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Chen CH, Reva B, Katabi N, Wizel A, Xu H, Ho AL, Morris LG, Bakst RL, Parikh AS, Drier Y, Deborde S, Wong RJ. Sympathetic axonogenesis promotes adenoid cystic carcinoma progression. J Exp Med 2025; 222:e20242250. [PMID: 40272482 PMCID: PMC12020745 DOI: 10.1084/jem.20242250] [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: 11/26/2024] [Revised: 02/07/2025] [Accepted: 03/12/2025] [Indexed: 04/25/2025] Open
Abstract
Nerves are integral to the adenoid cystic carcinoma (ACC) microenvironment. The strong association of ACC with perineural invasion (PNI) is considered a hallmark of this disease. In human salivary ACC, we identify intratumoral, small-caliber, disorganized sympathetic nerves not observed in other salivary neoplasms. Norepinephrine or sympathetic ganglia explants enhance ACC proliferation in vitro. Two novel orthotopic ACC patient-derived xenograft (PDX) models recapitulate ACC morphology and demonstrate sympathetic innervation. Pharmacologic or surgical blockade of sympathetic nerves decreases ACC PDX growth. Bulk RNA sequencing of salivary ACC reveals correlations between noradrenergic nerve development signatures and worse patient survival. Metastatic ACC foci exhibit lower nerve signature gene expression levels than primary ACC. Sympathetic innervation in ACC is distinct from PNI and reflects tumor axonogenesis driven by noradrenergic neural development programs. These programs support ACC progression, are associated with poor prognosis, and may be inhibited as a therapeutic strategy.
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Affiliation(s)
- Chun-Hao Chen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Boris Reva
- Department of Genetics and Genomic Sciences, Mount Sinai Medical Center, New York, NY, USA
| | - Nora Katabi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Avishai Wizel
- The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hongbo Xu
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Alan L. Ho
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Luc G.T. Morris
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Richard L. Bakst
- Department of Radiation Oncology, Mount Sinai Medical Center, New York, NY, USA
| | - Anuraag S. Parikh
- Department of Otolaryngology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Yotam Drier
- The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Sylvie Deborde
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Richard J. Wong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Tiwari RK, Rawat SG, Rai S, Kumar A. Stress regulatory hormones and cancer: the contribution of epinephrine and cancer therapeutic value of beta blockers. Endocrine 2025; 88:359-386. [PMID: 39869294 DOI: 10.1007/s12020-025-04161-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 01/08/2025] [Indexed: 01/28/2025]
Abstract
The word "cancer" evokes myriad emotions, ranging from fear and despair to hope and determination. Cancer is aptly defined as a complex and multifaceted group of diseases that has unapologetically led to the loss of countless lives and affected innumerable families across the globe. The battle with cancer is not only a physical battle, but also an emotional, as well as a psychological skirmish for patients and for their loved ones. Cancer has been a part of our history, stories, and lives for centuries and has challenged the ingenuity of health and medical science, and the resilience of the human spirit. From the early days of surgery and radiation therapy to cutting-edge developments in chemotherapeutic agents, immunotherapy, and targeted treatments, the medical field continues to make significant headway in the fight against cancer. However, even after all these advancements, cancer is still among the leading cause of death globally. This urges us to understand the central hallmarks of neoplastic cells to identify novel molecular targets for the development of promising therapeutic approaches. Growing research suggests that stress mediators, including epinephrine, play a critical role in the development and progression of cancer by inducing neoplastic features through activating adrenergic receptors, particularly β-adrenoreceptors. Further, our experimental data has also shown that epinephrine mediates the growth of T-cell lymphoma by inducing proliferation, glycolysis, and apoptosis evasion via altering the expression levels of key regulators of these vital cellular processes. The beauty of receptor-based therapy lies in its precision and higher therapeutic value. Interestingly, the enhanced expression of β-adrenergic receptors (ADRBs), namely ADRB2 (β2-adrenoreceptor) and ADRB3 (β3-adrenoreceptor) has been noted in many cancers, such as breast, colon, gastric, pancreatic, and prostate and has been reported to play a pivotal role in facilitating cancer growth mainly by promoting proliferation, evasion of apoptosis, angiogenesis, invasion and metastasis, and chemoresistance. The present review article is an attempt to summarize the available findings which indicate a distinct relationship between stress hormones and cancer, with a special emphasis on epinephrine, considered as a key stress regulatory molecule. This article also discusses the possibility of using beta-blockers for cancer therapy.
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Affiliation(s)
- Rajan Kumar Tiwari
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- School of Medicine and Health Sciences, The George Washington University, Washington DC, USA
| | - Shiv Govind Rawat
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- MD Anderson Cancer Center, The University of Texas, Texas, USA
| | - Siddharth Rai
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ajay Kumar
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
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Liao S, Kang K, Yao Z, Lu Y. Nervous system contributions to small cell lung cancer: Lessons from diverse oncological studies. Biochim Biophys Acta Rev Cancer 2025; 1880:189252. [PMID: 39725176 DOI: 10.1016/j.bbcan.2024.189252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 12/05/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
The nervous system plays a vital role throughout the entire lifecycle and it may regulate the formation, development and metastasis of tumors. Small cell lung cancer is a typical neuroendocrine tumor, and it is naturally equipped with neurotropism. In this review, we firstly summarize current preclinical and clinical evidence to demonstrate the reciprocal crosstalk among the nervous system, tumor, and tumor microenvironment in various ways, including neurotransmitter-receptor pathways, innervations of nerve fibers, different types of synapse formation by neurons, astrocytes, and cancer cells, neoneurogenesis. Futherly, we emphasize how the nervous system interacts with small cell lung cancer and discuss the limitations of current research methods for examining the interactions. We propose that integrating neuroscience, development biology, and tumor biology can be a promising direction to provide new insights into development and metastasis of small cell lung cancer and raise some novel treatment strategies.
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Affiliation(s)
- Shuangsi Liao
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Kai Kang
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhuoran Yao
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China.
| | - You Lu
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China.
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Kawaguchi Y, Okamoto K, Kataoka Y, Shibata K, Saito H, Shiratori T, Ueda K, Ohshio Y, Hanaoka J. Increasing monocytes after lung cancer surgery triggers the outgrowth of distant metastases, causing recurrence. Cancer Immunol Immunother 2024; 73:212. [PMID: 39235612 PMCID: PMC11377378 DOI: 10.1007/s00262-024-03800-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 08/05/2024] [Indexed: 09/06/2024]
Abstract
Patients with lung cancer have a high incidence of tumor recurrence even after curative surgical resection. Some reports indicated that immunosuppressive cells induced by surgical stress could contribute to tumor recurrence after surgery; however, the underlying mechanisms are not fully understood. In this study, we found that increased postoperative blood monocytes served as a risk factor for tumor recurrence in 192 patients with non-small cell lung cancer (NSCLC). We established the lung cancer recurrent mouse model after tumor resection and showed that the surgical stress immediately increased the level of serum monocyte chemoattractant protein-1 (MCP-1), which subsequently increased blood monocytes. These blood monocytes were rapidly recruited into distant micrometastases and became tumor growth-promoting tumor associated macrophages (TAMs). Furthermore, even after the blood MCP-1 and monocytes decreased enough 72 h after tumor resection, TAMs in micrometastases remained rich because the MCP-1 secreted by micrometastases themselves continued to recruit monocytes around the tumor. Consequently, tumor resection triggered the outgrowth of distant metastases via the MCP-1-Monocyte-TAM axis. When we administered the MCP-1 inhibitor to the lung cancer recurrent model mice, blood monocytes decreased after tumor resection, and TAMs in micrometastases also dramatically decreased. Finally, peri- and postoperative treatment with the MCP-1 inhibitor suppressed distant metastases after surgery. Targeting the MCP-1-Monocyte-TAM axis may inhibit surgical stress-induced NSCLC recurrence by attenuating postoperative immunosuppressive monocytes in micrometastases.
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Affiliation(s)
- Yo Kawaguchi
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan.
| | - Keigo Okamoto
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
| | - Yoko Kataoka
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
| | - Kohei Shibata
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
| | - Hiroki Saito
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
| | - Takuya Shiratori
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
| | - Keiko Ueda
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
| | - Yasuhiko Ohshio
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
| | - Jun Hanaoka
- Division of General Thoracic Surgery, Department of Surgery, Shiga University of Medical Science, Tsukinowacho, Seta, Otsu City, Shiga, 520-2192, Japan
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Cîmpeanu RC, Boldeanu MV, Ahrițculesei RV, Ciobanu AE, Cristescu AM, Forțofoiu D, Siloși I, Pirici DN, Cazacu SM, Boldeanu L, Vere CC. Correlation between Neurotransmitters (Dopamine, Epinephrine, Norepinephrine, Serotonin), Prognostic Nutritional Index, Glasgow Prognostic Score, Systemic Inflammatory Response Markers, and TNM Staging in a Cohort of Colorectal Neuroendocrine Tumor Patients. Int J Mol Sci 2024; 25:6977. [PMID: 39000088 PMCID: PMC11241815 DOI: 10.3390/ijms25136977] [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: 06/02/2024] [Revised: 06/20/2024] [Accepted: 06/22/2024] [Indexed: 07/16/2024] Open
Abstract
Neuroendocrine tumors are uncommon in the gastrointestinal system but can develop in the majority of the body's epithelial organs. Our goal was to examine the presence and clinical application of serum dopamine (DA), serotonin (ST), norepinephrine (NE), and epinephrine (EPI), in addition to determining the significance of the Prognostic Nutritional Index (PNI), Glasgow Prognostic Score (GPS), and systemic inflammatory response (SIR) markers as a prognostic factor for patients with colorectal neuroendocrine tumors (CR-NETs), in various tumor-node-metastasis (TNM) stages. We also wanted to identify the possible connection between them. This study included 25 consecutive patients who were diagnosed with CR-NETs and a control group consisting of 60 patients with newly diagnosed colorectal cancer (CRC). We used the Enzyme-Linked Immunosorbent Assay (ELISA) technique. This study revealed that CR-NET patients showed significantly higher serum levels of DA compared to CRC patients. We showed that serum DA was present in the early stages of CR-NETs, with increasing levels as we advanced through the TNM stages. Moreover, we found a close relationship between the levels of DA and the inflammation and nutritional status of the CR-NET patients in this study. CR-NET patients from the PNI < 47.00 subgroup had a higher level of DA than those from the PNI ≥ 47.00 subgroup. Pearson's correlation analysis revealed correlations between DA, PNI, and the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR). Both hematological indices were negatively correlated with albumin (ALB). Our investigation's findings relating to the PNI, GPS, SIR, and DA indicate that these tools can be markers of nutritional and systemic inflammatory status, are simple to use, and are repeatable. Further research on this topic could provide valuable insights into which biomarkers to incorporate into clinical practice for the management of CR-NET patients.
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Affiliation(s)
- Radu Cristian Cîmpeanu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.C.); (R.-V.A.); (A.E.C.); (A.-M.C.); (D.F.)
| | - Mihail Virgil Boldeanu
- Department of Immunology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Roxana-Viorela Ahrițculesei
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.C.); (R.-V.A.); (A.E.C.); (A.-M.C.); (D.F.)
| | - Alina Elena Ciobanu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.C.); (R.-V.A.); (A.E.C.); (A.-M.C.); (D.F.)
| | - Anda-Mihaela Cristescu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.C.); (R.-V.A.); (A.E.C.); (A.-M.C.); (D.F.)
| | - Dragoș Forțofoiu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.C.); (R.-V.A.); (A.E.C.); (A.-M.C.); (D.F.)
| | - Isabela Siloși
- Department of Immunology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Daniel-Nicolae Pirici
- Department of Histopathology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Sergiu-Marian Cazacu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (S.-M.C.); (C.C.V.)
| | - Lidia Boldeanu
- Department of Microbiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Cristin Constantin Vere
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (S.-M.C.); (C.C.V.)
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Zhang H, Yang Y, Cao Y, Guan J. Effects of chronic stress on cancer development and the therapeutic prospects of adrenergic signaling regulation. Biomed Pharmacother 2024; 175:116609. [PMID: 38678960 DOI: 10.1016/j.biopha.2024.116609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/14/2024] [Accepted: 04/17/2024] [Indexed: 05/01/2024] Open
Abstract
Long-term chronic stress is an important factor in the poor prognosis of cancer patients. Chronic stress reduces the tissue infiltration of immune cells in the tumor microenvironment (TME) by continuously activating the adrenergic signaling, inhibits antitumor immune response and tumor cell apoptosis while also inducing epithelial-mesenchymal transition (EMT) and tumor angiogenesis, promoting tumor invasion and metastasis. This review first summarizes how adrenergic signaling activates intracellular signaling by binding different adrenergic receptor (AR) heterodimers. Then, we focused on reviewing adrenergic signaling to regulate multiple functions of immune cells, including cell differentiation, migration, and cytokine secretion. In addition, the article discusses the mechanisms by which adrenergic signaling exerts pro-tumorigenic effects by acting directly on the tumor itself. It also highlights the use of adrenergic receptor modulators in cancer therapy, with particular emphasis on their potential role in immunotherapy. Finally, the article reviews the beneficial effects of stress intervention measures on cancer treatment. We think that enhancing the body's antitumor response by adjusting adrenergic signaling can enhance the efficacy of cancer treatment.
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Affiliation(s)
- Hao Zhang
- Department of Oncology, The Eighth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100091, China; Department of Oncology, The Fifth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100071, China.
| | - Yuwei Yang
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing Key Laboratory of OTIR, Beijing, 100091, China.
| | - Yan Cao
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing Key Laboratory of OTIR, Beijing, 100091, China.
| | - Jingzhi Guan
- Department of Oncology, The Fifth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100071, China.
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Chen Y, Liu H, Sun Y. Effect of acute inflammatory reaction induced by biopsy on tumor microenvironment. J Cancer Res Clin Oncol 2024; 150:177. [PMID: 38578317 PMCID: PMC10997701 DOI: 10.1007/s00432-024-05704-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 12/04/2023] [Indexed: 04/06/2024]
Abstract
When it comes to the diagnosis of solid tumors, biopsy is always the gold standard. However, traumatic and inflammatory stimuli are so closely related to tumor initiation and development that the acute inflammatory response induced by biopsy can give rise to changes in the tumor microenvironment, including recruitment of immunosuppressive cells (M2 macrophages, Treg cells, Tumor-associated neutrophils) and secretion of inflammation-associated cytokines, to create immunosuppressive conditions that enable the increase of circulating tumor cells in the peripheral circulation and promote the metastatic spread of tumors after surgery. In this review, we discuss dynamic changes and inhibitory characteristics of biopsy on tumor microenvironment. By investigating its mechanism of action and summarizing the current therapeutic strategies for biopsy-induced tumor immunosuppressive microenvironment, the future of using biopsy-induced inflammation to improve the therapeutic effects and prognosis of patients is prospected.
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Affiliation(s)
- Yuanyuan Chen
- Department of Stomatology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Hualian Liu
- Department of Stomatology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Yadong Sun
- Department of General Practice, Unit 94587 of the Chinese People's Liberation Army, Lianyungang, China
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Leschiera E, Al-Hity G, Flint MS, Venkataraman C, Lorenzi T, Almeida L, Audebert C. An individual-based model to explore the impact of psychological stress on immune infiltration into tumour spheroids. Phys Biol 2024; 21:026003. [PMID: 38266283 DOI: 10.1088/1478-3975/ad221a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 01/24/2024] [Indexed: 01/26/2024]
Abstract
In recentin vitroexperiments on co-culture between breast tumour spheroids and activated immune cells, it was observed that the introduction of the stress hormone cortisol resulted in a decreased immune cell infiltration into the spheroids. Moreover, the presence of cortisol deregulated the normal levels of the pro- and anti-inflammatory cytokines IFN-γand IL-10. We present an individual-based model to explore the interaction dynamics between tumour and immune cells under psychological stress conditions. With our model, we explore the processes underlying the emergence of different levels of immune infiltration, with particular focus on the biological mechanisms regulated by IFN-γand IL-10. The set-up of numerical simulations is defined to mimic the scenarios considered in the experimental study. Similarly to the experimental quantitative analysis, we compute a score that quantifies the level of immune cell infiltration into the tumour. The results of numerical simulations indicate that the motility of immune cells, their capability to infiltrate through tumour cells, their growth rate and the interplay between these cell parameters can affect the level of immune cell infiltration in different ways. Ultimately, numerical simulations of this model support a deeper understanding of the impact of biological stress-induced mechanisms on immune infiltration.
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Affiliation(s)
- Emma Leschiera
- Léonard de Vinci Pôle Universitaire, Research Center, 92 916 Paris, La Défense, France
- Univ. Bordeaux, CNRS, INRIA, Bordeaux INP, IMB, UMR 5251, F-33400 Talence, France
| | - Gheed Al-Hity
- School of Applied Sciences, University of Brighton, Centre for Stress and Age-related Diseases, Moulsecoomb, Brighton BN2 4GJ, United Kingdom
| | - Melanie S Flint
- School of Applied Sciences, University of Brighton, Centre for Stress and Age-related Diseases, Moulsecoomb, Brighton BN2 4GJ, United Kingdom
| | - Chandrasekhar Venkataraman
- School of Mathematical and Physical Sciences, University of Sussex, Department of Mathematics, Falmer, Brighton BN1 9QH, United Kingdom
| | - Tommaso Lorenzi
- Department of Mathematical Sciences 'G. L. Lagrange', Politecnico di Torino, 10129 Torino, Italy
| | - Luis Almeida
- Sorbonne Université, CNRS, Université de Paris, Laboratoire Jacques-Louis Lions UMR 7598, 75005 Paris, France
| | - Chloe Audebert
- Sorbonne Université, CNRS, Université de Paris, Laboratoire Jacques-Louis Lions UMR 7598, 75005 Paris, France
- Sorbonne Université, CNRS, Institut de biologie Paris-Seine (IBPS), Laboratoire de Biologie Computationnelle et Quantitative UMR 7238, 75005 Paris, France
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Moon J, Chun DH, Kong HJ, Lee HS, Jeon S, Park J, Kim NY, Kim HI. The Intraoperative Administration of Dexmedetomidine Alleviates Postoperative Inflammatory Response in Patients Undergoing Laparoscopy-Assisted Gastrectomy: A Double-Blind Randomized Controlled Trial. Biomedicines 2023; 11:3253. [PMID: 38137474 PMCID: PMC10741238 DOI: 10.3390/biomedicines11123253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/30/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Surgical stress can compromise the immune system of patients with cancer, affecting susceptibility to perioperative infections, tumor progression, treatment responses, and postoperative recovery. Perioperatively reducing inflammatory responses could improve outcomes. We determined the impact of intraoperative dexmedetomidine administration on the inflammatory response and postoperative recovery in patients undergoing elective laparoscopy-assisted gastrectomy. These patients were randomly assigned to the dexmedetomidine or control group (n = 42 each). The primary endpoint was the C-reactive protein (CRP) level on postoperative day 1. The secondary endpoints included the perioperative interleukin (IL)-6 levels, postoperative numerical rating scale (NRS) scores, and rescue analgesic doses. There were no significant between-group differences in terms of CRP levels. The IL-6 levels at the end of the surgery, NRS scores in the post-anesthesia care unit, and rescue pethidine requirements within the first hour postoperatively were significantly lower in the dexmedetomidine group than in the control group. The bolus deliveries-to-attempts ratio (via patient-controlled analgesia) at 2 h differed significantly between the two groups. However, IL-6 reduction was confined to a single timepoint, and the postoperative analgesic effects lasted for the first 2 h postoperatively. Low-dose dexmedetomidine infusion (0.4 µg kg-1 h-1) during laparoscopy-assisted gastrectomy exerts minimal anti-inflammatory effects.
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Affiliation(s)
- Jiae Moon
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.M.); (H.J.K.); (J.P.)
| | - Duk-Hee Chun
- Department of Anesthesiology and Pain Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Hee Jung Kong
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.M.); (H.J.K.); (J.P.)
| | - Hye Sun Lee
- Department of Research Affairs, Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (H.S.L.); (S.J.)
| | - Soyoung Jeon
- Department of Research Affairs, Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (H.S.L.); (S.J.)
| | - Jooeun Park
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.M.); (H.J.K.); (J.P.)
| | - Na Young Kim
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (J.M.); (H.J.K.); (J.P.)
| | - Hyoung-Il Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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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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11
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Chen Q, Rhodin KE, Li K, Kanu E, Zani S, Lidsky ME, Zhao J, Wei Q, Luo S, Zhao H. Impact of surgical approach on short- and long-term outcomes in gastroenteropancreatic neuroendocrine carcinomas. HPB (Oxford) 2023; 25:1255-1267. [PMID: 37414710 DOI: 10.1016/j.hpb.2023.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 05/23/2023] [Accepted: 06/10/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND Literature is lacking on the impact of advancements in minimally invasive surgery (MIS) on outcomes for patients with gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs). Herein, we compared perioperative and oncologic outcomes among patients with GEP-NECs undergoing open, laparoscopic, and robotic resection. METHODS Patients with GEP-NECs diagnosed 2010-2019 were identified from the National Cancer Database (NCDB). We used the inverse probability of treatment weighting method to account for selection bias. Patients were stratified by surgical approach; and pairwise comparisons were conducted by analyzing short- and long-term outcomes. RESULTS Receipt of MIS increased from 34.2% in 2010 to 67.5 % in 2019. Altogether, 6560 patients met study criteria: 3444 (52.5%) underwent open resection, 2783 (42.4%) underwent laparoscopic resection and 333 (5.1%) underwent robotic resection. Compared with open resection, laparoscopic or robotic resection were associated with shorter post-operative length of stay, reduced 30-day and 90-day post-operative mortality, and prolonged overall survival (OS). Compared with laparoscopic resection, robotic resection was associated with reduced 90-day post-operative mortality, however, there was no significant difference in OS. CONCLUSION This NCDB analysis demonstrates that MIS approaches for treating GEP-NECs have become more common, with improved perioperative mortality, shorter post-operative length of stay and favorable OS, compared with open resection.
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Affiliation(s)
- Qichen Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China; Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Kristen E Rhodin
- Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Kan Li
- Merck & Co., Inc., Rahway, NJ, USA
| | - Elishama Kanu
- Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Sabino Zani
- Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Michael E Lidsky
- Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Population Health Science, Duke University School of Medicine, Durham, NC 27110, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Duke Global Health Institute, Duke University School of Medicine, Durham, NC 27710, USA.
| | - Sheng Luo
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA.
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
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12
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Bhat BA, Saifi I, Khamjan NA, Hamdani SS, Algaissi A, Rashid S, Alshehri MM, Ganie SA, Lohani M, Abdelwahab SI, Dar SA. Exploring the tumor immune microenvironment in ovarian cancer: a way-out to the therapeutic roadmap. Expert Opin Ther Targets 2023; 27:841-860. [PMID: 37712621 DOI: 10.1080/14728222.2023.2259096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 07/21/2023] [Accepted: 09/11/2023] [Indexed: 09/16/2023]
Abstract
INTRODUCTION Despite cancer treatment strides, mortality due to ovarian cancer remains high globally. While immunotherapy has proven effective in treating cancers with low cure rates, it has limitations. Growing evidence suggests that both tumoral and non-tumoral components of the tumor immune microenvironment (TIME) play a significant role in cancer growth. Therefore, developing novel and focused therapy for ovarian cancer is critical. Studies indicate that TIME is involved in developing ovarian cancer, particularly genome-, transcriptome-, and proteome-wide studies. As a result, TIME may present a prospective therapeutic target for ovarian cancer patients. AREAS COVERED We examined several TIME-targeting medicines and the connection between TIME and ovarian cancer. The key protagonists and events in the TIME and therapeutic strategies that explicitly target these events in ovarian cancer are discussed. EXPERT OPINION We highlighted various targeted therapies against TIME in ovarian cancer, including anti-angiogenesis therapies and immune checkpoint inhibitors. While these therapies are in their infancy, they have shown promise in controlling ovarian cancer progression. The use of 'omics' technology is helping in better understanding of TIME in ovarian cancer and potentially identifying new therapeutic targets. TIME-targeted strategies could account for an additional treatment strategy when treating ovarian cancer.
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Affiliation(s)
- Basharat Ahmad Bhat
- Department of Bioresources, Amar Singh College Campus, Cluster University, Srinagar, India
| | - Ifra Saifi
- Department of Botany, Chaudhary Charan Singh University, Meerut India
| | - Nizar A Khamjan
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Syed Suhail Hamdani
- Department of Bioresources, Amar Singh College Campus, Cluster University, Srinagar, India
| | - Abdullah Algaissi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
- Medical Research Centre, Jazan University, Jazan, Saudi Arabia
| | - Safeena Rashid
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
| | | | - Showkat Ahmad Ganie
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Mohtashim Lohani
- Department of Emergency Medical Services, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | | | - Sajad Ahmad Dar
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, Saudi Arabia
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13
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Cui Q, Jiang D, Zhang Y, Chen C. The tumor-nerve circuit in breast cancer. Cancer Metastasis Rev 2023; 42:543-574. [PMID: 36997828 PMCID: PMC10349033 DOI: 10.1007/s10555-023-10095-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/16/2023] [Indexed: 04/01/2023]
Abstract
It is well established that innervation is one of the updated hallmarks of cancer and that psychological stress promotes the initiation and progression of cancer. The breast tumor environment includes not only fibroblasts, adipocytes, endothelial cells, and lymphocytes but also neurons, which is increasingly discovered important in breast cancer progression. Peripheral nerves, especially sympathetic, parasympathetic, and sensory nerves, have been reported to play important but different roles in breast cancer. However, their roles in the breast cancer progression and treatment are still controversial. In addition, the brain is one of the favorite sites of breast cancer metastasis. In this review, we first summarize the innervation of breast cancer and its mechanism in regulating cancer growth and metastasis. Next, we summarize the neural-related molecular markers in breast cancer diagnosis and treatment. In addition, we review drugs and emerging technologies used to block the interactions between nerves and breast cancer. Finally, we discuss future research directions in this field. In conclusion, the further research in breast cancer and its interactions with innervated neurons or neurotransmitters is promising in the clinical management of breast cancer.
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Affiliation(s)
- Qiuxia Cui
- Affiliated Hospital of Guangdong Medical University Science & Technology of China, Zhanjiang, 524000, China
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Dewei Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Yuanqi Zhang
- Affiliated Hospital of Guangdong Medical University Science & Technology of China, Zhanjiang, 524000, China.
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
- Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
- The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China.
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Ogawa K, Khan KN, Koshiba A, Fujishita A, Horiguchi G, Teramukai S, Itoh K, Guo SW, Mori T. Association between tissue stress reaction and ACE2/TMPRSS2 expression in endometria of reproductive aged women before and during Covid-19 pandemic. BMC Womens Health 2023; 23:229. [PMID: 37142998 PMCID: PMC10158702 DOI: 10.1186/s12905-023-02378-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/19/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND A potential concern has been raised regarding fertility and reproductive outcome during the Covid-19 pandemic with growing stress and anxiety. However, information on the association between tissue stress reaction and expression profiles of SARS-CoV-2 viral entry proteins, ACE2 and TMPRSS2, in endometria collected from women before (pre-pandemic) and during the Covid-19 pandemic (in-pandemic) is unknown. We aim to investigate the relationship between the expression of stress-reactive proteins and of ACE2 and TMPRSS2 in endometria collected from women during these two different time frames. METHODS We retrospectively retrieved tissue blocks of endometrial samples from 25 women in 2019 (pre-pandemic) and 25 women in 2020 (in-pandemic) who underwent hysterectomy for different gynecological indications. Immunohistochemical analysis was performed with endometrial tissue samples that were collected before and during the pandemic, using respective antibodies targeting ACE2/TMPRSS2, ADRB2 and NK1R (stress and anxiety receptor markers, respectively). The quantification of immunoreactive cells for each marker was calculated by the immunoreactive score (IRS) analysis. This retrospective cohort study was limited to small sample size. RESULTS No significant differences in the IRS of ACE2 and TMPRSS2 were found between the endometria that were collected before and during the pandemic with a lack of correlation between ACE2 and TMPRSS2 expression in respective endometria (r = 0.11, pre-pandemic; r = 0.04, in-pandemic). The immunostaining levels of stress marker, ADRB2 were significantly higher in the endometria of in-pandemic group (p = 0.015) comparing to that of pre-pandemic group. Pearson's correlation coefficient analysis showed a significant correlation in the expression between ADRB2 and TMPRSS2 (r = 0.41, p = 0.042) in the endometria of in-pandemic group but not in the pre-pandemic group. CONCLUSION The rise in stress and anxiety among women during current pandemic may elicit substantial amount of tissue stress reaction with consequent increase in the expression of SARS-CoV-2 viral entry proteins in their endometria. A lack of correlation between ACE2 and TMPRSS2 expression in endometria may reassure women in their reproductive age that they are not more susceptible to infection by SARS-CoV-2 and suggest that stressful women during this pandemic can safely decide to conceive naturally or by artificial reproductive technology.
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Affiliation(s)
- Kanae Ogawa
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, 602-8566, Kyoto, Japan
| | - Khaleque N Khan
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, 602-8566, Kyoto, Japan.
- The Clinical and Translational Research Center, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, 602-8566, Kyoto, Japan.
| | - Akemi Koshiba
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, 602-8566, Kyoto, Japan
| | - Akira Fujishita
- Department of Gynecology, Saiseikai Nagasaki Hospital, Nagasaki, Japan
| | - Go Horiguchi
- Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoshi Teramukai
- Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kyoko Itoh
- Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sun-Wei Guo
- Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Taisuke Mori
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, 602-8566, Kyoto, Japan
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15
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Perioperative escape from dormancy of spontaneous micro-metastases: A role for malignant secretion of IL-6, IL-8, and VEGF, through adrenergic and prostaglandin signaling. Brain Behav Immun 2023; 109:175-187. [PMID: 36646396 DOI: 10.1016/j.bbi.2023.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/08/2022] [Accepted: 01/12/2023] [Indexed: 01/15/2023] Open
Abstract
We recently showed that a minimally-invasive removal of MDA-MB-231HM primary tumors (PTs) and elimination of their secreted factors (including IL-6, IL-8, VEGF, EGF, PDGF-aa, MIF, SerpinE1, and M-CSF), caused regression of spontaneous micro-metastases into a non-growing dormant state. To explore the underlying mechanisms and potential clinical ramifications of this phenomenon, we herein used the MDA-MB-231HM human breast cancer cell-line, in-vitro, and in vivo following orthotopic implantation in immune-deficient BALB/C nu/nu mice. Employing bioluminescence imaging, we found that adding laparotomy to minimally-invasive removal of the PT caused an outbreak of micro-metastases. However, perioperative β-adrenergic and COX-2 inhibition, using propranolol + etodolac, maintained metastatic dormancy following laparotomy. In-vitro, β-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231HM secretion of the pro-metastatic factors IL-6, IL-8, and VEGF, whereas cortisol reduced their secretion, effects that were maintained even 12 h after the washout of these agonists. In-vivo, laparotomy elevated IL-6 and IL-8 levels in both plasma and ex-vivo PT spontaneous secretion, whereas perioperative propranolol + etodolac administration blocked these effects. Similar trends were evident for EGF and MIF. Promoter-based bioinformatics analyses of excised PT transcriptomes implicated elevated NF-kB activity and reduced IRF1 activity in the gene regulatory effects of laparotomy, and these effects were inhibited by pre-surgical propranolol + etodolac. Taken together, our findings suggest a novel mechanism of post-operative metastatic outbreak, where surgery-induced adrenergic and prostanoid signaling increase the secretion of pro-metastatic factors, including IL-6, IL-8, and VEGF, from PT and possibly residual malignant tissue, and thereby prevent residual disease from entering dormancy.
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16
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Spilsbury K, Tuesley KM, Pearson SA, Coory MD, Donovan P, Steer CB, Stewart LM, Pandeya N, Jordan SJ. Perioperative Beta-Blocker Supply and Survival in Women With Epithelial Ovarian Cancer and a History of Cardiovascular Conditions. J Clin Oncol 2023; 41:266-275. [PMID: 36001852 DOI: 10.1200/jco.22.00097] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 06/01/2022] [Accepted: 07/12/2022] [Indexed: 01/10/2023] Open
Abstract
PURPOSE Surgery for epithelial ovarian cancer (EOC) may activate stress-inflammatory responses that stimulate tumor growth and increase metastatic growth. Animal and in vitro studies have shown that inhibition of the catecholamine-induced inflammatory response via beta-adrenergic receptor blockade has antitumor potential in EOC. However, observational studies have reported mixed results. We assessed whether beta-blocker (BB) use at the time of primary ovarian cancer surgery was associated with improved survival in a large population-based study. MATERIALS AND METHODS Using linked administrative data, a population-based cohort of 3,844 Australian women age 50 years or older with a history of cardiovascular conditions who underwent surgery for EOC was followed for survival outcomes. The average treatment effect of selective BB (SBB) and nonselective BB (NSBB) supply at the time of surgery on survival was estimated from a causal inference perspective using covariate-balanced inverse probability of treatment weights with flexible parametric survival models that allowed for time-varying survival effects. RESULTS Around the time of surgery, 560 (14.5%) women were supplied a SBB and 67 (1.7%) were supplied a NSBB. At 2 years postsurgery, the survival proportion was 80% (95% CI, 68 to 88) for women dispensed NSBBs at surgery compared with 69% (95% CI, 67 to 70) for women not supplied NSBBs. The survival advantage appeared to extend to at least 8 years postsurgery. No association was observed for women dispensed a SBB around the time of surgery. CONCLUSION Perioperative supply of NSBBs appeared to confer a survival advantage for women age over 50 years with a history of cardiovascular conditions. Long-term clinical trials are required to confirm these findings.
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Affiliation(s)
- Katrina Spilsbury
- Institute for Health Research, The University of Notre Dame Australia, Fremantle, Australia
- School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Karen M Tuesley
- School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Australia
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Sallie-Anne Pearson
- Centre for Big Data Research in Health, The University of New South Wales, Sydney, Australia
| | - Michael D Coory
- Faculty of Medicine, Dentistry and Health Sciences University of Melbourne, Melbourne, Australia
| | - Peter Donovan
- Clinical Pharmacology Department, Royal Brisbane and Women's Hospital, Brisbane, Australia
- Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Christopher B Steer
- Border Medical Oncology, Albury-Wodonga Regional Cancer Center, Albury, Australia
- University of NSW Rural Clinical School, Albury Campus, Albury, New South Wales, Australia
| | - Louise M Stewart
- School of Population and Global Health, The University of Western Australia, Perth, Australia
| | - Nirmala Pandeya
- School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Australia
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Susan J Jordan
- School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Australia
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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17
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Wu Y, Yuan M, Wang C, Chen Y, Zhang Y, Zhang J. T lymphocyte cell: A pivotal player in lung cancer. Front Immunol 2023; 14:1102778. [PMID: 36776832 PMCID: PMC9911803 DOI: 10.3389/fimmu.2023.1102778] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/11/2023] [Indexed: 01/28/2023] Open
Abstract
Lung cancer is responsible for the leading cause of cancer-related death worldwide, which lacks effective therapies. In recent years, accumulating evidence on the understanding of the antitumor activity of the immune system has demonstrated that immunotherapy is one of the powerful alternatives in lung cancer therapy. T cells are the core of cellular immunotherapy, which are critical for tumorigenesis and the treatment of lung cancer. Based on the different expressions of surface molecules and functional points, T cells can be subdivided into regulatory T cells, T helper cells, cytotoxic T lymphocytes, and other unconventional T cells, including γδ T cells, nature killer T cells and mucosal-associated invariant T cells. Advances in our understanding of T cells' functional mechanism will lead to a number of clinical trials on the discovery and development of new treatment strategies. Thus, we summarize the biological functions and regulations of T cells on tumorigenesis, progression, metastasis, and prognosis in lung cancer. Furthermore, we discuss the current advancements of technologies and potentials of T-cell-oriented therapeutic targets for lung cancer.
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Affiliation(s)
- Yanan Wu
- Department of Oncology, Shandong First Medical University, Jinan, China.,Department of Oncology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Meng Yuan
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Chenlin Wang
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Yanfei Chen
- Department of Oncology, Shandong First Medical University, Jinan, China.,Department of Oncology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Yan Zhang
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jiandong Zhang
- Department of Oncology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
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18
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Bugada D, Drotar M, Finazzi S, Real G, Lorini LF, Forget P. Opioid-Free Anesthesia and Postoperative Outcomes in Cancer Surgery: A Systematic Review. Cancers (Basel) 2022; 15:cancers15010064. [PMID: 36612060 PMCID: PMC9817782 DOI: 10.3390/cancers15010064] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/11/2022] [Accepted: 12/15/2022] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Surgery is an essential component of the treatment of solid tumors, but the perioperative course can be complicated by different factors (including anesthesia). Opioid-free anesthesia (OFA) may mitigate adverse outcomes of opioid-based anesthesia (OBA), but major questions remain on the actual impact in terms of analgesia and the improvement of surgical outcomes. To address this issue, we present a systematic review to evaluate the efficacy of OFA compared to OBA in the specific subset of cancer patients undergoing surgery. METHODS following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), we searched MEDLINE, Embase and the Cochrane CENTRAL Library to include randomized controlled trials (RCTs) on adults undergoing oncological surgery, comparing OFA and OBA up to March 2022. Additional papers were added from the reference lists of identified sources. Papers were manually reviewed by two independent authors to ascertain eligibility and subsequent inclusion in qualitative analysis. RESULTS only two studies were eligible according to inclusion criteria. It was not possible to perform any meta-analysis. The two studies included patients undergoing prostate and gynecologic surgery on 177 patients, with significant heterogeneity in the outcomes. CONCLUSIONS randomized controlled trial specifically addressed to cancer patients are lacking. A knowledge gap exists, neither confirming nor rejecting the capacity of OFA to improve early postoperative outcomes in cancer surgery. Long-term consequences on specific oncological outcomes are far from being elucidated. We expect a growing body of literature in the coming years. Further studies are required with homogeneous methodology and endpoints.
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Affiliation(s)
- Dario Bugada
- Emergency and Intensive Care Department, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
- Correspondence:
| | - Megan Drotar
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK
| | - Simone Finazzi
- Department of Health Sciences, University of Milan, 20122 Milan, Italy
| | - Giovanni Real
- Department of Health Sciences, University of Milan, 20122 Milan, Italy
| | - Luca F. Lorini
- Emergency and Intensive Care Department, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
| | - Patrice Forget
- Epidemiology Group, Department of Anaesthesia, NHS Grampian, Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK
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19
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Wu Y, Zhou L, Zhang X, Yang X, Niedermann G, Xue J. Psychological distress and eustress in cancer and cancer treatment: Advances and perspectives. SCIENCE ADVANCES 2022; 8:eabq7982. [PMID: 36417542 PMCID: PMC9683699 DOI: 10.1126/sciadv.abq7982] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 10/03/2022] [Indexed: 05/31/2023]
Abstract
Facing cancer diagnosis, patients with cancer are prone to psychological stress and consequent psychological disorders. The association between psychological stress and cancer has long been a subject of high interest. To date, preclinical studies have gradually uncovered the promotive effects of psychological distress on tumor hallmarks. In contrast, eustress may exert suppressive effects on tumorigenesis and beneficial effects on tumor treatment, which brings a practicable means and psychosocial perspective to cancer treatment. However, the underlying mechanisms remain incompletely understood. Here, by focusing on the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, as well as stress-related crucial neurotransmitters and hormones, we highlight the effects of distress and eustress on tumorigenesis, the tumor microenvironment, and tumor treatment. We also discuss the findings of clinical studies on stress management in patients with cancer. Last, we summarize questions that remain to be addressed and provide suggestions for future research directions.
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Affiliation(s)
- Yuanjun Wu
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Laiyan Zhou
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xuanwei Zhang
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xue Yang
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Gabriele Niedermann
- Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany, German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg, Germany
| | - Jianxin Xue
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Chen Q, Li M, Chen J, Huang Z, Chen X, Zhao H, Cai J. AST·MLR index and operation injury condition are novel prognostic predictor for the prediction of survival in patients with colorectal cancer liver metastases undergoing surgical resection. BMC Cancer 2022; 22:921. [PMID: 36008803 PMCID: PMC9414420 DOI: 10.1186/s12885-022-10009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/16/2022] [Indexed: 11/23/2022] Open
Abstract
Background The prognostic values of preoperative aspartate aminotransferase (AST), monocyte-to-lymphocyte ratio (MLR), AST·MLR index (AMLRI) and operation injury condition in patients with colorectal cancer liver metastases (CRLM) remains unclear. This retrospective study assessed the relationship between these markers, progression-free survival (PFS), and overall survival (OS) in CRLM patients undergoing resection. Methods AMLRI was defined as AST × MLR. Operation injury condition was defined according to operation time and blood loss. Cox regression analyses were used to identify risk factors and to develop nomograms. C-indexes, time-dependent receiver operating characteristic (time-ROC) curves and calibration curves were used to assess the models. Results A total of 379 patients were enrolled. The optimal cut-off value of the AMLRI was 3.33. In the multivariable analysis, AMLRI > 3.33 (hazard ratio [HR] = 2.162, p = 0.002) and serious operation injury condition (HR = 1.539, p = 0.012) were predictive for unfavourable OS, and AMLRI > 3.33 (HR = 1.462, p = 0.021) was predictive for unfavourable PFS. The nomograms were superior to Fong’s Clinical Risk Score (CRS) according to the C-indexes (PFS: 0.682 vs. 0.600; OS: 0.730 vs. 0.586) and time-ROCs. Conclusions Preoperative AMLRI and operation injury condition are easily accessible predictors for prognosis. The nomograms performed better than CRS for the prediction of recurrence and survival. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10009-4.
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Affiliation(s)
- Qichen Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingxia Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinghua Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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21
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The Effect of Beta Adrenoreceptor Blockers on Viability and Cell Colony Formation of Non-Small Cell Lung Cancer Cell Lines A549 and H1299. Molecules 2022; 27:molecules27061938. [PMID: 35335303 PMCID: PMC8950283 DOI: 10.3390/molecules27061938] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/11/2022] [Accepted: 03/15/2022] [Indexed: 12/24/2022] Open
Abstract
Beta adrenoblockers are a large class of drugs used to treat cardiovascular diseases, migraines, glaucoma and hyperthyroidism. Over the last couple of decades, the anticancer effects of these compounds have been extensively studied. However, the exact mechanism is still not known, and more detailed studies are required. The aim of our study was to evaluate the anticancer activity of beta adrenoblockers in non-small cell lung cancer cell lines A549 and H1299. In order to find the relationship with their selectivity to beta adrenoreceptors, selective (atenolol, betaxolol, esmolol, metoprolol) and non-selective (pindolol, propranolol and timolol) beta blockers were tested. The effect on cell viability was evaluated by MTT assay, and the activity on cell ability to form colonies was tested by clonogenic assay. The type of cell death was evaluated by cell double staining with Hoechst 33342 and Propidium iodide. The most active adrenoblockers against both tested cancer cell lines were propranolol and betaxolol. They completely inhibited lung cancer cell colony formation at 90% of the EC50 (half-maximal effective concentration) value. Most tested compounds induced cell death through apoptosis and necrosis. There was no correlation established between beta adrenoblocker anticancer activity and their selectivity to beta adrenoreceptors.
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22
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Tsai HJ, Chang WK, Yen FY, Lin SP, Lin TP, Chang KY. Influential Factors and Personalized Prediction Model of Acute Pain Trajectories after Surgery for Renal Cell Carcinoma. J Pers Med 2022; 12:jpm12030360. [PMID: 35330359 PMCID: PMC8949910 DOI: 10.3390/jpm12030360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 12/04/2022] Open
Abstract
Background: Renal cell carcinoma (RCC) is the most common neoplasm in kidneys, and surgical resection remains the mainstay treatment. Few studies have investigated how the postoperative pain changes over time and what has affected its trajectory. This study aimed to characterize the variations in postoperative pain over time and investigate associated factors after RCC surgery. Methods: This retrospective study was conducted in a single medical center in Taiwan, where maximal pain scores in a numeric rating scale were recorded daily in the first five postoperative days (PODs) after RCC surgery. Latent curve models were developed, using two latent variables, intercept and slope, which represented the baseline pain and rate of pain resolution. These models explain the variations in postoperative pain scores over time. A predictive model for postoperative pain trajectories was also constructed. Results: There were 861 patients with 3850 pain observations included in the analysis. Latent curve analysis identified that female patients and those with advanced cancer (stage III and IV) tended to have increased baseline pain scores (p = 0.028 and 0.012, respectively). Furthermore, patients over 60 years, without PCA use (both p < 0.001), and with more surgical blood loss (p = 0.001) tended to have slower pain resolution. The final predictive model fit the collected data acceptably (RMSEA = 0.06, CFI = 0.95). Conclusion: Latent curve analysis identified influential factors of acute pain trajectories after RCC surgery. This study may also help elucidate the complex relationships between the variations in pain intensity over time and their determinants, and guide personalized pain management after surgery for RCC.
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Affiliation(s)
- Hsin-Jung Tsai
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-J.T.); (W.-K.C.); (S.-P.L.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; (F.-Y.Y.); (T.-P.L.)
| | - Wen-Kuei Chang
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-J.T.); (W.-K.C.); (S.-P.L.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; (F.-Y.Y.); (T.-P.L.)
| | - Fang-Yu Yen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; (F.-Y.Y.); (T.-P.L.)
- Department of Anesthesiology, Taoyuan Armed Forces General Hospital, Taoyuan City 32551, Taiwan
| | - Shih-Pin Lin
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-J.T.); (W.-K.C.); (S.-P.L.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; (F.-Y.Y.); (T.-P.L.)
| | - Tzu-Ping Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; (F.-Y.Y.); (T.-P.L.)
- Department of Urology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Kuang-Yi Chang
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-J.T.); (W.-K.C.); (S.-P.L.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; (F.-Y.Y.); (T.-P.L.)
- Correspondence: ; Tel.: +886-2-28757549; Fax: +886-2-28751597
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Abstract
BACKGROUND Colorectal cancer (CRC) is a deadly disease with a poor prognosis. Lidocaine is preferred by surgical procedures due to the excellent anesthesia. Circular RNA integrin alpha FG-GAP repeat containing 2 (circITFG2) has been recognized as a momentous participator in CRC progression. The specific role of circITFG2 was further studied in this research. METHODS Quantitative real-time PCR (qRT-PCR) was devoted to examining the expression of circITFG2, microRNA-1204 (miR-1204) and SOCS2 mRNA in CRC cells. Western blot was used to determine SOCS2 protein expression in CRC cells. Cell viability, colony formation and apoptosis were detected by cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay respectively. Cell migration and invasion were tested by wound healing assay and transwell assay. Dual-luciferase reporter system, RNA pull down and RNA-binding protein immunoprecipitation (RIP) assays were applied to verify the combination between miR-1204 and circITFG2 or SOCS2. RESULTS CircITFG2 was strikingly downregulated; however, lidocaine treatment induced a significant increase in the expression of circITFG2 and SOCS2 and a decrease in miR-1204 expression in CRC cells. Meanwhile, SOCS2 protein expression was upregulated by lidocaine treatment or miR-1204 silence in CRC cells and downregulated by circITFG2 knockdown or miR-1204 overexpression in lidocaine-treated CRC cells. CircITFG2 knockdown or miR-1204 overexpression abolished lidocaine-induced inhibition in proliferation, metastasis and promotion in apoptosis in CRC cells. CircITFG2 overexpression, SOCS3 overexpression or lidocaine treatment suppressed proliferation, metastasis and facilitated apoptosis in CRC cells. CircITFG2 sponged miR-1204 to regulate SOCS3 expression in lidocaine-treated CRC cells. CONCLUSION Lidocaine hindered CRC progression by circITFG2/miR-1204/SOCS2 axis. This finding might beat a path in improving CRC therapy.
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Jing Y, Zhang Y, Pan R, Ding K, Chen R, Meng Q. Effect of Inhalation Anesthetics on Tumor Metastasis. Technol Cancer Res Treat 2022; 21:15330338221121092. [PMID: 36131554 PMCID: PMC9502254 DOI: 10.1177/15330338221121092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Many factors affect the prognosis of patients undergoing tumor surgery, and anesthesia is one of the potential influencing factors. In general anesthesia, inhalation anesthesia is widely used in the clinic because of its strong curative effect and high controllability. However, the effect of inhalation anesthetics on the tumor is still controversial. More and more research has proved that inhalation anesthetics can intervene in local recurrence and distant metastasis of tumor by acting on tumor biological behavior, immune response, and gene regulation. In this paper, we reviewed the research progress of diverse inhalation anesthetics promoting or inhibiting cancer in the critical events of tumor recurrence and metastasis, and compared the effects of inhalation anesthetics on patients' prognosis in clinical studies, to provide theoretical reference for anesthesia management of patients undergoing tumor surgery.
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Affiliation(s)
- Yixin Jing
- Department of Anesthesiology, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Yiguo Zhang
- Department of Anesthesiology, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Rui Pan
- Department of Anesthesiology, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Ke Ding
- Department of Anesthesiology, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Rong Chen
- Department of Anesthesiology, 117921Renmin Hospital of Wuhan University, Wuhan, China.,Department of Anesthesiology, East Hospital, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Qingtao Meng
- Department of Anesthesiology, 117921Renmin Hospital of Wuhan University, Wuhan, China.,Department of Anesthesiology, East Hospital, 117921Renmin Hospital of Wuhan University, Wuhan, China
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25
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Psychological intervention to treat distress: An emerging frontier in cancer prevention and therapy. Biochim Biophys Acta Rev Cancer 2021; 1877:188665. [PMID: 34896258 DOI: 10.1016/j.bbcan.2021.188665] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/27/2021] [Accepted: 12/01/2021] [Indexed: 02/05/2023]
Abstract
Psychological distress, such as chronic depression and anxiety, is a topical problem. In the context of cancer patients, prevalence rates of psychological distress are four-times higher than in the general population and often confer worse outcomes. In addition to evidence from epidemiological studies confirming the links between psychological distress and cancer progression, a growing body of cellular and molecular studies have also revealed the complex signaling networks which are modulated by psychological distress-derived chronic stress during cancer progression. In this review, aiming to uncover the intertwined networks of chronic stress-driven oncogenesis and progression, we summarize physiological stress response pathways, like the HPA, SNS, and MGB axes, that modulate the release of stress hormones with potential carcinogenic properties. Furthermore, we discuss in detail the mechanisms behind these chronic stimulations contributing to the initiation and progression of cancer through direct regulation of cancer hallmarks-related signaling or indirect promotion of cancer risk factors (including obesity, disordered circadian rhythms, and premature senescence), suggesting a novel research direction into cancer prevention and therapy on the basis of psychological interventions.
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26
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Shin S, Kim KJ, Hwang HJ, Noh S, Oh JE, Yoo YC. Immunomodulatory Effects of Perioperative Dexmedetomidine in Ovarian Cancer: An In Vitro and Xenograft Mouse Model Study. Front Oncol 2021; 11:722743. [PMID: 34692497 PMCID: PMC8529066 DOI: 10.3389/fonc.2021.722743] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/21/2021] [Indexed: 01/23/2023] Open
Abstract
Background The surgical stress response (SSR) causes immunosuppression which may cause residual tumor growth and micrometastasis after cancer surgery. We investigated whether dexmedetomidine affects cancer cell behavior and immune function in an ovarian cancer xenograft mouse model. Methods The effect of dexmedetomidine on cell viability and cell cycle was assessed using SK-OV-3 cells at drug concentrations of 0.5, 0.1, 5, and 10 µg mL-1. BALB/c nude mice were used for the ovarian cancer model with the Dexmedetomidine group (n=6) undergoing surgery with dexmedetomidine infusion and the Control group (n=6) with saline infusion for 4 weeks. Natural killer (NK) cell activity, serum proinflammatory cytokines, and cortisol were measured at predetermined time points and tumor burden was assessed 4 weeks after surgery. Results Dexmedetomidine had no effect on cell viability or cell cycle. Following a sharp decrease on postoperative day (POD) 1, NK cell activity recovered faster in the Dexmedetomidine group with significant difference vs. the Control group on POD 3 (P=0.028). In the Dexmedetomidine group, cortisol levels were lower on POD 3 (P=0.004) and TNF-α levels were lower at 4 weeks after surgery (P<0.001) compared to the Control group. The Dexmedetomidine group showed lower tumor burden at 4 weeks vs. the Control group as observed by both tumor weight (P<0.001) and the in vivo imaging system (P=0.03). Conclusions Dexmedetomidine infusion may improve ovarian cancer surgery outcome by suppressing the SSR and stress mediator release. Further studies are needed to elucidate the mechanisms by which dexmedetomidine acts on cancer and immune cells.
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Affiliation(s)
- Seokyung Shin
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Ki Jun Kim
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Jeong Hwang
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Sewon Noh
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Ju Eun Oh
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Young-Chul Yoo
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
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Abstract
Current cancer therapies aim at eradicating cancer cells from the body. However, killing cells generates cell “debris” which can promote tumor progression. Thus, therapy can be a double-edged sword. Specifically, injury and debris generated by cancer therapies, including chemotherapy, radiation, and surgery, may offset their benefit by promoting the secretion of pro-tumorigenic factors (e.g., eicosanoid-driven cytokines) that stimulate regrowth and metastasis of surviving cells. The debris produced by cytotoxic cancer therapy can also contribute to a tumor microenvironment that promotes tumor progression and recurrence. Although not well understood, several molecular mechanisms have been implicated in debris-stimulated tumor growth that we review here, such as the involvement of extracellular vesicles, exosomal miR-194-5p, Bax, Bak, Smac, HMGB1, cytokines, and caspase-3. We discuss the cases of pancreatic and other cancer types where debris promotes postoperative tumor recurrence and metastasis, thus offering a new opportunity to prevent cancer progression intrinsically linked to treatment by stimulating resolution of tumor-promoting debris.
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Affiliation(s)
- Victoria M Haak
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
| | - Sui Huang
- Institute for Systems Biology, Seattle, WA, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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28
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Abstract
Cancer therapy, such as chemotherapy, induces tumor cell death (“debris”), which can stimulate metastasis. Chemotherapy-generated debris upregulates soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4), which triggers a macrophage-derived storm of proinflammatory and proangiogenic lipid autacoid and cytokine mediators. Although sEH inhibitors and EP4 antagonists are in clinical development for multiple inflammatory diseases, their combined role in cancer is unknown. Here, we show that the synergistic antitumor activity of sEH and EP4 inhibition suppresses hepato-pancreatic tumor growth, without overt toxicity, via macrophage phagocytosis of debris and counterregulation of a debris-stimulated cytokine storm. Thus, stimulating the resolution of inflammation via combined inhibition of sEH and EP4 may be an approach for preventing metastatic progression driven by cancer therapy. Cancer therapy reduces tumor burden via tumor cell death (“debris”), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.
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29
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Zhao S, Zheng X, Zhu X, Ning J, Zhu K, Yan Y, Zhang J, Bu J, Liu M, Xu S. Surgical Trauma-induced CCL2 Upregulation Mediates Lung Cancer Progression by Promoting Treg Recruitment in Mice and Patients. Cancer Invest 2021; 40:91-102. [PMID: 34515610 DOI: 10.1080/07357907.2021.1977314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Surgical removal of the tumor is currently the first-line treatment for lung cancer, but the procedure may accelerate cancer progression through immunosuppression. However, whether CCL2 (C-C motif chemokine ligand 2) enhances cancer progression by affecting regulatory T cells (Tregs) remains unknown. We found that the volume and weight of tumors were larger in the surgical trauma group than in the control group. CCL2 expression and Treg abundance were increased in tumor tissues after surgical trauma, and CCL2 expression was positively associated with Treg abundance. These results demonstrated that surgical trauma contributes to lung cancer progression by increasing CCL2 expression, thus promoting Treg recruitment.
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Affiliation(s)
- Su Zhao
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Xiaoyu Zheng
- Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Xidong Zhu
- Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Jinfeng Ning
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Kaibin Zhu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Yubo Yan
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Jian Zhang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Jianlong Bu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Mengfeng Liu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
| | - Shidong Xu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China
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Administration of Low-Dose Dexmedetomidine Did Not Affect Acute Inflammatory Response after Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemotherapy: A Double-Blind Randomized Controlled Trial. J Clin Med 2021; 10:jcm10143145. [PMID: 34300310 PMCID: PMC8303433 DOI: 10.3390/jcm10143145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/07/2021] [Accepted: 07/14/2021] [Indexed: 11/16/2022] Open
Abstract
During cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), attenuation of inflammatory responses that increase susceptibility to postoperative complications, morbidity, and mortality is important. We aimed to evaluate whether intraoperative dexmedetomidine infusion impacted inflammatory response in patients undergoing CRS with HIPEC. Fifty-six patients scheduled for CRS with HIPEC were randomly assigned to the control (n = 28) and dexmedetomidine (n = 28) groups. The primary endpoint was the effect of dexmedetomidine on the interleukin-6 (IL-6) level measured at pre-operation (Pre-OP), before HIPEC initiation (Pre-HIPEC), immediately after HIPEC; after the end of the operation; and on postoperative day (POD) 1. In both groups, the IL-6 levels from Pre-HIPEC until POD 1 and the C-reactive protein (CRP) levels on PODs 1, 2, and 3 were significantly higher than the Pre-OP values (all Bonferroni corrected, p < 0.001). However, total differences in IL-6 and CRP levels, based on the mean area under the curve, were not detected between the two groups. The continuous intraoperative infusion of dexmedetomidine (0.4 μg/kg/h) in patients undergoing CRS with HIPEC did not significantly lower the inflammatory indices. Further dose investigative studies are needed to find the dexmedetomidine dose that provides anti-inflammatory and sympatholytic effects during HIPEC.
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Meguro S, Haga N, Imai H, Yoshida Y, Takinami-Honda R, Matsuoka K, Hoshi S, Hata J, Sato Y, Akaihata H, Kataoka M, Ogawa S, Kojima Y. Association Between Surgical Stress and Biochemical Recurrence After Robotic Radical Prostatectomy. JSLS 2021; 25:JSLS.2020.00078. [PMID: 33879996 PMCID: PMC8035824 DOI: 10.4293/jsls.2020.00078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background and Objectives This study was conducted to identify whether surgical stress during the peri-operative period of robot-assisted radical prostatectomy might affect biochemical recurrence in patients with positive surgical margins. Methods Participants in the present study were 324 consecutive patients with localized prostate cancer who underwent robot-assisted radical prostatectomy between February 2013 and June 2018. Positive surgical margins were diagnosed in 61 of them. Patients with positive surgical margins were divided into those with (n = 19) and those without (n = 42) biochemical recurrence. Lymph node dissection, estimated blood loss, inhalation anesthetic volume, and surgical duration were evaluated as indicators of surgical stress. White blood cell count, C-reactive protein, body temperature, and usage of analgesics were postoperatively evaluated as surrogate markers of surgical stress. The associations between factors, including patients' characteristics and pathological features, and biochemical recurrence were investigated. Results In univariate analyses, surgical duration (P = 0.004), D'Amico risk class (P = 0.002), Gleason score (P = 0.022) and the number of positive cores in prostate biopsy (P = 0.009) were statistically significantly associated with biochemical recurrence. In multivariate analyses, only surgical duration was significantly associated with biochemical recurrence (P = 0.042), at a cut-off value of surgical duration of 228.5 minutes. Conclusions Prolonged surgical duration is associated with biochemical recurrence in patients with positive surgical margins. Thus, surgical duration should be limited as much as possible to reduce surgical stress, which might cause biochemical recurrence.
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Affiliation(s)
- Satoru Meguro
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Nobuhiro Haga
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hitomi Imai
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuki Yoshida
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Ruriko Takinami-Honda
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kanako Matsuoka
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Seiji Hoshi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Junya Hata
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuichi Sato
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hidenori Akaihata
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Masao Kataoka
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Soichiro Ogawa
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yoshiyuki Kojima
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
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Madel MB, Elefteriou F. Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis. Cancers (Basel) 2021; 13:cancers13122887. [PMID: 34207620 PMCID: PMC8228198 DOI: 10.3390/cancers13122887] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/06/2021] [Accepted: 06/08/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Bone represents the most common site of metastasis for breast cancer and the establishment and growth of metastatic cancer cells within the skeleton significantly reduces the quality of life of patients and their survival. The interplay between sympathetic nerves and bone cells, and its influence on the process of breast cancer bone metastasis is increasingly being recognized. Several mechanisms, all dependent on β-adrenergic receptor signaling in stromal bone cells, were shown to promote the establishment of disseminated cancer cells into the skeleton. This review provides a summary of these mechanisms in support of the therapeutic potential of β-blockers for the early management of breast cancer metastasis. Abstract The skeleton is heavily innervated by sympathetic nerves and represents a common site for breast cancer metastases, the latter being the main cause of morbidity and mortality in breast cancer patients. Progression and recurrence of breast cancer, as well as decreased overall survival in breast cancer patients, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. Preclinical studies have demonstrated that sympathetic stimulation of β-adrenergic receptors in osteoblasts increases bone vascular density, adhesion of metastatic cancer cells to blood vessels, and their colonization of the bone microenvironment, whereas β-blockade prevented these events in mice with high endogenous sympathetic activity. These findings in preclinical models, along with clinical data from breast cancer patients receiving β-blockers, support the pathophysiological role of excess sympathetic nervous system activity in the formation of bone metastases, and the potential of commonly used, safe, and low-cost β-blockers as adjuvant therapy to improve the prognosis of bone metastases.
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Affiliation(s)
| | - Florent Elefteriou
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, TX 77030, USA;
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Correspondence:
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33
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Ahmed J, Chard LS, Yuan M, Wang J, Howells A, Li Y, Li H, Zhang Z, Lu S, Gao D, Wang P, Chu Y, Al Yaghchi C, Schwartz J, Alusi G, Lemoine N, Wang Y. A new oncolytic V accinia virus augments antitumor immune responses to prevent tumor recurrence and metastasis after surgery. J Immunother Cancer 2021; 8:jitc-2019-000415. [PMID: 32217766 PMCID: PMC7206973 DOI: 10.1136/jitc-2019-000415] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2019] [Indexed: 01/02/2023] Open
Abstract
Background Local recurrence and remote metastasis are major challenges to overcome in order to improve the survival of patients with cancer after surgery. Oncolytic viruses are a particularly attractive option for prevention of postsurgical disease as they offer a non-toxic treatment option that can directly target residual tumor deposits and beneficially modulate the systemic immune environment that is suppressed post surgery and allows residual disease escape from control. Here, we report that a novel Vaccinia virus (VV), VVΔTKΔN1L (with deletion of both thymidine kinase (TK) and N1L genes) armed with interleukin 12 (IL-12), can prolong postoperative survival when used as a neoadjuvant treatment in different murine and hamster surgical models of cancer. Methods A tumor-targeted replicating VV with deletion of TK gene and N1L gene (VVΔTKΔN1L) was created. This virus was armed rationally with IL-12. The effect of VVΔTKΔN1L and VVΔTKΔN1L-IL12 on modulation of the tumor microenvironment and induction of tumor-specific immunity as well the feasibility and safety as a neoadjuvant agent for preventing recurrence and metastasis after surgery were assessed in several clinically relevant models. Results VVΔTKΔN1L can significantly prolong postoperative survival when used as a neoadjuvant treatment in three different surgery-induced metastatic models of cancer. Efficacy was critically dependent on elevation of circulating natural killer cells that was achieved by virus-induced cytokine production from cells infected with N1L-deleted, but not N1L-intact VV. This effect was further enhanced by arming VVΔTKΔN1L with IL-12, a potent antitumor cytokine. Five daily treatments with VVΔTKΔN1L-IL12 before surgery dramatically improved postsurgical survival. VVΔTKΔN1L armed with human IL-12 completely prevented tumor recurrence in surgical models of head and neck cancer in Syrian hamsters. Conclusions These data provide a proof of concept for translation of the regime into clinical trials. VVΔTKΔN1L-IL12 is a promising agent for use as an adjuvant to surgical treatment of solid tumors.
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Affiliation(s)
- Jahangir Ahmed
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Louisa S Chard
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Ming Yuan
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Jiwei Wang
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Anwen Howells
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Yuenan Li
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Haoze Li
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhongxian Zhang
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Shuangshuang Lu
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Dongling Gao
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Pengju Wang
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Yongchao Chu
- National Centre for International Research in Cell and Gene Therapy, Zhengzhou University, Zhengzhou, Henan, China
| | - Chadwan Al Yaghchi
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Joel Schwartz
- University of Illinois at Chicago, Chicago, Illinois, USA.,University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ghassan Alusi
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Nicholas Lemoine
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Yaohe Wang
- Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
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Shibuya T, Kamiyama A, Sawada H, Kikuchi K, Maruyama M, Sawado R, Ikeda N, Asano K, Kurotaki D, Tamura T, Yoneda A, Imada K, Satoh T, Akira S, Tanaka M, Yotsumoto S. Immunoregulatory Monocyte Subset Promotes Metastasis Associated With Therapeutic Intervention for Primary Tumor. Front Immunol 2021; 12:663115. [PMID: 34163472 PMCID: PMC8215602 DOI: 10.3389/fimmu.2021.663115] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Systemic and local inflammation associated with therapeutic intervention of primary tumor occasionally promotes metastatic recurrence in mouse and human. However, it remains unclear what types of immune cells are involved in this process. Here, we found that the tissue-repair-promoting Ym1+Ly6Chi monocyte subset expanded as a result of systemic and local inflammation induced by intravenous injection of lipopolysaccharide or resection of primary tumor and promoted lung metastasis originating from circulating tumor cells (CTCs). Deletion of this subset suppressed metastasis induced by the inflammation. Furthermore, transfer of Ym1+Ly6Chi monocytes into naïve mice promoted lung metastasis in the mice. Ym1+Ly6Chi monocytes highly expressed matrix metalloproteinase-9 (MMP-9) and CXCR4. MMP-9 inhibitor and CXCR4 antagonist decreased Ym1+Ly6Chi-monocyte-promoted lung metastasis. These findings indicate that Ym1+Ly6Chi monocytes are therapeutic target cells for metastasis originating from CTCs associated with systemic and local inflammation. In addition, these findings provide a novel predictive cellular biomarker for metastatic recurrence after intervention for primary tumor.
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Affiliation(s)
- Takumi Shibuya
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Asami Kamiyama
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Hirotaka Sawada
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Kenta Kikuchi
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Mayu Maruyama
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Rie Sawado
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Naoki Ikeda
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Kenichi Asano
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Daisuke Kurotaki
- Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiko Tamura
- Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.,Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Atsuko Yoneda
- Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Keisuke Imada
- Center for Fundamental Laboratory Education, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Takashi Satoh
- Department of Immune Regulation, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shizuo Akira
- Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Masato Tanaka
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Satoshi Yotsumoto
- Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
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35
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Li C, Fu Q, Cai J, Mei H, Shangguan W. Effects of propofol on the proliferation and migration of liver cancer cells. Exp Ther Med 2021; 22:733. [PMID: 34055050 PMCID: PMC8138278 DOI: 10.3892/etm.2021.10165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 03/10/2021] [Indexed: 12/21/2022] Open
Abstract
Liver cancer is a malignant cancer with worldwide prevalence. It has been reported that cancer cells are usually exposed to a hypoxic microenvironment, which is associated with a poor prognosis in patients with cancer. Propofol is an intravenous anesthetic that is widely used in cancer surgery. The present study aimed to determine the effects of propofol stimulation on the viability, proliferation and migration of liver cancer cells under normoxia and cobalt chloride (CoCl2)-induced hypoxia. Under normoxia, HepG2 and HCCLM3 cells were randomly divided into six groups as follows: i) Control group; ii) 10 µM propofol group; iii) 25 µM propofol group; iv) 50 µM propofol group; v) 100 µM propofol group; and vi) DMSO group. Cell viability and proliferation were analyzed using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, respectively, following 24 or 48 h of propofol treatment. In addition, wound healing and Transwell migration assays were used to determine the changes in cell migration. Under CoCl2-induced hypoxia, the protein levels of hypoxia inducible factor-1α (HIF-1α) of HepG2 cells were analyzed using western blotting. Subsequently, CCK-8 and wound healing assays were used to determine the effect of propofol on cell viability and migration. The results of the present study revealed that propofol stimulation had no significant effect on the viability, proliferation and migration of HepG2 and HCCLM3 cells under normoxia. The protein levels of HIF-1α were significantly upregulated following the treatment with 200 µM CoCl2 for 12 h. However, no significant differences were found in the viability and migration of HepG2 cells following the stimulation with propofol in the presence of CoCl2. In conclusion, the findings of the present study revealed that propofol exerted no effect on the viability, proliferation and migration of HepG2 and HCCLM3 cells under normoxic and hypoxic conditions.
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Affiliation(s)
- Chan Li
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Qingxia Fu
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Jin Cai
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Hongxia Mei
- Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Wangning Shangguan
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
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Jin YY, Yang WZ, Sun ZY, Wang ZB, Chen J, Wu CT, Yang ZY. NK cells adjuvant therapy shows survival benefits in a gastric mixed signet ring cell carcinoma patient: A case report. Medicine (Baltimore) 2021; 100:e24979. [PMID: 33725867 PMCID: PMC7969222 DOI: 10.1097/md.0000000000024979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Advanced signet ring cell (SRC) carcinoma has a worse prognosis. Therefore, early diagnosis and prevention is particularly important; SRC tumors have lower R0 resection rate and are thought to be less chemosensitive than non-SRCC. Consequently, a novel postoperative adjuvant treatment is urgently needed to improve clinical outcomes. PATIENT CONCERNS A 41-year-old female with advanced gastric SRC carcinoma was treated with radical gastrectomy and oxaliplatin-based regimen for 6 cycles after surgery. She was suspected of recurrence with the high level of carbohydrate antigen (CA) 72-4. DIAGNOSES The gastroscopy revealed SRC carcinoma of gastric antrum and poorly differentiated adenocarcinoma in some areas. The diagnosis of postoperative pathology report was gastric cancer with stage III C (T4a, N3a, M0). INTERVENTIONS The level of CA72-4 rapidly increased during the 2 follow-up after the completion of conventional treatment, ex vivo-cultured allogeneic natural killer (NK) cell infusion was offered to prevent recurrence. OUTCOMES Intravenous injections of NK cells combination with surgical treatment and chemotherapy showed therapeutic effects in this patient with possible relapse. The patient remained disease-free 46 months after the infusion of NK cells until the latest follow-up. LESSONS CA72-4 appeared to be the most sensitive and specific marker in the gastric cancer patient, and the high level of CA72-4 may indicate the risk of recurrence. This case report provide rationale for NK cell infusion following the rapid increase of CA72-4 to prevent recurrence.
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MESH Headings
- Adult
- Antigens, Tumor-Associated, Carbohydrate/blood
- Antigens, Tumor-Associated, Carbohydrate/immunology
- Carcinoma, Signet Ring Cell/diagnosis
- Carcinoma, Signet Ring Cell/immunology
- Carcinoma, Signet Ring Cell/pathology
- Carcinoma, Signet Ring Cell/therapy
- Combined Modality Therapy/methods
- Female
- Gastrectomy
- Humans
- Killer Cells, Natural/transplantation
- Neoplasm Staging
- Postoperative Care/methods
- Prognosis
- Stomach Neoplasms/diagnosis
- Stomach Neoplasms/immunology
- Stomach Neoplasms/pathology
- Stomach Neoplasms/therapy
- Transplantation, Homologous
- Treatment Outcome
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Affiliation(s)
- Yuan-Yuan Jin
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing
| | - Wen-Zhuo Yang
- Sun Yat-sen University School of Medicine, Guangzhou
| | - Zheng-Yang Sun
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing
| | - Zhong-Bo Wang
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing
| | - Jian Chen
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong
| | - Chun-Tao Wu
- North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Zhao-Yong Yang
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing
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Neuroimmune Regulation of Surgery-Associated Metastases. Cells 2021; 10:cells10020454. [PMID: 33672617 PMCID: PMC7924204 DOI: 10.3390/cells10020454] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/12/2021] [Accepted: 02/17/2021] [Indexed: 02/06/2023] Open
Abstract
Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous system has been recognized as another contributor to cancer development and metastasis, little is known about the contribution of tumor-associated neuronal and neuroglial elements in the metastatic disease related to surgical trauma and wound healing. Specifically, although numerous clinical and experimental data suggest that biopsy- and surgery-induced wound healing can promote survival and metastatic spread of residual and dormant malignant cells, the involvement of the tumor-associated neuroglial cells in the formation of metastases following tissue injury has not been well understood. Understanding the clinical significance and underlying mechanisms of neuroimmune regulation of surgery-associated metastasis will not only advance the field of neuro–immuno–oncology and contribute to basic science and translational oncology research but will also produce a strong foundation for developing novel mechanism-based therapeutic approaches that may protect patients against the oncologically adverse effects of primary tumor biopsy and excision.
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38
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Liu Y, Zou L, Wang P, Zhou J, Yuan C, Wang J. Construction of differential expression plasmids of NGF to detect its influence on PC12 cell neuronal differentiation. Exp Ther Med 2021; 21:363. [PMID: 33732336 PMCID: PMC7903390 DOI: 10.3892/etm.2021.9794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 11/13/2020] [Indexed: 11/30/2022] Open
Abstract
Alongside angiogenesis and lymphangiogenesis, neurogenesis also occurs within the cancer microenvironment. Neurogenesis is a complex process involving multiple factors, among which nerve growth factor (NGF) possesses the dual biological roles of neuron nutrition and axon growth promotion. Thus, NGF might be a key molecule involved in regulating cancer-related neurogenesis, which could play a crucial role in the signal transmission system that controls nerve growth in tumors, and enhances the abilities of migration, invasion and metastasis of tumor cells. The present study aimed to construct differential expression plasmids of NGF, in order to detect whether NGF has a vital role in neurogenesis in breast cancer cells. In the present study, 92 clinical cases of breast cancer were collected and immunohistochemical analysis was performed to verify the existence of neurons in the breast cancer microenvironment. Furthermore, recombinant NGF lentiviral overexpression, knockout and silencing plasmids were constructed, and whether NGF has an effect on neuron growth was preliminarily confirmed, indicating that the successfully constructed plasmids could be used to verify the roles of NGF in cancer-associated neurogenesis.
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Affiliation(s)
- Yu Liu
- Central Laboratory, The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China.,Department of Oncology, Gong'an County Hospital, Jingzhou, Hubei 434300, P.R. China
| | - Lili Zou
- Central Laboratory, The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China.,Infection and Inflammation Institute, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Peng Wang
- Central Laboratory, The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China.,Infection and Inflammation Institute, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Jingxuan Zhou
- Central Laboratory, The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China.,Infection and Inflammation Institute, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Chunling Yuan
- Central Laboratory, The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China
| | - Jun Wang
- Central Laboratory, The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China
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Ishikawa M, Iwasaki M, Zhao H, Saito J, Hu C, Sun Q, Sakamoto A, Ma D. Sevoflurane and Desflurane Exposure Enhanced Cell Proliferation and Migration in Ovarian Cancer Cells via miR-210 and miR-138 Downregulation. Int J Mol Sci 2021; 22:ijms22041826. [PMID: 33673181 PMCID: PMC7917656 DOI: 10.3390/ijms22041826] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
Inhalational anaesthetics were previously reported to promote ovarian cancer malignancy, but underlying mechanisms remain unclear. The present study aims to investigate the role of sevoflurane- or desflurane-induced microRNA (miRNA) changes on ovarian cancer cell behaviour. The cultured SKOV3 cells were exposed to 3.6% sevoflurane or 10.3% desflurane for 2 h. Expression of miR-138, -210 and -335 was determined with qRT-PCR. Cell proliferation and migration were assessed with wound healing assay, Ki67 staining and Cell Counting Kit-8 (CCK8) assay with or without mimic miR-138/-210 transfections. The miRNA downstream effector, hypoxia inducible factor-1α (HIF-1α), was also analysed with immunofluorescent staining. Sevoflurane or desflurane exposure to cancer cells enhanced their proliferation and migration. miR-138 expression was suppressed by both sevoflurane and desflurane, while miR-210 expression was suppressed only by sevoflurane. miR-335 expression was not changed by either sevoflurane or desflurane exposure. The administration of mimic miR-138 or -210 reduced the promoting effects of sevoflurane and desflurane on cancer cell proliferation and migration, in line with the HIF-1α expression changes. These data indicated that inhalational agents sevoflurane and desflurane enhanced ovarian cancer cell malignancy via miRNA deactivation and HIF-1α. The translational value of this work needs further study.
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Affiliation(s)
- Masashi Ishikawa
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (M.I.); (M.I.); (A.S.)
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Masae Iwasaki
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (M.I.); (M.I.); (A.S.)
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Hailin Zhao
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Junichi Saito
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
- Department of Anesthesiology, Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori 036-8562, Japan
| | - Cong Hu
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Qizhe Sun
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Atsuhiro Sakamoto
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (M.I.); (M.I.); (A.S.)
| | - Daqing Ma
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
- Correspondence:
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40
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Fishbein A, Hammock BD, Serhan CN, Panigrahy D. Carcinogenesis: Failure of resolution of inflammation? Pharmacol Ther 2021; 218:107670. [PMID: 32891711 PMCID: PMC7470770 DOI: 10.1016/j.pharmthera.2020.107670] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
Abstract
Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.
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Affiliation(s)
- Anna Fishbein
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Bruce D. Hammock
- Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
| | - Charles N. Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Iftikhar A, Islam M, Shepherd S, Jones S, Ellis I. Cancer and Stress: Does It Make a Difference to the Patient When These Two Challenges Collide? Cancers (Basel) 2021; 13:cancers13020163. [PMID: 33418900 PMCID: PMC7825104 DOI: 10.3390/cancers13020163] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Head and neck cancers are the sixth most common cancer in the world. The burden of the disease has remained challenging over recent years despite the advances in treatments of other malignancies. The very use of the word malignancy brings about a stress response in almost all adult patients. Being told you have a tumour is not a word anyone wants to hear. We have embarked on a study which will investigate the effect of stress pathways on head and neck cancer patients and which signalling pathways may be involved. In the future, this will allow clinicians to better manage patients with head and neck cancer and reduce the patients’ stress so that this does not add to their tumour burden. Abstract A single head and neck Cancer (HNC) is a globally growing challenge associated with significant morbidity and mortality. The diagnosis itself can affect the patients profoundly let alone the complex and disfiguring treatment. The highly important functions of structures of the head and neck such as mastication, speech, aesthetics, identity and social interactions make a cancer diagnosis in this region even more psychologically traumatic. The emotional distress engendered as a result of functional and social disruption is certain to negatively affect health-related quality of life (HRQoL). The key biological responses to stressful events are moderated through the combined action of two systems, the hypothalamus–pituitary–adrenal axis (HPA) which releases glucocorticoids and the sympathetic nervous system (SNS) which releases catecholamines. In acute stress, these hormones help the body to regain homeostasis; however, in chronic stress their increased levels and activation of their receptors may aid in the progression of cancer. Despite ample evidence on the existence of stress in patients diagnosed with HNC, studies looking at the effect of stress on the progression of disease are scarce, compared to other cancers. This review summarises the challenges associated with HNC that make it stressful and describes how stress signalling aids in the progression of cancer. Growing evidence on the relationship between stress and HNC makes it paramount to focus future research towards a better understanding of stress and its effect on head and neck cancer.
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Teng WN, Wu HL, Tai YH, Lei HJ, Tsou MY, Chang KY. Group-based trajectory analysis of postoperative pain and outcomes after liver cancer surgery. J Chin Med Assoc 2021; 84:95-100. [PMID: 33177401 DOI: 10.1097/jcma.0000000000000446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Although previous studies have shown connections between pain and worse cancer outcomes, few clinical studies have evaluated their direct association, and the current study aimed to investigate the potential association between acute pain trajectories and postoperative outcomes after liver cancer surgery. METHODS This retrospective study was conducted in a single medical center and included patients who received liver cancer surgery between January 2010 and December 2016. Maximal pain intensity was recorded daily using a numerical rating scale during the first postoperative week. Group-based trajectory analysis was performed to classify the variations in pain scores over time. Cox and linear regression analyses were used to assess the effect of pain trajectories on recurrence-free survival, overall survival, and length of hospital stay (LOS) after surgery and to explore predictors of these outcomes. RESULTS A total of 804 patients with 5396 pain score observations were analyzed within the present study. Group-based trajectory analysis categorized the changes in postoperative pain into three groups: group 1 had constantly mild pain (76.6%), group 2 had moderate/severe pain dropping to mild (10.1%), and group 3 had mild pain rebounding to moderate (13.3%). Multivariable analysis demonstrated that on average, group 3 had a 7% increase in LOS compared with the group 1 (p = 0.02) and no significant difference in the LOS was noted between pain trajectory groups 2 and 1 (p = 0.93). Pain trajectories were not associated with recurrence-free survival or overall survival after liver cancer surgery. CONCLUSION Acute pain trajectories were associated with LOS but not cancer recurrence and survival after liver cancer surgery. Group-based trajectory analysis provided a promising approach for investigating the complex relationships between variations in postoperative pain over time and clinical outcomes.
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Affiliation(s)
- Wei-Nung Teng
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Hsiang-Ling Wu
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Ying-Hsuan Tai
- Department of Anesthesiology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, ROC
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Hao-Jan Lei
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Mei-Yung Tsou
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Kuang-Yi Chang
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
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Ben-Eliyahu S. Tumor Excision as a Metastatic Russian Roulette: Perioperative Interventions to Improve Long-Term Survival of Cancer Patients. Trends Cancer 2020; 6:951-959. [DOI: 10.1016/j.trecan.2020.06.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/09/2020] [Accepted: 06/19/2020] [Indexed: 01/27/2023]
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Cubuk S, Uckan S, Ozdemir H, Taslica ZF, Bacanli D. The efficiency of propranolol on occurrence and development of 4-nitroquinoline 1-oxide-induced squamous cell carcinoma of the tongue in rats. J Oral Maxillofac Pathol 2020; 24:400. [PMID: 33456259 PMCID: PMC7802876 DOI: 10.4103/jomfp.jomfp_88_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 05/11/2020] [Indexed: 12/18/2022] Open
Abstract
Aims: The aim of this study to investigate the efficiency of propranolol on occurrence and development of 4-nitroquinoline 1-oxide (4NQO)-induced squamous cell carcinogenesis of the tongue in rats. Subjects and Methods: The sample was composed of 27 male Sprague Dawley rats that received 50 ppm 4NQO for 20 weeks in drinking water. Group 1 (n = 9) was treated with 50 mg/kg/day propranolol for 20 weeks, Group 2 (n = 9), after carcinogenesis inducement for 20 weeks, received propranolol (50 mg/kg/day) for 2 weeks and Group 3 (n = 9) received no treatment. At the end of the experimental stage, the tongue specimens were evaluated under a light microscope and categorized as low- or high-risk lesions according to a binary system. Statistical Analysis Used: The statistical comparison was performed with a likelihood ratio test. Results: Histopathological analysis revealed the risk of malignant transformation rates as 33.3% in Group 1, 55.5% in Group 2 and 77.8% in Group 3; however, the difference between the groups was not statistically significant (P > 0.05). Conclusion: The results of the study suggest that propranolol has a tendency to preventive effect against carcinogenesis.
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Affiliation(s)
- Secil Cubuk
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Başkent University, İstanbul, Turkey
| | - Sina Uckan
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Medipol University, İstanbul, Turkey
| | - Handan Ozdemir
- Department of Pathology, Faculty of Medicine, Başkent University, İstanbul, Turkey
| | - Zeynep Firdevs Taslica
- Pathology Laboratory, Council of Forensic Medicine, Ankara Group Chairmanship, İstanbul, Turkey
| | - Didem Bacanli
- Animal Research Center, Başkent University, İstanbul, Turkey
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Zhao S, Fan S, Shi Y, Ren H, Hong H, Gao X, Zhang M, Qin Q, Li H. Propranolol induced apoptosis and autophagy via the ROS/JNK signaling pathway in Human Ovarian Cancer. J Cancer 2020; 11:5900-5910. [PMID: 32922532 PMCID: PMC7477428 DOI: 10.7150/jca.46556] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/20/2020] [Indexed: 01/06/2023] Open
Abstract
Propranolol has a significant anti-cancer effect towards various cancers. Our study aimed at investigating the underlying mechanism of Propranolol's therapeutic effect towards ovarian cancer. Specifically, Propranolol significantly reduced the viability of human ovarian cancer cell lines SKOV-3 and A2780 in a dose- and time-dependent manner. Flow cytometry analysis revealed that Propranolol induced the cell cycle arrest at G2/M phase therefore leading to apoptosis. Moreover, autophagy inhibitor 3-MA markedly enhanced the Propranolol-induced apoptosis. In addition, reactive oxygen species (ROS) increased dramatically after Propranolol treatment and Propranolol activated the phosphorylation of JNK. What is more, p38 inhibitor SB203580 and JNK inhibitor SP600125 attenuated the upregulated expression of LC3-II and cleaved-caspase-3 by the effect of Propranolol. ROS exclusive inhibitor antioxidant N-acetyl cysteine (NAC) weakens the phosphorylation of JNK proteins induced by Propranolol. In summary, these results suggested that Propranolol induced cell apoptosis and protective autophagy through the ROS/JNK signaling pathway in human ovarian cancer cells.
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Affiliation(s)
- Shujun Zhao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China.,Zhengzhou Key Laboratory of Gynecological Oncology, 450052 Zhengzhou, China
| | - Suzhen Fan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China
| | - Yanyu Shi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China
| | - Hongyan Ren
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China
| | - Hanqing Hong
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China
| | - Xiang Gao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China
| | - Min Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China
| | - Qiaohong Qin
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China
| | - Hongyu Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Street, Zhengzhou, 450000, P.R.China.,Zhengzhou Key Laboratory of Gynecological Oncology, 450052 Zhengzhou, China
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Erin N. Role of sensory neurons, neuroimmune pathways, and transient receptor potential vanilloid 1 (TRPV1) channels in a murine model of breast cancer metastasis. Cancer Immunol Immunother 2020; 69:307-314. [PMID: 31912230 DOI: 10.1007/s00262-019-02463-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 12/26/2019] [Indexed: 12/23/2022]
Abstract
Sensory nerves sensitive to capsaicin are afferent nerve fibers which contain TRPV1 channels. Activation of these channels induces release of neuropeptides which regulate local blood flow and immune response. Inactivation of sensory neurons either with high-dose capsaicin treatment or local ablation of vagal sensory nerve activity markedly increases metastasis of breast carcinoma formed by 4T1 derivative cells. These cancer cells also induce an extensive systemic inflammatory response. Further findings have documented that lack of local sensory neuromediators alters phenotype of cancer cells within primary tumor leading to overgrowth of metastatic subsets. This might be due to decreases in local and systemic immune response to growing tumor. Specifically, Substance P, one of the most abundant sensory neuropeptides, enhances anti-tumoral immune response evoked by radiotherapy under in vivo conditions. These findings further suggest that activation of TRPV1 channels on sensory neurons may induce an anti-tumoral immune response. We are testing this hypothesis. Our initial results as reported here demonstrate anti-inflammatory consequences of low-dose systemic capsaicin treatment. In conclusion, sensory nerve fibers sensitive to capsaicin have important roles in defense against metastatic breast carcinoma; hence, controlled activation of these neural pathways might be effective in cancer therapy. Specifically, activation of sensory fibers of left vagus nerve using a perineuronal stimulation may inhibit metastasis of breast carcinoma. Likewise, pharmacological modulators of TRPV1 channels may induce anti-tumoral immune response. Exact players of this newly explored defense system are, however, only partly validated, and further studies are required.
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Affiliation(s)
- Nuray Erin
- Department of Medical Pharmacology, Immunopharmacology and Immunooncology Research Unit, School of Medicine, Akdeniz University, B-blok kat 1 Immunoloji, 07070, Antalya, Turkey.
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Cata JP, Corrales G, Speer B, Owusu-Agyemang P. Postoperative acute pain challenges in patients with cancer. Best Pract Res Clin Anaesthesiol 2019; 33:361-371. [DOI: 10.1016/j.bpa.2019.07.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 07/19/2019] [Indexed: 12/13/2022]
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Beyond the boundaries of cardiology: Still untapped anticancer properties of the cardiovascular system-related drugs. Pharmacol Res 2019; 147:104326. [DOI: 10.1016/j.phrs.2019.104326] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 06/18/2019] [Accepted: 06/21/2019] [Indexed: 02/07/2023]
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Ramondetta LM, Hu W, Thaker PH, Urbauer DL, Chisholm GB, Westin SN, Sun Y, Ramirez PT, Fleming N, Sahai SK, Nick AM, Arevalo JMG, Dizon T, Coleman RL, Cole SW, Sood AK. Prospective pilot trial with combination of propranolol with chemotherapy in patients with epithelial ovarian cancer and evaluation on circulating immune cell gene expression. Gynecol Oncol 2019; 154:524-530. [PMID: 31353053 DOI: 10.1016/j.ygyno.2019.07.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/26/2019] [Accepted: 07/01/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. METHODS Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. RESULTS Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn't meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53-81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P < 0.05) and leukocyte expression of pro-inflammatory genes declined (P = 0.03) after completion of therapy. Decrease from baseline of serum IL-6 and IL-8 preceded response to chemotherapy (P < 0.0014). Change from baseline IL-10 preceded complete response. CONCLUSION Use of propranolol during primary treatment of EOC is feasible and treatment resulted in decrease in markers of adrenergic stress response. In combination with chemotherapy, propranolol potentially results in improved QOL over baseline.
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Affiliation(s)
- Lois M Ramondetta
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
| | - Wei Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Premal H Thaker
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States of America
| | - Diana L Urbauer
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Gary B Chisholm
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Yunjie Sun
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Pedro T Ramirez
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Nicole Fleming
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Sunil K Sahai
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Alpa M Nick
- St. Thomas Medical Partners, Gynecologic Oncology, Nashville, TN, United States of America; The University of Tennessee Health Sciences Center, Memphis, TN, United States of America
| | - Jesusa M G Arevalo
- Department of Psychiatry and Biobehavioral Sciences and Medicine, University of California, Los Angeles, CA, United States of America
| | - Thomas Dizon
- Department of Psychiatry and Biobehavioral Sciences and Medicine, University of California, Los Angeles, CA, United States of America
| | - Robert L Coleman
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Steve W Cole
- Department of Psychiatry and Biobehavioral Sciences and Medicine, University of California, Los Angeles, CA, United States of America
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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Schack A, Fransgaard T, Klein MF, Gögenur I. Perioperative Use of Nonsteroidal Anti-inflammatory Drugs Decreases the Risk of Recurrence of Cancer After Colorectal Resection: A Cohort Study Based on Prospective Data. Ann Surg Oncol 2019; 26:3826-3837. [DOI: 10.1245/s10434-019-07600-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Indexed: 02/06/2023]
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