Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, FL, U.S.A
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27
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Larson CM, Wilcox GL, Fairbanks CA. The Study of Pain in Rats and Mice. Comp Med 2019; 69:555-570. [PMID: 31822322 PMCID: PMC6935695 DOI: 10.30802/aalas-cm-19-000062] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/17/2019] [Accepted: 09/30/2019] [Indexed: 01/07/2023]
Abstract
Pain is a clinical syndrome arising from a variety of etiologies in a heterogeneous population, which makes successfully treating the individual patient difficult. Organizations and governments recognize the need for tailored and specific therapies, which drives pain research. This review summarizes the different types of pain assessments currently being used and the various rodent models that have been developed to recapitulate the human pain condition.
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Affiliation(s)
- Christina M Larson
- Comparative and Molecular Biosciences, University of Minnesota College of Veterinary Medicine, St Paul, Minnesota
| | - George L Wilcox
- Departments of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Carolyn A Fairbanks
- Departments of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota;,
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28
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The emergence of animal models of chronic pain and logistical and methodological issues concerning their use. J Neural Transm (Vienna) 2019; 127:393-406. [DOI: 10.1007/s00702-019-02103-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 11/07/2019] [Indexed: 12/12/2022]
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Saloman JL, Albers KM, Cruz-Monserrate Z, Davis BM, Edderkaoui M, Eibl G, Epouhe AY, Gedeon JY, Gorelick FS, Grippo PJ, Groblewski GE, Husain SZ, Lai KK, Pandol SJ, Uc A, Wen L, Whitcomb DC. Animal Models: Challenges and Opportunities to Determine Optimal Experimental Models of Pancreatitis and Pancreatic Cancer. Pancreas 2019; 48:759-779. [PMID: 31206467 PMCID: PMC6581211 DOI: 10.1097/mpa.0000000000001335] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
At the 2018 PancreasFest meeting, experts participating in basic research met to discuss the plethora of available animal models for studying exocrine pancreatic disease. In particular, the discussion focused on the challenges currently facing the field and potential solutions. That meeting culminated in this review, which describes the advantages and limitations of both common and infrequently used models of exocrine pancreatic disease, namely, pancreatitis and exocrine pancreatic cancer. The objective is to provide a comprehensive description of the available models but also to provide investigators with guidance in the application of these models to investigate both environmental and genetic contributions to exocrine pancreatic disease. The content covers both nongenic and genetically engineered models across multiple species (large and small). Recommendations for choosing the appropriate model as well as how to conduct and present results are provided.
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Affiliation(s)
- Jami L. Saloman
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Kathryn M. Albers
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Brian M. Davis
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Mouad Edderkaoui
- Basic and Translational Pancreas Research, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Ariel Y. Epouhe
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Jeremy Y. Gedeon
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Fred S. Gorelick
- Department of Internal Medicine, Section of Digestive Diseases & Department of Cell Biology Yale University School of Medicine; Veterans Affairs Connecticut Healthcare, West Haven, CT
| | - Paul J. Grippo
- Department of Medicine, Division of Gastroenterology and Hepatology, UI Cancer Center, University of Illinois at Chicago, Chicago, IL
| | - Guy E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI
| | | | - Keane K.Y. Lai
- Department of Pathology (National Medical Center), Department of Molecular Medicine (Beckman Research Institute), and Comprehensive Cancer Center, City of Hope, Duarte, CA
| | - Stephen J. Pandol
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Aliye Uc
- Stead Family Department of Pediatrics, University of Iowa, Stead Family Children’s Hospital, Iowa City, IA
| | - Li Wen
- Department of Pediatrics, Stanford University, Palo Alto, CA
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Mantyh PW. Mechanisms that drive bone pain across the lifespan. Br J Clin Pharmacol 2018; 85:1103-1113. [PMID: 30357885 DOI: 10.1111/bcp.13801] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 10/18/2018] [Accepted: 10/19/2018] [Indexed: 02/06/2023] Open
Abstract
Disorders of the skeleton are frequently accompanied by bone pain and a decline in the functional status of the patient. Bone pain occurs following a variety of injuries and diseases including bone fracture, osteoarthritis, low back pain, orthopedic surgery, fibrous dysplasia, rare bone diseases, sickle cell disease and bone cancer. In the past 2 decades, significant progress has been made in understanding the unique population of sensory and sympathetic nerves that innervate bone and the mechanisms that drive bone pain. Following physical injury of bone, mechanotranducers expressed by sensory nerve fibres that innervate bone are activated and sensitized so that even normally non-noxious loading or movement of bone is now being perceived as noxious. Injury of the bone also causes release of factors that; directly excite and sensitize sensory nerve fibres, upregulate proalgesic neurotransmitters, receptors and ion channels expressed by sensory neurons, induce ectopic sprouting of sensory and sympathetic nerve fibres resulting in a hyper-innervation of bone, and central sensitization in the brain that amplifies pain. Many of these mechanisms appear to be involved in driving both nonmalignant and malignant bone pain. Results from human clinical trials suggest that mechanism-based therapies that attenuate one type of bone pain are often effective in attenuating pain in other seemingly unrelated bone diseases. Understanding the specific mechanisms that drive bone pain in different diseases and developing mechanism-based therapies to control this pain has the potential to fundamentally change the quality of life and functional status of patients suffering from bone pain.
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Affiliation(s)
- Patrick W Mantyh
- Department of Pharmacology, University of Arizona, Tucson, AZ, USA.,Cancer Center, University of Arizona, Tucson, AZ, USA
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31
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Guo KK, Deng CQ, Lu GJ, Zhao GL. Comparison of analgesic effect of oxycodone and morphine on patients with moderate and advanced cancer pain: a meta-analysis. BMC Anesthesiol 2018; 18:132. [PMID: 30249205 PMCID: PMC6154420 DOI: 10.1186/s12871-018-0583-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 08/21/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Morphine and oxycodone are considered as wide-spreadly used opioids for moderate/severe cancer pain. However, debate exists about the evidence regarding their relative tolerability and underlying results. METHODS A systematic search of online electronic databases, including PubMed, Embase, Cochrane library updated on October 2017 were conducted. The meta-analysis was performed including the studies that were designed as randomized controlled trials. RESULTS In total, seven randomized clinical trials met our inclusion criteria. No statistical differences in analgesic effect between oxycodone and morphine were observed. Both the pooled analysis of API (MD =0.01, 95% CI -0.22 - 0.23; p = 0.96) and WPI (MD = - 0.05, 95% CI -0.21 - 0.30; p = 0.72) demonstrated clinical non-inferiority of the efficacy of morphine compared with oxycodone, respectively. Additionally, no significant difference in PRR response was observed in either oxycodone or morphine that were used in patients (MD =0.99, 95% CI -0.88 - 1.11; p = 0.87). With the pooled result of AEs indicating the comparable safety profiles between the 2 treatment groups, the meta-analysis on the nausea (OR = 1.20, 95% CI 0.90-1.59; p = 0.22), vomiting (OR = 1.33, 95% CI 0.75-2.38; p = 0.33), somnolence (OR = 1.35, 95% CI 0.95-1.93; p = 0.10), diarrhea (OR = 1.01, 95% CI 0.60-1,67; p = 0.98), and constipation (OR = 1.04, 95% CI 0.77-1.41; p = 0.79) was conducted, respectively. CONCLUSIONS In the current study, no remarkable difference was identified either in analgesic efficacy or in tolerability of oxycodone and morphine as the first-line therapy for patients with moderate to severe cancer pain. Thus, no sufficient clinical evidence on the superior effects of oxycodone to morphine was provided in this experimental hypothesis.
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Affiliation(s)
- Kai-Kai Guo
- Department of Pain Management, The Center of Anaesthetized Operation, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Cheng-Qi Deng
- Department of Anesthesiology, First Affiliated Hospital of General Hospital of PLA, Beijing, 100048, China
| | - Gui-Jun Lu
- Department of Pain Management, The Center of Anaesthetized Operation, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China.
| | - Guo-Li Zhao
- Department of Pain Management, The Center of Anaesthetized Operation, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
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Association Between Opioid Use and Survival Time in Patients With Unresectable Pancreatic Cancer: 10 Years of Clinical Experience. Pancreas 2018; 47:837-842. [PMID: 29939907 DOI: 10.1097/mpa.0000000000001094] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Patients with pancreatic cancer generally experience increasing pain as their disease progresses, making the titration of opioids difficult. This study aimed to determine a correlation between prescribed opioid doses and survival time in patients with unresectable pancreatic cancer. METHODS This retrospective observational cohort study in a tertiary care institution reviewed the medical records of patients diagnosed with unresectable pancreatic cancer and treated over a 10-year period. RESULTS We screened 1152 patients with unresectable pancreatic cancer, and 566 were eligible for inclusion in this study. There was a statistically significant negative correlation between initial opioid dose and survival time from initial opioid dose (correlation coefficient, -0.184; P < 0.01) and survival time from initial pancreatic cancer diagnosis (correlation coefficient, -0.177; P < 0.01). In addition, there were 0.8% and 0.6% increases in initial opioid dosage (morphine equivalent daily dose) and rate of increasing opioid dose (morphine equivalent daily dose per month), respectively, associated with the risk of early death (≤180 days, P < 0.05). CONCLUSIONS Correlations between patient survival, initial opioid dose, final opioid dose, and the rate of increase of opioid dosage could provide useful information for clinicians treating unresectable pancreatic cancer patients.
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Should functional renal scans be obtained prior to upper abdominal IMRT for pancreatic cancer? Pract Radiat Oncol 2017; 7:e449-e455. [PMID: 28886941 DOI: 10.1016/j.prro.2017.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/08/2017] [Accepted: 06/26/2017] [Indexed: 11/22/2022]
Abstract
BACKGROUND Upper abdominal irradiation for pancreatic cancer is administered in close proximity to the radiation-sensitive kidneys. There is difficulty in defining dose-volume parameters to predict late renal toxicity after partial kidney irradiation. Less than 10% of the general population is estimated to have asymmetrical kidney function; however, there are no studies that examine this in patients with pancreatic cancer. The primary purpose of this study was to determine the prevalence of asymmetrical kidney function in patients with pancreatic cancer. A secondary aim was to determine if asymmetrical kidney function was associated with abnormal laboratory values or kidney size on computed tomography scans. Finally, we aimed to develop recommendations for when a functional renal scan in patients with pancreatic cancer should be ordered. METHODS AND MATERIALS We performed a retrospective review of patients with resectable, borderline resectable, and locally advanced pancreatic cancer who received abdominal radiation therapy and had preradiation functional renal scans between 2009 and 2015. Asymmetrical kidney function was defined as a difference between the 2 kidneys that was ≥60%/40% on a functional renal scan. Serum studies (blood urea nitrogen [BUN], creatinine [Cr], and glomerular filtration rate [GFR]) and abdominal computed tomography scans were routinely obtained before simulation. RESULTS Of the 204 patients examined, 23 (11.2%) had asymmetrical kidney function that was identified on preradiation functional renal scans. Elevated Cr or BUN, a GFR <60, or a medical history that suggested abnormal renal function were not significantly associated with asymmetrical kidney function. Only 6 of 23 patients (26%) with asymmetrical kidney function had a notable difference in kidney size. CONCLUSIONS In our series, approximately 11% of patients with pancreatic cancer have asymmetrical kidney function that was not identified by kidney size, serum BUN, Cr, GFR, or a significant medical history. These data suggest that in cases in which renal radiation doses exceed a V18 of 20% to 30% or there is concern about baseline renal function, a functional renal scan should be considered.
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Sarabia-Estrada R, Ruiz-Valls A, Guerrero-Cazares H, Ampuero AM, Jimenez-Estrada I, De Silva S, Bernhardt LJ, Goodwin CR, Ahmed AK, Li Y, Phillips NA, Gokaslan ZL, Quiñones-Hinojosa A, Sciubba DM. Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents. Spine J 2017; 17:1325-1334. [PMID: 28412561 PMCID: PMC5628502 DOI: 10.1016/j.spinee.2017.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/10/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. PURPOSE The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. STUDY DESIGN/SETTING This is a basic science study. METHODS Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. RESULTS Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. CONCLUSIONS We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis.
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Affiliation(s)
| | - Alejandro Ruiz-Valls
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Ana M. Ampuero
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ismael Jimenez-Estrada
- Physiology, Biophysics and Neurosciences, Research Center and Advanced Studies, IPN, Mexico City, MEXICO
| | - Samantha De Silva
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lydia J. Bernhardt
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - C. Rory Goodwin
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - A. Karim Ahmed
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yuxin Li
- Department of Neurosurgery, Jinan General Hospital of PLA, Jinan, 250031, CHINA
| | - Neil A. Phillips
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ziya L. Gokaslan
- Department of Neurosurgery, The Warren Alpert Medical School of Brown University Providence, Rhode Island, USA
| | | | - Daniel M. Sciubba
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Austin M, Elliott L, Nicolaou N, Grabowska A, Hulse RP. Breast cancer induced nociceptor aberrant growth and collateral sensory axonal branching. Oncotarget 2017; 8:76606-76621. [PMID: 29100335 PMCID: PMC5652729 DOI: 10.18632/oncotarget.20609] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 08/15/2017] [Indexed: 12/11/2022] Open
Abstract
The tumour and neuron interaction has a significant impact upon disease progression and the patients quality of life. In breast cancer patients, it is known that there is an interaction between the tumour microenvironment and the sensory neurons to influence the progression of cancer as well as pain, though these mechanisms still need to be clearly defined. Here it is demonstrated that in a rodent orthotopic model of breast cancer (MDA MB 231) there was an increase in nerve fibre innervation into the tumour microenvironment (protein gene product 9.5), which were calcitonin gene related peptide positive C fibre nociceptors. In contrast, there was a reduction in myelinated nerve fibres (NF200). A sensory neuronal cell line was cultured in response to conditioned media from MDA MB231 and MCF7 as well as vascular endothelial growth factor-A (VEGF-A). All these experimental conditions induced sensory neuronal growth, with increased formation of collateral axonal branches. Furthermore, it was demonstrated that MDA MB231 and VEGF-A induced sensory neuronal sensitisation in response to capsaicin a TRPV1 agonist. MDA MB231 induced neuronal growth was suppressed by VEGFR2 inhibition (ZM323881 and neutralising antibody DC101), in addition both MDA MB231 and VEGF-A induced neurite growth was attenuated by the inhibition of ARP2/3 complex through co-treatment with CK666. This demonstrates that breast cancer can interact with the sensory nervous system to drive neuritogenesis through a VEGF-A/VEGFR2/ARP2/3 mediated pathway.
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Affiliation(s)
- Matt Austin
- Cancer Biology, School of Cancer and Stem Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Laura Elliott
- Cancer Biology, School of Cancer and Stem Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Niovi Nicolaou
- Cancer Biology, School of Cancer and Stem Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Anna Grabowska
- Cancer Biology, School of Cancer and Stem Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Richard P Hulse
- Cancer Biology, School of Cancer and Stem Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom
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Zhu J, Miao XR, Tao KM, Zhu H, Liu ZY, Yu DW, Chen QB, Qiu HB, Lu ZJ. Trypsin-protease activated receptor-2 signaling contributes to pancreatic cancer pain. Oncotarget 2017; 8:61810-61823. [PMID: 28977906 PMCID: PMC5617466 DOI: 10.18632/oncotarget.18696] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 05/05/2017] [Indexed: 01/13/2023] Open
Abstract
Pain treatment is a critical aspect of pancreatic cancer patient clinical care. This study investigated the role of trypsin-protease activated receptor-2 (PAR-2) in pancreatic cancer pain. Pancreatic tissue samples were collected from pancreatic cancer (n=22) and control patients (n=22). Immunofluorescence analyses confirmed colocalization of PAR-2 and neuronal markers in pancreatic cancer tissues. Trypsin levels and protease activities were higher in pancreatic cancer tissue specimens than in the controls. Supernatants from cultured human pancreatic cancer tissues (PC supernatants) induced substance P and calcitonin gene-related peptide release in dorsal root ganglia (DRG) neurons, and FS-NH2, a selective PAR-2 antagonist, inhibited this effect. A BALB/c nude mouse orthotopic tumor model was used to confirm the role of PAR-2 signaling in pancreatic cancer visceral pain, and male Sprague-Dawley rats were used to assess ambulatory pain. FS-NH2 treatment decreased hunch scores, mechanical hyperalgesia, and visceromotor reflex responses in tumor-bearing mice. In rats, subcutaneous injection of PC supernatant induced pain behavior, which was alleviated by treatment with FS-NH2 or FUT-175, a broad-spectrum serine protease inhibitor. Our findings suggest that trypsin-PAR-2 signaling contributes to pancreatic cancer pain in vivo. Treatment strategies targeting PAR-2 or its downstream signaling molecules might effectively relieve pancreatic cancer pain.
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Affiliation(s)
- Jiao Zhu
- Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Xue-Rong Miao
- Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Kun-Ming Tao
- Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Hai Zhu
- Department of Anesthesiology, Maternity and Infant Health Hospital of Putuo District, Shanghai 200062, China
| | - Zhi-Yun Liu
- Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Da-Wei Yu
- Department of Anesthesiology, No.101 hospital of PLA, Wuxi 214000, China
| | - Qian-Bo Chen
- Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Hai-Bo Qiu
- Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zhi-Jie Lu
- Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
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Tan X, Camacho TF, LeBaron VT, Blackhall LJ, Balkrishnan R. Opioid use among female breast cancer patients using different adjuvant endocrine therapy regimens. Breast Cancer Res Treat 2017. [PMID: 28639031 DOI: 10.1007/s10549-017-4348-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
PURPOSE To explore differences in opioid use across different adjuvant endocrine therapy (AET) regimens, factors associated with opioid use, and the impact of opioid use on overall survival in female breast cancer patients treated with AET. METHODS This retrospective study analyzed 2006-2012 SEER-Medicare datasets, following patients for at least two years from the index date, defined as the first date they filled an AET prescription. The study included adult women with incident, primary, hormone-receptor-positive, stage I-III breast cancer. They were also first-time AET users, and fee-for-service Medicare enrollees continuously enrolled in Medicare Parts A, B, and D. The main independent variable was the AET regimen. We measured whether patients used opioids after the initiation of AET. RESULTS After the adjustment of inverse probability treatment weights and unbalanced covariates, the average treatment effect probabilities of opioid use were similar between those who used aromatase inhibitors (AI) only and those used tamoxifen (TAM) only (56.2 vs. 55.3%, respectively). Opioid use probabilities for those who switched from AI to TAM were higher than those for the TAM-only and AI-only groups. Opioid use was also significantly associated with AET non-adherence. Opioid users had a significantly higher risk of death (adjusted hazard ratio [HR] = 1.59, p < 0.001). CONCLUSIONS Switching from AI to TAM was associated with a high likelihood of opioid use. Opioid use was significantly associated with AET non-adherence and higher risk of mortality in female Medicare beneficiaries with breast cancer even after adjusting for adherence.
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Affiliation(s)
- Xi Tan
- Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV, USA
| | - Tareq Fabian Camacho
- Department of Public Health Sciences, School of Medicine, University of Virginia, 560 Ray C. Hunt Drive, Charlottesville, VA, 22903, USA
| | - Virginia T LeBaron
- Department of Acute & Specialty Care, School of Nursing, University of Virginia, Charlottesville, VA, USA
| | - Leslie J Blackhall
- Department of Internal Medicine, School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Rajesh Balkrishnan
- Department of Public Health Sciences, School of Medicine, University of Virginia, 560 Ray C. Hunt Drive, Charlottesville, VA, 22903, USA.
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Saloman JL, Albers KM, Rhim AD, Davis BM. Can Stopping Nerves, Stop Cancer? Trends Neurosci 2016; 39:880-889. [PMID: 27832915 DOI: 10.1016/j.tins.2016.10.002] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 10/10/2016] [Accepted: 10/13/2016] [Indexed: 02/07/2023]
Abstract
The nervous system is viewed as a tissue affected by cancer and as a conduit for the transmission of cancer pain and perineural invasion. Here, we review recent studies that indicate a more direct role. Several studies have shown that reducing stress or suppressing sympathetic drive correlates with improved outcomes and prolonged survival. Recent studies using animal models of visceral and somatic cancer further support a role for the nervous system in cancer progression. Specifically, nerve ablation had a profound impact on disease progression, including delayed development of precancerous lesions, and decreased tumor growth and metastasis. In this review, we summarize new evidence and discuss how future studies may address the role of neural signaling in the modulation of tumorigenesis.
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Affiliation(s)
- Jami L Saloman
- University of Pittsburgh, Center for Pain Research and Department of Neurobiology, Pittsburgh, PA 15261, USA.
| | - Kathryn M Albers
- University of Pittsburgh, Center for Pain Research and Department of Neurobiology, Pittsburgh, PA 15261, USA
| | - Andrew D Rhim
- Zayed Center for Pancreatic Cancer Research and Department of Gastroenterology, Hepatology and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Brian M Davis
- University of Pittsburgh, Center for Pain Research and Department of Neurobiology, Pittsburgh, PA 15261, USA
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40
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Nowara E, Huszno J. Masitinib plus gemcitabine for personalized treatment of PDAC patients with overexpression of ACOX1. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2016. [DOI: 10.1080/23808993.2016.1257911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Elzbieta Nowara
- Clinical and Experimental Chemotherapy Department, Cancer Center and Institution of Oncology, Gliwice, Poland
| | - Joanna Huszno
- Clinical and Experimental Chemotherapy Department, Cancer Center and Institution of Oncology, Gliwice, Poland
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41
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Lahoud MJ, Kourie HR, Antoun J, El Osta L, Ghosn M. Road map for pain management in pancreatic cancer: A review. World J Gastrointest Oncol 2016; 8:599-606. [PMID: 27574552 PMCID: PMC4980650 DOI: 10.4251/wjgo.v8.i8.599] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 03/25/2016] [Accepted: 05/13/2016] [Indexed: 02/05/2023] Open
Abstract
Beside its poor prognosis and its late diagnosis, pancreatic cancer remains one of the most painful malignancies. Optimal management of pain in this cancer represents a real challenge for the oncologist whose objective is to ensure a better quality of life to his patients. We aimed in this paper to review all the treatment modalities incriminated in the management of pain in pancreatic cancer going from painkillers, chemotherapy, radiation therapy and interventional techniques to agents under investigation and alternative medicine. Although specific guidelines and recommendations for pain management in pancreatic cancer are still absent, we present all the possible pain treatments, with a progression from medical multimodal treatment to radiotherapy and chemotherapy then interventional techniques in case of resistance. In addition, alternative methods such as acupuncture and hypnosis can be added at any stage and seems to contribute to pain relief.
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Abstract
The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.
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Affiliation(s)
- Moran Amit
- Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel
| | - Shorook Na'ara
- Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel
| | - Ziv Gil
- Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel
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43
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Saloman JL, Albers KM, Li D, Hartman DJ, Crawford HC, Muha EA, Rhim AD, Davis BM. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc Natl Acad Sci U S A 2016; 113:3078-83. [PMID: 26929329 PMCID: PMC4801275 DOI: 10.1073/pnas.1512603113] [Citation(s) in RCA: 258] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.
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MESH Headings
- Adenocarcinoma in Situ/pathology
- Adenocarcinoma in Situ/physiopathology
- Afferent Pathways
- Animals
- Animals, Newborn
- Capsaicin/administration & dosage
- Capsaicin/pharmacology
- Capsaicin/therapeutic use
- Carcinoma, Pancreatic Ductal/etiology
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/physiopathology
- Carcinoma, Pancreatic Ductal/prevention & control
- Carcinoma, Pancreatic Ductal/therapy
- Ceruletide/toxicity
- Denervation
- Disease Progression
- Female
- Ganglia, Sympathetic/physiopathology
- Genes, ras
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Myelitis/complications
- Myelitis/genetics
- Myelitis/physiopathology
- Neoplasm Invasiveness
- Pancreas/innervation
- Pancreatic Neoplasms/etiology
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/physiopathology
- Pancreatic Neoplasms/prevention & control
- Pancreatic Neoplasms/therapy
- Pancreatitis/chemically induced
- Pancreatitis/complications
- Pancreatitis/physiopathology
- Precancerous Conditions/chemically induced
- Precancerous Conditions/complications
- Precancerous Conditions/physiopathology
- Sensory Receptor Cells/drug effects
- Sensory Receptor Cells/physiology
- Spinal Cord/physiopathology
- Spinothalamic Tracts/physiopathology
- Thoracic Vertebrae
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Affiliation(s)
- Jami L Saloman
- Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261
| | - Kathryn M Albers
- Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261
| | - Dongjun Li
- Comprehensive Cancer Center and Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109
| | - Douglas J Hartman
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
| | - Howard C Crawford
- Department of Internal Medicine, Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109
| | - Emily A Muha
- Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261
| | - Andrew D Rhim
- Comprehensive Cancer Center and Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
| | - Brian M Davis
- Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261;
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Slosky LM, Largent-Milnes TM, Vanderah TW. Use of Animal Models in Understanding Cancer-induced Bone Pain. CANCER GROWTH AND METASTASIS 2015; 8:47-62. [PMID: 26339191 PMCID: PMC4552039 DOI: 10.4137/cgm.s21215] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 06/14/2015] [Accepted: 06/16/2015] [Indexed: 12/13/2022]
Abstract
Many common cancers have a propensity to metastasize to bone. Although malignancies often go undetected in their native tissues, bone metastases produce excruciating pain that severely compromises patient quality of life. Cancer-induced bone pain (CIBP) is poorly managed with existing medications, and its multifaceted etiology remains to be fully elucidated. Novel analgesic targets arise as more is learned about this complex and distinct pain state. Over the past two decades, multiple animal models have been developed to study CIBP’s unique pathology and identify therapeutic targets. Here, we review animal models of CIBP and the mechanistic insights gained as these models evolve. Findings from immunocompromised and immunocompetent host systems are discussed separately to highlight the effect of model choice on outcome. Gaining an understanding of the unique neuromolecular profile of cancer pain through the use of appropriate animal models will aid in the development of more effective therapeutics for CIBP.
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Affiliation(s)
- Lauren M Slosky
- Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Tally M Largent-Milnes
- Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Todd W Vanderah
- Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA
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45
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Bhatnagar S, Gupta M. Evidence-based Clinical Practice Guidelines for Interventional Pain Management in Cancer Pain. Indian J Palliat Care 2015; 21:137-47. [PMID: 26009665 PMCID: PMC4441173 DOI: 10.4103/0973-1075.156466] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Intractable cancer pain not amenable to standard oral or parenteral analgesics is a horrifying truth in 10-15% of patients. Interventional pain management techniques are an indispensable arsenal in pain physician's armamentarium for severe, intractable pain and can be broadly classified into neuroablative and neuromodulation techniques. An array of neurolytic techniques (chemical, thermal, or surgical) can be employed for ablation of individual nerve fibers, plexuses, or intrathecalneurolysis in patients with resistant pain and short life-expectancy. Neuraxial administration of drugs and spinal cord stimulation to modulate or alter the pain perception constitutes the most frequently employed neuromodulation techniques. Lately, there is a rising call for early introduction of interventional techniques in carefully selected patients simultaneously or even before starting strong opioids. After decades of empirical use, it is the need of the hour to head towards professionalism and standardization in order to secure credibility of specialization and those practicing it. Even though the interventional management has found a definite place in cancer pain, there is a dearth of evidence-based practice guidelines for interventional therapies in cancer pain. This may be because of paucity of good quality randomized controlled trials (RCTs) evaluating their safety and efficacy in cancer pain. Laying standardized guidelines based on existing and emerging evidence will act as a foundation step towards strengthening, credentialing, and dissemination of the specialty of interventional cancer pain management. This will also ensure an improved decision-making and quality of life (QoL) of the suffering patients.
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Affiliation(s)
- Sushma Bhatnagar
- Department of Onco-Anaesthesia, Pain and Palliative Care, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Maynak Gupta
- Department of Anaesthesia, Shri Guru Rai Institute of Medical and Health Sciences, Shri Mahant Indiresh Hospital, Dehradun, Uttarakhand, India
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MiRNA-615-5p functions as a tumor suppressor in pancreatic ductal adenocarcinoma by targeting AKT2. PLoS One 2015; 10:e0119783. [PMID: 25856297 PMCID: PMC4391776 DOI: 10.1371/journal.pone.0119783] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 01/16/2015] [Indexed: 12/25/2022] Open
Abstract
Background Aberrant microRNA (miRNA) expression is associated with tumor development. This study aimed to elucidate the role of miR-615-5p in the development of pancreatic ductal adenocarcinoma (PDAC). Methods Locked nucleic acid in situ hybridization (LNA-ISH) was performed to compare miR-615-5p expression in patients between PDAC and matched adjacent normal tissues. Effects of miR-615-5p overexpression on cell proliferation, apoptosis, colony formation, migration, and invasion were determined in the pancreatic cancer cell lines PANC-1 and MIA PaCa-2. Effects of miR-615-5p on AKT2 were examined by dual-luciferase reporter assay. Lentivirus expressing miR-615 was used to create stable overexpression cell lines, which were subsequently used in mouse xenograft and metastasis models to assess tumor growth, apoptosis and metastasis. Results miR-615-5p expression was significantly lower in PDAC than in adjacent normal tissues. Low levels of miR-615-5p were independently associated with poor prognosis (HR: 2.243, 95% CI: 1.190-4.227, P=0.013). AKT2 protein expression was inversely correlated with miR-615-5p expression (r=-0.3, P=0.003). miR-615-5p directly targeted the 3’-untranslated region of AKT2 mRNA and repressed its expression. miR-615-5p overexpression inhibited pancreatic cancer cell proliferation, migration, and invasion in vitro, and tumor growth and metastasis in vivo. Furthermore, miR-615-5p overexpression also induced pancreatic cancer cell apoptosis both in vitro and in vivo. Conclusions These results show that miR-615-5p inhibits pancreatic cancer cell proliferation, migration, and invasion by targeting AKT2. The data implicate miR-615-5p in the prognosis and treatment of PDAC.
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47
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The power of automated behavioural homecage technologies in characterizing disease progression in laboratory mice: A review. Appl Anim Behav Sci 2015. [DOI: 10.1016/j.applanim.2014.11.018] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Secq V, Leca J, Bressy C, Guillaumond F, Skrobuk P, Nigri J, Lac S, Lavaut MN, Bui TT, Thakur AK, Callizot N, Steinschneider R, Berthezene P, Dusetti N, Ouaissi M, Moutardier V, Calvo E, Bousquet C, Garcia S, Bidaut G, Vasseur S, Iovanna JL, Tomasini R. Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling. Cell Death Dis 2015; 6:e1592. [PMID: 25590802 PMCID: PMC4669755 DOI: 10.1038/cddis.2014.557] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 11/10/2014] [Accepted: 11/20/2014] [Indexed: 02/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/β-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.
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Affiliation(s)
- V Secq
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
- Department of Pathology, Hospital North/Mediterranean University, Marseille, France
| | - J Leca
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - C Bressy
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - F Guillaumond
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - P Skrobuk
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - J Nigri
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - S Lac
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - M-N Lavaut
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
- Department of Pathology, Hospital North/Mediterranean University, Marseille, France
| | - T-t Bui
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - A K Thakur
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - N Callizot
- Neuronexperts, Medical North Faculty, Marseille, France
| | | | - P Berthezene
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - N Dusetti
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - M Ouaissi
- Aix-Marseille University, INSERM, CRO2, UMR 911, Marseille 13385, France
| | - V Moutardier
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - E Calvo
- Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec City, QCue, Canada
| | - C Bousquet
- INSERM UMR 1037, CRCT, University Toulouse III, Toulouse, France
| | - S Garcia
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
- Department of Pathology, Hospital North/Mediterranean University, Marseille, France
| | - G Bidaut
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - S Vasseur
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - J L Iovanna
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
| | - R Tomasini
- CRCM, Cellular Stress, INSERM, U1068, Parc scientifique de Luminy, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, CNRS, UMR7258, Marseille 13009, France
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49
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Chang WP, Lin CC. Use of opioid analgesics or sleeping medication and survival of cancer patients. Eur J Oncol Nurs 2014; 19:199-206. [PMID: 25553718 DOI: 10.1016/j.ejon.2014.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 11/07/2014] [Accepted: 11/13/2014] [Indexed: 01/15/2023]
Abstract
PURPOSE OF THE RESEARCH Pain and sleep disturbance have been shown to have a profound influence on the outcomes of cancer treatment. This study sought to determine whether administering opioid analgesics or sleeping medication to cancer patients during their first admission to a hospital is associated with poor prognoses. METHODS AND SAMPLE We conducted a population-based retrospective cohort study by analyzing data obtained from the National Health Insurance Research Database in Taiwan. The study population comprised cancer patients whose first admission to a hospital for initial cancer treatment was in 2004. KEY RESULTS We collected data on 2302 cancer patients. To analyze the effect of opioid analgesic and sleeping medication usage on cancer patient survival, we compared the 3-year survival rates among 4 groups of patients (no use, sleeping medications-only, opioid analgesics-only, both used). The 3-year Kaplan-Meier plots for these 4 groups show that the difference was statistically significant (log rank 48.244, p < 0.001). The longevity of cancer patients was the greatest among the no-use group, followed by the sleeping medications-only group, then the opioid analgesics-only group, and finally, the group in which both sleeping medications and opioid analgesics were used. CONCLUSIONS The use of opioid analgesics or sleeping medication was shown to be negatively correlated with the survival rate of cancer patients.
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Affiliation(s)
- Wen-Pei Chang
- Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan; Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, Taipei, Taiwan
| | - Chia-Chin Lin
- School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan.
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50
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Stopczynski RE, Normolle DP, Hartman DJ, Ying H, DeBerry JJ, Bielefeldt K, Rhim AD, DePinho RA, Albers KM, Davis BM. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res 2014; 74:1718-27. [PMID: 24448244 DOI: 10.1158/0008-5472.can-13-2050] [Citation(s) in RCA: 144] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Perineural tumor invasion of intrapancreatic nerves, neurogenic inflammation, and tumor metastases along extrapancreatic nerves are key features of pancreatic malignancies. Animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. Although genetic mutations are required for cancer development, inflammation has been shown to be a precipitating event that can accelerate the transition of precancerous lesions to cancer. These observations led us to hypothesize that inflammation that accompanies early phases of pancreatic ductal adenocarcinoma (PDAC) would produce pathologic changes in pancreatic neurons and innervation. Using a lineage-labeled genetically engineered mouse model of PDAC, we found that pancreatic neurotrophic factor mRNA expression and sensory innervation increased dramatically when only pancreatic intraepithelial neoplasia were apparent. These changes correlated with pain-related decreases in exploratory behavior and increased expression of nociceptive genes in sensory ganglia. At later stages, cells of pancreatic origin could be found in the celiac and sensory ganglia along with metastases to the spinal cord. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede the appearance of cancer.
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Affiliation(s)
- Rachelle E Stopczynski
- Authors' Affiliations: Departments of Neurobiology, Biostatistics, Pathology, and Medicine, University of Pittsburgh School of Medicine; Departments of Genomic Medicine and Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
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