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Kim K, Khazan N, McDowell JL, Snyder CWA, Miller JP, Singh RK, Whittum ME, Turner R, Moore RG. The NF-κB-HE4 axis: A novel regulator of HE4 secretion in ovarian cancer. PLoS One 2024; 19:e0314564. [PMID: 39621651 PMCID: PMC11611113 DOI: 10.1371/journal.pone.0314564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/12/2024] [Indexed: 12/09/2024] Open
Abstract
Ovarian cancer is the leading cause of death among gynecologic malignancies. Despite recent advancements in targeted therapies such as PARP inhibitors, recurrence is common and frequently resistant to existing therapies. A powerful diagnostic tool, coupled with a comprehensive understanding of its implications, is crucial. HE4, a clinical serum biomarker for ovarian cancer, has shown efficacy in monitoring malignant phenotypes, yet little is known about its biological role and regulatory mechanisms. Our research demonstrates that HE4 expression in ovarian cancer can be regulated by the NF-κB signaling pathway. We found that the activation of NF-κB signaling by tumor necrosis factor (TNF)-α, a cytokine found in ovarian cancer tumors and ascites, enhanced the secretion of HE4 while its inhibition suppressed HE4 levels. Nuclear translocation of the NF-κB component p65 was found to be critical for HE4 expression; induced NF-κB activation through p65 expression or constitutive IKK2 activity elevated HE4 expression, while p65 knockdown had the opposite effect. Furthermore, we observed that NF-κB mediated HE4 expression at the transcriptional level. Our data also suggests that there is a regulatory role for HE4 in the expression of α5-Integrin, a crucial adhesion molecule in ovarian cancer metastasis; HE4 knockdown corresponded with reduced α5-Integrin expression, cell migration and cell adhesion to fibronectin.
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Affiliation(s)
- Kyukwang Kim
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Negar Khazan
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Jamie L. McDowell
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Cameron W. A. Snyder
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
| | - John P. Miller
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY, United States of America
| | - Rakesh K. Singh
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Michelle E. Whittum
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Rachael Turner
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Richard G. Moore
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States of America
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Chuang CH, Huang PM, Liang ST, Chen KC, Lin MW, Kuo SW, Liao HC, Lee JM. Plasma Cytokines Pattern as a Prognostic Marker for Esophageal Squamous Cell Carcinoma via Unsupervised Clustering Analyses. Oncology 2024; 103:427-438. [PMID: 39307133 PMCID: PMC12048106 DOI: 10.1159/000541371] [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: 03/29/2024] [Accepted: 09/05/2024] [Indexed: 10/23/2024]
Abstract
INTRODUCTION Cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL6), interferon-gamma (IFN-γ), interleukin 17-alpha (IL17-α), and interleukin 33 (IL33) play critical roles in immune responses and may impact cancer prognosis in future. However, few studies have simultaneously explored the prognostic impact of these cytokines for cancer. In this study, we aim to apply the unsupervised clustering analysis to approach the correlation between the expression of these cytokines and the subsequent prognosis of patients with esophageal squamous cell carcinoma (ESCC). METHODS A robust clustering algorithm was used, the Gaussian mixture method (GMM), through the mclust R package to group patients based on the expression of their cytokines in plasma or tumors. The 324 NTU patients were grouped into 4 clusters, and the 179 GSE53625 patients were grouped into 3 clusters based on expression in plasma and tumors, respectively. Five- and 3-year overall survival (OS) and progression-free survival (PFS) curves of each cluster were compared. Univariate and multivariate Cox regression analyses were also performed. RESULTS We successfully distinguished the multimodal distribution of cytokines through GMM clustering and discovered the relationship between cytokines and clinical outcomes. We observed that NTU-G3 and NTU-G4 subgroups showed most variation in 5-, 3-year OS and 5-, 3-year PFS with NTU-G3 being associated with poorer prognosis compared to NTU-G4 (p = 0.016, 0.0052, 0.0575, and 0.0168, respectively). NTU-G3 was characterized with higher TNF-α (median = 3.855, N = 78) and lower IL33 (median = 0.000, N = 78), while NTU-G4 showed lower TNF-α (median = 1.76, N = 51) and higher IL33 (median = 1.070, N = 51). The difference was statistically significant for TNF-α and IL33, with p = 0.0002 and p < 0.0001, respectively. A multivariate Cox-regression analysis revealed that GMM clustering and T/N stage were independent factors for prognosis, suggesting that the prognosis might be dependent on these cytokines. CONCLUSIONS Our data suggest that expression patterns of IL33 and TNF-α in plasma might serve as a convenient marker to predict the prognosis of ESCC in the future.
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Affiliation(s)
- Cheng-Hsun Chuang
- Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- TCI Gene Inc., Taipei, Taiwan
| | - Pei-Ming Huang
- Department of Thoracic Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Tzu Liang
- Department of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ke-Cheng Chen
- Department of Thoracic Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Mong-Wei Lin
- Department of Thoracic Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Shuenn-Wen Kuo
- Department of Thoracic Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsien-Chi Liao
- Department of Thoracic Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Jang-Ming Lee
- Department of Thoracic Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Tuncer SB, Celik B, Kılıc Erciyas S, Sukruoglu Erdogan O, Pasin O, Avsar M, Kurt Gultaslar B, Adamnejad Ghafour A, Uyaroglu G, Akdeniz Odemis D, Yazıcı H. Aberrant miR-3135b and miR-1273g-3p expression in the peripheral blood samples of BRCA1/2 (±) ovarian cancer patients. Heliyon 2024; 10:e23876. [PMID: 38234891 PMCID: PMC10792459 DOI: 10.1016/j.heliyon.2023.e23876] [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: 04/20/2023] [Revised: 12/04/2023] [Accepted: 12/14/2023] [Indexed: 01/19/2024] Open
Abstract
Ovarian cancer (OC) ranks as the eighth most prevalent malignancy among women globally. The short non-coding RNA molecules, microRNAs (miRNAs) target multiple mRNAs and regulate the gene expression. Here in this study, we aimed to validate miR-3135b and miR-1273g-3p as novel biomarkers for prognostic and diagnostic factor OC. After RNA isolation, we analyzed the miR-3135b and miR-1273g-3p expression in peripheral blood samples derived from 150 OC patients. Subsequently, we compared their expression levels with 100 healthy controls. The differences of miR-3135b and miR-1273g-3p expression were detected using the Quantitative Real Time-PCR (qRT-PCR) technique following miRNA-specific cDNA synthesis pursing miRNA separation. The miR-3135b and miR-1273g-3p were higher in OC patients who tested positive for BRCA1/2 compared to BRCA-negative patients, and healthy cases. The level of miR-3135b demonstrated a roughly 4.82-fold increase in OC patients in comparison to the healthy cases, while miR-1273g-3p expression exhibited a roughly 6.77-fold increase. The receiver operating characteristic (ROC) analysis has demonstrated the potential of miR-3135b and miR-1273g-3p as markers for distinguishing between OC patients and healthy controls. The higher expressions of miR-3135b and miR-1273g-3p could be associated with OC development. Moreover, miR-3135b may have a diagnostic potential and miR-1273g-3p may have both diagnostic and prognostic potential in OC cell differentiation. The string analysis has revealed an association between miR-1273g-3p and the MDM2 gene, suggesting a potential link to tumor formation through the proteasomal degradation of the TP53 tumor suppressor gene. Additionally, the analysis indicates an association of miR-1273g-3p with CHEK1, a gene involved in checkpoint-mediated cell cycle arrest. String analysis also indicates that miR-3135b is associated with the MAPK1 gene, causing activation of the oncogenesis cascade. In conclusion, miR-1273g-3p, and miR-3135b exhibit significant potential as diagnostic markers. However, further research is needed to comprehensively investigate these miRNAs diagnostic and predictive characteristics in a larger cohort.
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Affiliation(s)
- Seref Bugra Tuncer
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Betul Celik
- Molecular Biology Department, Erzincan Binali Yıldırım University, Erzincan, Türkiye
| | - Seda Kılıc Erciyas
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Ozge Sukruoglu Erdogan
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Ozge Pasin
- Faculty of Medicine, Department of Biostatistics, Bezmialem Vakıf University, Istanbul, Türkiye
| | - Mukaddes Avsar
- Department of Medical Services and Techniques, Istanbul Aydın University, Istanbul, Türkiye
| | - Busra Kurt Gultaslar
- Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Türkiye
| | | | - Gamze Uyaroglu
- Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Türkiye
| | - Demet Akdeniz Odemis
- Department of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Türkiye
| | - Hulya Yazıcı
- Department of Medical Biology, Istanbul Arel University, Istanbul, Türkiye
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Liu W, Li Z, Li X, Cao H, Jiang H, Niu Q, Hu B. Influence of tumor mycobiome on cancer pathogenesis (Review). Oncol Lett 2023; 26:541. [PMID: 38020300 PMCID: PMC10660446 DOI: 10.3892/ol.2023.14128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Cancer tissues harbor a large microbiome. There is growing evidence that the tumor microbiome is significantly correlated with the prognosis of cancer patients, but the exact underlying mechanisms have remained elusive. Although the tumor mycobiome is less abundant than the biome of bacteria, it is prevalent in most cancers in humans. The present review describes in detail the impact of the tumor mycobiome on cancer pathogenesis. The tumor mycobiome promotes tumor progression and metastasis by affecting the human immune system, maintaining a pro-inflammatory environment, producing aflatoxins, attenuating cell adhesion mechanisms and fungal-bacterial interactions. Furthermore, the tumor mycobiome likewise has great potential for cancer prevention, diagnosis and treatment.
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Affiliation(s)
- Weipeng Liu
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Zongrui Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Xiaopeng Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Haiyang Cao
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - He Jiang
- Breast Treatment Center, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong 271000, P.R. China
| | - Qingbin Niu
- Department of Gastrointestinal Surgery, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Baoguang Hu
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
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5
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Pal S, Bhowmick S, Sharma A, Sierra-Fonseca JA, Mondal S, Afolabi F, Roy D. Lymphatic vasculature in ovarian cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188950. [PMID: 37419192 PMCID: PMC10754213 DOI: 10.1016/j.bbcan.2023.188950] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/29/2023] [Accepted: 06/29/2023] [Indexed: 07/09/2023]
Abstract
Ovarian cancer (OVCA) is the second most common gynecological cancer and one of the leading causes of cancer related mortality among women. Recent studies suggest that among ovarian cancer patients at least 70% of the cases experience the involvement of lymph nodes and metastases through lymphatic vascular network. However, the impact of lymphatic system in the growth, spread and the evolution of ovarian cancer, its contribution towards the landscape of ovarian tissue resident immune cells and their metabolic responses is still a major knowledge gap. In this review first we present the epidemiological aspect of the OVCA, the lymphatic architecture of the ovary, we discuss the role of lymphatic circulation in regulation of ovarian tumor microenvironment, metabolic basis of the upregulation of lymphangiogenesis which is often observed during progression of ovarian metastasis and ascites development. Further we describe the implication of several mediators which influence both lymphatic vasculature as well as ovarian tumor microenvironment and conclude with several therapeutic strategies for targeting lymphatic vasculature in ovarian cancer progression in present day.
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Affiliation(s)
- Sarit Pal
- Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX 77843, United States
| | - Sramana Bhowmick
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India
| | - Anurag Sharma
- Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States
| | | | - Susmita Mondal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India
| | - Favour Afolabi
- Department of Biological Sciences, Alcorn State University, Lorman, MS 39096, United States
| | - Debarshi Roy
- Department of Biological Sciences, Alcorn State University, Lorman, MS 39096, United States.
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6
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Jou E. Type 1 and type 2 cytokine-mediated immune orchestration in the tumour microenvironment and their therapeutic potential. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:474-497. [PMID: 37455828 PMCID: PMC10345208 DOI: 10.37349/etat.2023.00146] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/25/2023] [Indexed: 07/18/2023] Open
Abstract
Cancer remains the second leading cause of death worldwide despite modern breakthroughs in medicine, and novel treatments are urgently needed. The revolutionary success of immune checkpoint inhibitors in the past decade serves as proof of concept that the immune system can be effectively harnessed to treat cancer. Cytokines are small signalling proteins with critical roles in orchestrating the immune response and have become an attractive target for immunotherapy. Type 1 immune cytokines, including interferon γ (IFNγ), interleukin-12 (IL-12), and tumour necrosis factor α (TNFα), have been shown to have largely tumour suppressive roles in part through orchestrating anti-tumour immune responses mediated by natural killer (NK) cells, CD8+ T cells and T helper 1 (Th1) cells. Conversely, type 2 immunity involving group 2 innate lymphoid cells (ILC2s) and Th2 cells are involved in tissue regeneration and wound repair and are traditionally thought to have pro-tumoural effects. However, it is found that the classical type 2 immune cytokines IL-4, IL-5, IL-9, and IL-13 may have conflicting roles in cancer. Similarly, type 2 immunity-related cytokines IL-25 and IL-33 with recently characterised roles in cancer may either promote or suppress tumorigenesis in a context-dependent manner. Furthermore, type 1 cytokines IFNγ and TNFα have also been found to have pro-tumoural effects under certain circumstances, further complicating the overall picture. Therefore, the dichotomy of type 1 and type 2 cytokines inhibiting and promoting tumours respectively is not concrete, and attempts of utilising these for cancer immunotherapy must take into account all available evidence. This review provides an overview summarising the current understanding of type 1 and type 2 cytokines in tumour immunity and discusses the prospects of harnessing these for immunotherapy in light of previous and ongoing clinical trials.
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Affiliation(s)
- Eric Jou
- Queens’ College, University of Cambridge, CB3 9ET Cambridge, UK
- MRC Laboratory of Molecular Biology, CB2 0QH Cambridge, UK
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7
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Yoon JH, Kim MY, Cho JY. Apigenin: A Therapeutic Agent for Treatment of Skin Inflammatory Diseases and Cancer. Int J Mol Sci 2023; 24:ijms24021498. [PMID: 36675015 PMCID: PMC9861958 DOI: 10.3390/ijms24021498] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 01/13/2023] Open
Abstract
The skin is the main barrier between the body and the environment, protecting it from external oxidative stress induced by ultraviolet rays. It also prevents the entrance of infectious agents such as viruses, external antigens, allergens, and bacteria into our bodies. An overreaction to these agents causes severe skin diseases, including atopic dermatitis, pruritus, psoriasis, skin cancer, and vitiligo. Members of the flavonoid family include apigenin, quercetin, luteolin, and kaempferol. Of these, apigenin has been used as a dietary supplement due to its various biological activities and has been shown to reduce skin inflammation by downregulating various inflammatory markers and molecular targets. In this review, we deal with current knowledge about inflammatory reactions in the skin and the molecular mechanisms by which apigenin reduces skin inflammation.
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Affiliation(s)
- Ji Hye Yoon
- Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Mi-Yeon Kim
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea
- Correspondence: (M.-Y.K.); (J.Y.C.); Tel.: +82-2-820-0458 (M.-Y.K.); +82-31-290-7868 (J.Y.C.)
| | - Jae Youl Cho
- Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Republic of Korea
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea
- Correspondence: (M.-Y.K.); (J.Y.C.); Tel.: +82-2-820-0458 (M.-Y.K.); +82-31-290-7868 (J.Y.C.)
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8
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Olivera I, Sanz-Pamplona R, Bolaños E, Rodriguez I, Etxeberria I, Cirella A, Egea J, Garasa S, Migueliz I, Eguren-Santamaria I, Sanmamed MF, Glez-Vaz J, Azpilikueta A, Alvarez M, Ochoa MC, Malacrida B, Propper D, de Andrea CE, Berraondo P, Balkwill FR, Teijeira Á, Melero I. A Therapeutically Actionable Protumoral Axis of Cytokines Involving IL-8, TNFα, and IL-1β. Cancer Discov 2022; 12:2140-2157. [PMID: 35771565 DOI: 10.1158/2159-8290.cd-21-1115] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 05/20/2022] [Accepted: 06/26/2022] [Indexed: 11/16/2022]
Abstract
Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants. Although IL8 is absent from the mouse genome, a similar murine axis in which TNFα and IL-1β upregulate CXCL1 and CXCL2 in tumor cells was revealed. Furthermore, intratumoral injection of TNFα and IL-1β induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNFα blockers infliximab and etanercept or the IL-1β inhibitor anakinra was able to interfere with this pathogenic cytokine loop. Finally, in paired plasma samples of patients with cancer undergoing TNFα blockade with infliximab in a clinical trial, reductions of circulating IL-8 were substantiated. SIGNIFICANCE IL-8 attracts immunosuppressive protumor myeloid cells to the tumor microenvironment, and IL-8 levels correlate with poor response to checkpoint inhibitors. TNFα and IL-1β are identified as major inducers of IL-8 expression on malignant cells across cancer types and models in a manner that is druggable with clinically available neutralizing agents. This article is highlighted in the In This Issue feature, p. 2007.
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Affiliation(s)
- Irene Olivera
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Rebeca Sanz-Pamplona
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Oncobell Program, Catalan Institute of Cancer (ICO), Bellvitge Biomedical Research Institute (IDIBELL), CIBERESP, Hospitalet de Llobregat, Barcelona, Spain and ARAID Researcher, Aragon Health Research institute (IIS Aragon), Zaragoza, Spain
| | - Elixabet Bolaños
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Inmaculada Rodriguez
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Iñaki Etxeberria
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Assunta Cirella
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Josune Egea
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Saray Garasa
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Itziar Migueliz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Iñaki Eguren-Santamaria
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Miguel F Sanmamed
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Javier Glez-Vaz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Arantza Azpilikueta
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
| | - Maite Alvarez
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - María C Ochoa
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Beatrice Malacrida
- Center for tumour microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kindgom
| | - David Propper
- Center for tumour microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kindgom
| | - Carlos E de Andrea
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Frances R Balkwill
- Center for tumour microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kindgom
| | - Álvaro Teijeira
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain
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9
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Ghods A, Mehdipour F, Rasolmali R, Talei AR, Ghaderi A. The expression pattern of membranous TNF-α is distinct from its intracellular form in breast cancer-draining lymph nodes. Clin Immunol 2022; 238:109026. [PMID: 35489644 DOI: 10.1016/j.clim.2022.109026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 03/02/2022] [Accepted: 04/23/2022] [Indexed: 11/03/2022]
Abstract
Tumor necrosis factor-alpha (TNF-α) is mostly known as a soluble cytokine. This study, however, focused on its membranous form whose significance is rarely investigated in antitumor immunity. Herein, we assessed the expression of both membranous and intracellular forms of TNF-α (m/icTNF-α) in the lymphocytes derived from breast cancer-draining lymph nodes. CD4+T cells were the main subset expressing mTNF-α with the highest intensity, whereas icTNF-α expression was most intense in CD8+T cells. An inverse correlation was seen between the frequency of mTNF-α and the expression intensity of this cytokine in B cells. In the clinical context, the higher intensity of mTNF-α expression in CD19+ cells correlated with poor prognosticators, while the frequency of mTNF-α+CD19+ cells showed a reverse correlation with the number of involved lymph nodes. The two forms of TNF-α did not show similar associations with cancer parameters, which highlights the complex role of this cytokine in breast cancer immunity.
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Affiliation(s)
- Atri Ghods
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fereshteh Mehdipour
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Reza Rasolmali
- Department of Pathology, Shiraz Central Hospital, Shiraz, Iran
| | - Abdol-Rasoul Talei
- Breast Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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10
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Yang Q, Ouyang J, Pi D, Feng L, Yang J. Malassezia in Inflammatory Bowel Disease: Accomplice of Evoking Tumorigenesis. Front Immunol 2022; 13:846469. [PMID: 35309351 PMCID: PMC8931276 DOI: 10.3389/fimmu.2022.846469] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/10/2022] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence indicates that patients with inflammatory bowel disease (IBD) have a significantly higher risk of developing different cancers, while the exact mechanism involved is not yet fully understood. Malassezia is a lipid-dependent opportunistic yeast, which colonizes on mammalian skin and internal organs. Also, dysbiosis in fungal communities accompanied by high level of Malassezia are fairly common in inflammatory diseases such as IBD and various cancers. In cancer patients, higher levels of Malassezia are associated with worse prognosis. Once it is ablated in tumor-bearing mice, their prognostic conditions will be improved. Moreover, Malassezia manifests multiple proinflammatory biological properties, such as destruction of epithelial barrier, enrichment of inflammatory factors, and degradation of extracellular matrix (ECM), all of which have been reported to contribute to tumor initiation and malignant progression. Based on these facts, we hypothesize that high levels of Malassezia together with mycobiome dysbiosis in patients with IBD, would aggravate the microecological imbalance, worsen the inflammatory response, and further promote tumorigenesis and deterioration. Herein, we will discuss the detrimental properties of Malassezia and explore the key role of this fungus in the correlation between IBD and cancer, in order to take early surveillance and intervention to minimize the cancer risk in individuals with IBD.
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Affiliation(s)
- Qiyu Yang
- Department of Radiation Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Jing Ouyang
- Chongqing Public Health Medical Center, Chongqing, China
| | - Damao Pi
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Feng
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing, China
- *Correspondence: Li Feng, ; Jiadan Yang,
| | - Jiadan Yang
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Li Feng, ; Jiadan Yang,
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11
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Kang SY, Hwang D, Shin S, Park J, Kim M, Rahman MDH, Rahman MA, Ko SG, Kim B. Potential of Bioactive Food Components against Gastric Cancer: Insights into Molecular Mechanism and Therapeutic Targets. Cancers (Basel) 2021; 13:cancers13184502. [PMID: 34572730 PMCID: PMC8469857 DOI: 10.3390/cancers13184502] [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: 07/26/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer, also known as stomach cancer, is a cancer that develops from the lining of the stomach. Accumulated evidence and epidemiological studies have indicated that bioactive food components from natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action has not yet been elucidated. Particularly, experimental studies have shown that natural bioactive food products display a protective effect against gastric cancer via numerous molecular mechanisms, such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy, as well as immunotherapy, and its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. However, administration of naturally occurring bioactive phytochemical food components could increase the efficacy of gastric chemotherapy and other chemotherapeutic resistance. Additionally, several studies have suggested that bioactive food components with structural stability, potential bioavailability, and powerful bioactivity are important to develop novel treatment strategies for gastric cancer management, which may minimize the adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural bioactive food products on the prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.
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Affiliation(s)
- Seog Young Kang
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Dongwon Hwang
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Soyoung Shin
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Jinju Park
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Myoungchan Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
| | - MD. Hasanur Rahman
- Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh;
| | - Md. Ataur Rahman
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
| | - Seong-Gyu Ko
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
- Correspondence:
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12
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Thaklaewphan P, Ruttanapattanakul J, Monkaew S, Buatoom M, Sookkhee S, Nimlamool W, Potikanond S. Kaempferia parviflora extract inhibits TNF-α-induced release of MCP-1 in ovarian cancer cells through the suppression of NF-κB signaling. Biomed Pharmacother 2021; 141:111911. [PMID: 34328090 DOI: 10.1016/j.biopha.2021.111911] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/29/2021] [Accepted: 07/06/2021] [Indexed: 11/25/2022] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is an uncommon subtype of epithelial cell ovarian cancers (EOCs) that has poor response to conventional platinum-based therapy. Therefore, finding new potential therapeutic agents is required. Since inflammatory cytokine, tumor necrosis factor alpha (TNF-α), is strongly expressed in EOCs and associated with the level of tumor grade, disruption of this inflammation pathway may provide another potential target for OCCC treatment. We previously reported that Kaempferia parviflora (KP) extract decreased cell proliferation and induced apoptosis. However, the effects of KP on OCCC, especially the aspects related to inflammatory cytokines, have not been elucidated. Our current study demonstrated the effects of KP extract on cytokine production in TNF-α-induced OCCC TOV-21G cell line. This study showed that KP extract inhibited interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production at both transcription and translation levels via the suppression of nuclear factor-kappa B (NF-κB) signal transduction. In contrast, KP extract increased the expression of inhibitor kappa B (IκB) protein which may delay NF-κB translocation into the nucleus upon TNF-α activation. Moreover, the suppression of cytokines released from KP treated-TOV-21G reduced the migration of monocyte cell (THP-1). KP extract also exhibited the inhibition of IL-6 and MCP-1 production from THP-1 activated by lipopolysaccharides (LPS). Cells treated with KP extract exhibited a decrease in extracellular signal-regulated kinases (ERK1/2) and protein kinase B (AKT) phosphorylation and induced myeloid leukemia cell differentiation protein Mcl-1 (MCL-1) expression. Suppression of inflammatory cytokine and chemokine production and inhibition of tumor-associated macrophage (TAM) migration support the possibility of using KP for OCCC treatment.
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Affiliation(s)
- Phatarawat Thaklaewphan
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Graduate School, Chiang Mai University, Chiang Mai, Thailand.
| | | | - Sathit Monkaew
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
| | - Montanee Buatoom
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
| | - Siriwoot Sookkhee
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
| | - Wutigri Nimlamool
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Thailand.
| | - Saranyapin Potikanond
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Thailand.
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13
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Mao W, Fan Y, Cheng C, Yuan X, Lan T, Mao K, Wang J. Efficacy and safety of Kanglaite injection combined with chemotherapy for colorectal cancer: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e22357. [PMID: 32991451 PMCID: PMC7523838 DOI: 10.1097/md.0000000000022357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The incidence and mortality of colorectal cancer are high. Chemotherapy is currently the commonly used therapeutic scheme, but there are drug resistance and toxic and side effects. Kanglaite (KLT) injection is a broad-spectrum anticancer drug extracted from Semen Coicis (Yi Yi Ren), which has been widely used in the treatment of colorectal cancer. Clinical practice shows that KLT injection combined with chemotherapy has certain therapeutic advantages, but there is a lacking of evidence of evidence-based medicine. The purpose of this study is to systematically investigate the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer. METHODS Randomized controlled trials of KLT injection combined with chemotherapy in the treatment of colorectal cancer were retrieved from English databases (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, Wanfang, Chongqing VIP Chinese Science and Technology Periodical Database, Chinese Biological and Medical database), as well as searching Baidu academic and Google academic manually, and the retrieval time was from their establishment to August 2020. Two researchers independently conducted data extraction and literature quality evaluation on the quality of the included literatures, and meta-analysis was conducted on the included literatures using RevMan 5.3 (developed by the UK's International Cochrane Collaboration). RESULTS This study assessed the efficacy and safety of KLT injection combined with chemotherapy in the treatment of colorectal cancer by effective rate, Karnofsky Performance Status, Carcinoemybryonic Angtigen remission rate, pain remission rate, and incidence of adverse reactions etc. CONCLUSIONS:: This study will provide reliable evidence-based evidence for the clinical application of KLT injection combined with chemotherapy in the treatment of colorectal cancer. ETHICS AND DISSEMINATION The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER DOI 10.17605/OSF.IO/EKVAF.
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Affiliation(s)
- Weili Mao
- People's Hospital of QuZhou, Quzhou, Zhejiang province
| | - Yihua Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine
| | - Chao Cheng
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xingyu Yuan
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tian Lan
- People's Hospital of QuZhou, Quzhou, Zhejiang province
| | - Kaili Mao
- People's Hospital of QuZhou, Quzhou, Zhejiang province
| | - Jun Wang
- People's Hospital of QuZhou, Quzhou, Zhejiang province
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14
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Macpherson AM, Barry SC, Ricciardelli C, Oehler MK. Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy. J Clin Med 2020; 9:E2967. [PMID: 32937961 PMCID: PMC7564553 DOI: 10.3390/jcm9092967] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/28/2020] [Accepted: 09/03/2020] [Indexed: 12/11/2022] Open
Abstract
Recent advances in the understanding of immune function and the interactions with tumour cells have led to the development of various cancer immunotherapies and strategies for specific cancer types. However, despite some stunning successes with some malignancies such as melanomas and lung cancer, most patients receive little or no benefit from immunotherapy, which has been attributed to the tumour microenvironment and immune evasion. Although the US Food and Drug Administration have approved immunotherapies for some cancers, to date, only the anti-angiogenic antibody bevacizumab is approved for the treatment of epithelial ovarian cancer. Immunotherapeutic strategies for ovarian cancer are still under development and being tested in numerous clinical trials. A detailed understanding of the interactions between cancer and the immune system is vital for optimisation of immunotherapies either alone or when combined with chemotherapy and other therapies. This article, in two main parts, provides an overview of: (1) components of the normal immune system and current knowledge regarding tumour immunology, biology and their interactions; (2) strategies, and targets, together with challenges and potential innovative approaches for cancer immunotherapy, with attention given to epithelial ovarian cancer.
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Affiliation(s)
- Anne M. Macpherson
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide 5000, Australia; (A.M.M.); (C.R.)
| | - Simon C. Barry
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide 5005, Australia;
| | - Carmela Ricciardelli
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide 5000, Australia; (A.M.M.); (C.R.)
| | - Martin K. Oehler
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide 5000, Australia; (A.M.M.); (C.R.)
- Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide 5000, Australia
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15
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Wang W, Wu J, Mukherjee A, He T, Wang XY, Ma Y, Fang X. Lysophosphatidic acid induces tumor necrosis factor-alpha to regulate a pro-inflammatory cytokine network in ovarian cancer. FASEB J 2020; 34:13935-13948. [PMID: 32851734 DOI: 10.1096/fj.202001136r] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022]
Abstract
Epithelial ovarian carcinoma tissues express high levels of tumor necrosis factor-alpha (TNF-α) and other inflammatory cytokines. The underlying mechanism leading to the abnormal TNF-α expression in ovarian cancer remains poorly understood. In the current study, we demonstrated that lysophosphatidic acid (LPA), a lipid mediator present in ascites of ovarian cancer patients, induced expression of TNF-α mRNA and release of TNF-α protein in ovarian cancer cells. LPA also induced expression of interleukin-1β (IL-1β) mRNA but no significant increase in IL-1β protein was detected. LPA enhanced TNF-α mRNA through NF-κB-mediated transcriptional activation. Inactivation of ADAM17, a disintegrin and metalloproteinase, with a specific inhibitor TMI-1 or by shRNA knockdown prevented ovarian cancer cells from releasing TNF-α protein in response to LPA, indicating that LPA-mediated TNF-α production relies on both transcriptional upregulations of the TNF-α gene and the activity of ADAM17, the membrane-associated TNF-α-converting enzyme. Like many other biological responses to LPA, induction of TNF-α by LPA also depended on the transactivation of the epidermal growth factor receptor (EGFR). Interestingly, our results revealed that ADAM17 was also the shedding protease responsible for the transactivation of EGFR by LPA in ovarian cancer cells. To explore the biological outcomes of LPA-induced TNF-α, we examined the effects of a TNF-α neutralizing antibody and recombinant TNF-α soluble receptor on LPA-stimulated expression of pro-tumorigenic cytokines and chemokines overexpressed in ovarian cancer. Blockade of TNF-α signaling significantly reduced the production of IL-8, IL-6, and CXCL1, suggesting a hierarchy of mechanisms contributing to the robust expression of the inflammatory mediators in response to LPA in ovarian cancer cells. In contrast, TNF-α inhibition did not affect LPA-dependent cell proliferation. Taken together, our results establish that the bioactive lipid LPA drives the expression of TNF-α to regulate an inflammatory network in ovarian cancer.
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Affiliation(s)
- Wei Wang
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jinhua Wu
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Abir Mukherjee
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Tianhai He
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Yibao Ma
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Xianjun Fang
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
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16
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Zhang K, Qiu W, Wu B, Fang F. Long non‑coding RNAs are novel players in oral inflammatory disorders, potentially premalignant oral epithelial lesions and oral squamous cell carcinoma (Review). Int J Mol Med 2020; 46:535-545. [PMID: 32626947 PMCID: PMC7307862 DOI: 10.3892/ijmm.2020.4628] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 05/15/2020] [Indexed: 12/14/2022] Open
Abstract
In recent years, a large number of studies have shown that the abnormal expression of long non‑coding (lnc)RNAs can lead to a variety of different diseases, including inflammatory disorders, cardiovascular disease, nervous system diseases, and cancers. Recent research has demonstrated the biological characteristics of lncRNAs and the important functions of lncRNAs in oral inflammation, precancerous lesions and cancers. The present review aims to explore and discuss the potential roles of candidate lncRNAs in oral diseases by summarizing multiple lncRNA profiles in diseased and healthy oral tissues to determine the altered lncRNA signatures. In addition, to highlight the exact regulatory mechanism of lncRNAs in oral inflammatory disorders, potentially premalignant oral epithelial lesions and oral squamous cell carcinoma. The detection of lncRNAs in oral samples has the potential to be used as a diagnostic and an early detection tool for oral diseases. Furthermore, lncRNAs are promising future therapeutic targets in oral diseases, and research in this field may expand in the future.
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Affiliation(s)
- Kaiying Zhang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
| | - Wei Qiu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
| | - Buling Wu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
| | - Fuchun Fang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
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17
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Abstract
Inflammation is often associated with the development and progression of cancer. The cells responsible for cancer-associated inflammation are genetically stable and thus are not subjected to rapid emergence of drug resistance; therefore, the targeting of inflammation represents an attractive strategy both for cancer prevention and for cancer therapy. Tumor-extrinsic inflammation is caused by many factors, including bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption, all of which increase cancer risk and stimulate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation can be triggered by cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells. Both extrinsic and intrinsic inflammations can result in immunosuppression, thereby providing a preferred background for tumor development. The current review provides a link between inflammation and cancer development.
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Affiliation(s)
- Nitin Singh
- Department of Pedodontics and Preventive Dentistry, Chandra Dental College and Hospital, Safedabad, Barabanki, Uttar Pradesh, India
| | - Deepak Baby
- Department of Conservative and Endodontics, P.S.M Dental College and Research Centre, Akkikavu, Thrissur, Kerala, India
| | - Jagadish Prasad Rajguru
- Department of Oral Pathology and Microbiology, Hi-Tech Dental College and Hospital, Bhubaneswar, Odisha, India
| | - Pankaj B Patil
- Department of Oral and Maxillofacial Surgery, School of Dental Sciences, Krishna Institute of Health Sciences Deemed to be University, Karad, Maharashtra, India
| | - Savita S Thakkannavar
- Department of Oral Pathology and Microbiology, Tatyasaheb Kore Dental College and Research Centre, New Pargaon, Kolhapur, Maharashtra, India
| | - Veena Bhojaraj Pujari
- Department of Oral Medicine and Radiology, Tatyasaheb Kore Dental College and Research Centre, New Pargaon, Kolhapur, Maharashtra, India
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18
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Liu W, Lu X, Shi P, Yang G, Zhou Z, Li W, Mao X, Jiang D, Chen C. TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway. Sci Rep 2020; 10:1804. [PMID: 32019974 PMCID: PMC7000832 DOI: 10.1038/s41598-020-58642-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/15/2020] [Indexed: 12/18/2022] Open
Abstract
Breast cancer patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem-like cells (BCSCs). Numerous studies have reported that high levels of inflammatory factors, including tumor necrosis factor alpha (TNF-α), promote BCSCs. However, the mechanism by which TNF-α promotes BCSCs is unclear. In this study, we demonstrate that TNF-α up-regulates TAZ, a transcriptional co-activator promoting BCSC self-renewal capacity in human breast cancer cell lines. Depletion of TAZ abrogated the increase in BCSCs mediated by TNF-α. TAZ is induced by TNF-α through the non-canonical NF-κB pathway, and our findings suggest that TAZ plays a crucial role in inflammatory factor-promoted breast cancer stemness and could serve as a promising therapeutic target.
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Affiliation(s)
- Wenjing Liu
- 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, 650223, China
- University of the Chinese Academy of Sciences, Beijing, 101407, China
- Medical Faculty of Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Xiaoqing Lu
- Department of breast surgery, The second hospital of Shanxi medical University, Taiyuan, 030071, China
| | - Peiguo Shi
- 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, 650223, China
| | - Guangxi Yang
- 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, 650223, China
| | - Zhongmei Zhou
- 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, 650223, China
| | - Wei Li
- Medical Faculty of Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming, 650032, China
| | - Xiaoyun Mao
- Breast surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, 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, 650223, 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, 650223, China.
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
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19
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Wieser V, Tsibulak I, Degasper C, Welponer H, Leitner K, Parson W, Zeimet AG, Marth C, Fiegl H. Tumor necrosis factor receptor modulator spermatogenesis-associated protein 2 is a novel predictor of outcome in ovarian cancer. Cancer Sci 2019; 110:1117-1126. [PMID: 30697874 PMCID: PMC6398874 DOI: 10.1111/cas.13955] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 01/09/2019] [Accepted: 01/15/2019] [Indexed: 01/08/2023] Open
Abstract
Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor-α (TNF-α) as a key mediator. Recently, spermatogenesis-associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF-induced inflammation and apoptosis. The available data on TNF-α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real-time polymerase chain reaction in tissues of 171 patients with low-grade serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non-malignant control tissues. We stimulated OC cells (OVCAR3) with pro-inflammatory (TNF-α, interleukin [IL]-1β) and mitogenic stimuli (IL-6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro-inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, rs = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression-free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF-α and IL-1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies.
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Affiliation(s)
- Verena Wieser
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Irina Tsibulak
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christine Degasper
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Hannah Welponer
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Katharina Leitner
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Walther Parson
- Institute of Legal Medicine, Medical University Innsbruck, Innsbruck, Austria
| | - Alain G Zeimet
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Marth
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Heidelinde Fiegl
- Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Innsbruck, Austria
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Lee W, Ko SY, Mohamed MS, Kenny HA, Lengyel E, Naora H. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J Exp Med 2019; 216:176-194. [PMID: 30567719 PMCID: PMC6314534 DOI: 10.1084/jem.20181170] [Citation(s) in RCA: 315] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/09/2018] [Accepted: 11/15/2018] [Indexed: 12/12/2022] Open
Abstract
Ovarian cancer preferentially metastasizes to the omentum, a fatty tissue characterized by immune structures called milky spots, but the cellular dynamics that direct this tropism are unknown. Here, we identified that neutrophil influx into the omentum is a prerequisite premetastatic step in orthotopic ovarian cancer models. Ovarian tumor-derived inflammatory factors stimulated neutrophils to mobilize and extrude chromatin webs called neutrophil extracellular traps (NETs). NETs were detected in the omentum of ovarian tumor-bearing mice before metastasis and of women with early-stage ovarian cancer. NETs, in turn, bound ovarian cancer cells and promoted metastasis. Omental metastasis was decreased in mice with neutrophil-specific deficiency of peptidylarginine deiminase 4 (PAD4), an enzyme that is essential for NET formation. Blockade of NET formation using a PAD4 pharmacologic inhibitor also decreased omental colonization. Our findings implicate NET formation in rendering the premetastatic omental niche conducive for implantation of ovarian cancer cells and raise the possibility that blockade of NET formation prevents omental metastasis.
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Affiliation(s)
- WonJae Lee
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Song Yi Ko
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Muhaned S Mohamed
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Hilary A Kenny
- Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
| | - Ernst Lengyel
- Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
| | - Honami Naora
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
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21
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Günel T, Gumusoglu E, Dogan B, Ertem FB, Hosseini MK, Cevik N, Senol T, Topuz S, Aydinli K. Potential biomarker of circulating hsa-miR-1273g-3p level for detection of recurrent epithelial ovarian cancer. Arch Gynecol Obstet 2018; 298:1173-1180. [DOI: 10.1007/s00404-018-4913-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/19/2018] [Indexed: 12/18/2022]
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22
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Mantovani A, Schioppa T, Biswas SK, Marchesi F, Allavena P, Sica A. Tumor-Associated Macrophages and Dendritic Cells as Prototypic Type II Polarized Myeloid Populations. TUMORI JOURNAL 2018; 89:459-68. [PMID: 14870765 DOI: 10.1177/030089160308900501] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Environmental signals polarize mononuclear phagocytes which can express different functional programmes. Fully polarized type I and type II (or alternatively activated) macrophages are the extremes of a continuum of functional states. Tumor-derived and T cell-derived cytokines stimulate tumor associated macrophages (TAM) to acquire a polarized type II phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, play a key role in subversion of adaptive immunity and in inflammatory circuits which promote tumor growth and progression.
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23
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Papadopoulou E, Tripsianis G, Anagnostopoulos K, Tentes I, Kakolyris S, Galazios G, Sivridis E, Simopoulos K, Kortsaris A. Significance of Serum Tumor Necrosis Factor-Alpha and its Combination with Her-2 Codon 655 Polymorphism in the Diagnosis and Prognosis of Breast Cancer. Int J Biol Markers 2018; 25:126-35. [DOI: 10.1177/172460081002500302] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Purpose The present study was conducted to clarify the diagnostic and prognostic significance of TNF-alpha and its combination with HER-2 Ile655Val SNP in breast cancer. Methods In this case-control study, 56 consecutive patients with primary breast cancer were prospectively evaluated. The control group consisted of 45 healthy women. Serum concentrations of TNF-alpha were measured by quantitative sandwich enzyme immunoassay (ELISA). HER-2 SNP was genotyped using the PCR-RFLP method. Results Serum TNF-alpha was significantly increased in patients compared to controls. ROC analysis indicated a cutoff point of 11.00 pg/mL to classify breast cancer patients (sensitivity, 86%; specificity, 71%). Elevated TNF-alpha levels were associated with larger, poorly differentiated, invasive and advanced-stage tumors, and >3 positive lymph nodes. Regarding HER-2 SNP, patients with Ile-Val and Val-Val genotypes had significant TNF-α elevation compared with homozygous Ile-Ile patients. In multivariate analysis, high serum TNF-alpha remained an independent prognostic factor of worse overall survival; its combination with Val-Val genotype predicted a worse prognosis than high TNF-alpha alone. Conclusions Serum TNF-a could be used clinically as a useful tumor marker for diagnosis, disease extent and outcome of breast cancer. The negative impact on survival seems to be enhanced through the interaction with HER-2 Ile655Val SNP.
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Affiliation(s)
- Evropi Papadopoulou
- Laboratory of Biochemistry, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
| | - Gregory Tripsianis
- Department of Medical Statistics, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
| | | | - Ioannis Tentes
- Laboratory of Biochemistry, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
| | - Stylianos Kakolyris
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
| | - Georgios Galazios
- Obstetrics and Gy-necology Clinic, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
| | - Efthimios Sivridis
- Laboratory of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
| | - Konstantinos Simopoulos
- Second Division of Surgery Clinic, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
| | - Alexandros Kortsaris
- Laboratory of Biochemistry, Medical School, Democritus University of Thrace, Alexandroupolis - Greece
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24
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Shi G, Zheng X, Zhang S, Wu X, Yu F, Wang Y, Xing F. Kanglaite inhibits EMT caused by TNF-α via NF-κΒ inhibition in colorectal cancer cells. Oncotarget 2018; 9:6771-6779. [PMID: 29467927 PMCID: PMC5805513 DOI: 10.18632/oncotarget.23645] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 12/01/2017] [Indexed: 12/24/2022] Open
Abstract
Tumor necrosis factor-alpha is a critical pro-inflammatory cytokine produced by macrophages and was once considered an anti-tumor agent. However, a low dose of tumor necrosis factor-alpha can cause epithelial mesenchymal transition, angiogenesis and metastasis. NF-κΒ contributes to epithelial mesenchymal transition induced by tumor necrosis factor-alpha. Kanglaite, an extract from the Coix lacryma-jobi (adlay) seed, is an NF-κΒ inhibitor. The aim of this study was to investigate whether Kanglaite could inhibit epithelial mesenchymal transition caused by tumor necrosis factor-alpha using four colorectal cancer cell lines, HCT106, HCT116, LoVo and CT26. Our results showed that tumor necrosis factor-alpha -mediated activation of NF-κΒ, caused changes in epithelial mesenchymal transition -related protein expression, and increased migration and invasion in all four cell lines. However, these effects were inhibited by Kanglaite when used in combination with tumor necrosis factor-alpha. In a subcutaneous tumor model of CT26, tumor necrosis factor-alpha enhanced the tumorigenic ability of the cells, and again this was inhibited by Kanglaite. However, treatment with Kanglaite alone caused almost no inhibition of epithelial mesenchymal transition -mediated tumor growth, when cells were pretreated with tumor necrosis factor-alpha prior to injection. These results suggest that Kanglaite inhibits tumor necrosis factor-alpha -mediated epithelial mesenchymal transition in colorectal cancer cell lines via inhibition of NF-κΒ.
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Affiliation(s)
- Guiling Shi
- Tianjin Union Medical Center, Tianjin 300121, China
| | - Xiaoli Zheng
- Tianjin Union Medical Center, Tianjin 300121, China
| | - Shiwu Zhang
- Tianjin Union Medical Center, Tianjin 300121, China
| | - Xiaojing Wu
- Tianjin Union Medical Center, Tianjin 300121, China
| | - Fei Yu
- School of Pharmacy, Tianjin Medical University, Tianjin 300121, China
| | - Yijia Wang
- Tianjin Union Medical Center, Tianjin 300121, China
| | - Fei Xing
- The Key Laboratory of Weak Light Nonlinear Photonics, Ministry of Education, Teda Applied Physics School and School of Physics, Nankai University, Tianjin 300071, China
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25
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Shi X, Shiao SL. The role of macrophage phenotype in regulating the response to radiation therapy. Transl Res 2018; 191:64-80. [PMID: 29175267 PMCID: PMC6018060 DOI: 10.1016/j.trsl.2017.11.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 10/23/2017] [Accepted: 11/11/2017] [Indexed: 12/14/2022]
Abstract
Increasing experimental and clinical evidence has revealed a critical role for myeloid cells in the development and progression of cancer. The ability of monocytes and macrophages to regulate inflammation allows them to manipulate the tumor microenvironment to support the growth and development of malignant cells. Recent studies have shown that macrophages can exist in several functional states depending on the microenvironment they encounter in the tissue. These functional phenotypes influence not only the genesis and propagation of tumors, but also the efficacy of cancer therapies, particularly radiation. Early classification of the macrophage phenotypes, or "polarization states," identified 2 major states, M1 and M2, that have cytotoxic and wound repair capacity, respectively. In the context of tumors, classically activated or M1 macrophages driven by interferon-gamma support antitumor immunity while alternatively activated or M2 macrophages generated in part from interleukin-4 exposure hinder antitumor immunity by suppressing cytotoxic responses against a tumor. In this review, we discuss the role that the functional phenotype of a macrophage population plays in tumor development. We will then focus specifically on how macrophages and myeloid cells regulate the tumor response to radiation therapy.
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Affiliation(s)
- Xiaoshan Shi
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Stephen L Shiao
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA.
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26
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Thuwajit C, Ferraresi A, Titone R, Thuwajit P, Isidoro C. The metabolic cross-talk between epithelial cancer cells and stromal fibroblasts in ovarian cancer progression: Autophagy plays a role. Med Res Rev 2017; 38:1235-1254. [PMID: 28926101 PMCID: PMC6032948 DOI: 10.1002/med.21473] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/16/2017] [Accepted: 08/23/2017] [Indexed: 12/17/2022]
Abstract
Cancer and stromal cells, which include (cancer‐associated) fibroblasts, adipocytes, and immune cells, constitute a mixed cellular ecosystem that dynamically influences the behavior of each component, creating conditions that ultimately favor the emergence of malignant clones. Ovarian cancer cells release cytokines that recruit and activate stromal fibroblasts and immune cells, so perpetuating a state of inflammation in the stroma that hampers the immune response and facilitates cancer survival and propagation. Further, the stroma vasculature impacts the metabolism of the cells by providing or limiting the availability of oxygen and nutrients. Autophagy, a lysosomal catabolic process with homeostatic and prosurvival functions, influences the behavior of cancer cells, affecting a variety of processes such as the survival in metabolic harsh conditions, the invasive growth, the development of immune and chemo resistance, the maintenance of stem‐like properties, and dormancy. Further, autophagy is involved in the secretion and the signaling of promigratory cytokines. Cancer‐associated fibroblasts can influence the actual level of autophagy in ovarian cancer cells through the secretion of pro‐inflammatory cytokines and the release of autophagy‐derived metabolites and substrates. Interrupting the metabolic cross‐talk between cancer cells and cancer‐associated fibroblasts could be an effective therapeutic strategy to arrest the progression and prevent the relapse of ovarian cancer.
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Affiliation(s)
- Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Alessandra Ferraresi
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Rossella Titone
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ciro Isidoro
- Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.,Visiting Professor at Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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27
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Lau TS, Chan LKY, Wong ECH, Hui CWC, Sneddon K, Cheung TH, Yim SF, Lee JHS, Yeung CSY, Chung TKH, Kwong J. A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR. Oncogene 2017; 36:3576-3587. [PMID: 28166193 PMCID: PMC5485181 DOI: 10.1038/onc.2016.509] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 11/28/2016] [Accepted: 12/13/2016] [Indexed: 02/06/2023]
Abstract
Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.
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Affiliation(s)
- T-S Lau
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - L K-Y Chan
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - E C-H Wong
- Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - C W-C Hui
- Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - K Sneddon
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - T-H Cheung
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - S-F Yim
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - J H-S Lee
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - C S-Y Yeung
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - T K-H Chung
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - J Kwong
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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Abstract
Now clear evidences are available to support the hypothesis that inflammation accelerates the conditions including events and molecules that reach to various types of cancers. Inflammation is a normal response to infection containing the innate and adaptive immune systems. However, when allowed to continue, unresolved, perturbation of cellular microenvironment takes place; therefore, it leads to adaptations in genes that are linked to cancer. In addition, a lot of data are accessible confirming the concept that tumour microenvironment is orchestrated by various inflammatory cells and goes to neoplastic process and finally invasion, migration and metastasis. However, infiltrations of leucocytes lead to angiogenesis, propagation and invasion. An inflammatory microenvironment that perhaps fostering impact of angiogenesis include cytokines, chemokines, enzymes and growth factors that play key role for expansion and invasion of cancer cells. This insight highlights the pathogenesis of inflammation-associated cancers and also touches and fosters the role of acetamides for the treatment and chemoprevention of carcinomas that are allied with inflammation.
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Affiliation(s)
- Priyanka Rani
- a Department of Chemistry , School of Sciences, IFTM University Moradabad , Uttar Pradesh , India
| | - Dilipkumar Pal
- b Department of Pharmaceutical Sciences , Guru Ghasidas Vishwavidyalaya (A Central University) , Koni, Bilaspur , CG , India
| | - Rahul Rama Hegde
- c Department of Pharmaceutics , School of Pharmaceutical Sciences, IFTM University Moradabad , Uttar Pradesh , India
| | - Syed Riaz Hashim
- d Department of Chemistry , School of Pharmaceutical Sciences, IFTM University Moradabad , Uttar Pradesh , India
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29
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Tanaka T, Maekawa N, Kashio T, Izawa K, Ishiba R, Shirakura K, Ishimoto K, Hino N, Aird WC, Doi T, Okada Y. Tumor Necrosis Factor α Induces the Expression of the Endothelial Cell-Specific Receptor Roundabout4 through the Nuclear Factor-κB Pathway. Biol Pharm Bull 2017; 40:504-509. [DOI: 10.1248/bpb.b16-00938] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Toru Tanaka
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - Naoki Maekawa
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - Taito Kashio
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - Kohei Izawa
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - Ryosuke Ishiba
- Graduate School of Pharmaceutical Sciences, Osaka University
| | | | - Kenji Ishimoto
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - Nobumasa Hino
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - William C. Aird
- Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center
| | - Takefumi Doi
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - Yoshiaki Okada
- Graduate School of Pharmaceutical Sciences, Osaka University
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30
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Rasool M, Malik A, Basit Ashraf MA, Parveen G, Iqbal S, Ali I, Qazi MH, Asif M, Kamran K, Iqbal A, Iram S, Khan SU, Mustafa MZ, Zaheer A, Shaikh R, Choudhry H, Jamal MS. Evaluation of Matrix Metalloproteinases, Cytokines and Their Potential Role in the Development of Ovarian Cancer. PLoS One 2016; 11:e0167149. [PMID: 27902750 PMCID: PMC5130238 DOI: 10.1371/journal.pone.0167149] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/09/2016] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Ovarian cancer is the 5th most common cause of deaths in the women among gynecological tumors. There are many growing evidences that stress and other behavioral factors may affect cancer progression and patient survival. The purpose of this study is to determine the key role of matrix metalloproteinases (MMPs), and cytokines in the aggregation and progression of ovarian cancer. METHODOLOGY Stress variables (MDA, AGEs, AOPPs, NO), profile of antioxidants (SOD, Catalase, Vitamin E & A, GSH, GRx, GPx) and inflammatory biomarkers (MMP-9, MMP-2, MMP-11, IL-1α and TNF-α) were biochemically assessed from venous blood of fifty ovarian cancer patients and twenty healthy control subjects. The results of all parameters were analyzed statistically by independent sample t-test. RESULTS The results of the study demonstrated that the levels of stress variables like MDA (3.38±1.12nmol/ml), AGEs (2.72±0.22 ng/ml), AOPPs (128.48±27.23 ng/ml) and NO (58.71±8.67 ng/ml) were increased in the patients of ovarian cancer as compared to control individuals whereas the profile of antioxidants like SOD, Catalase, Vitamin E, Vitamin A, GSH and GRx were decreased in ovarian cancer patients (0.11±0.08 μg/ml, 2.41±1.01μmol/mol of protein, 0.22±0.04 μg/ml, 45.84±9.07μg/ml, 4.88±1.18μg/ml, 5.33±1.26 μmol/ml respectively). But the level of GPx antioxidant was increased in ovarian cancer patients (6.58±0.21μmol/ml). Moreover the levels of MMP-9 (64.87±5.35 ng/ml), MMP-2 (75.87±18.82 ng/ml) and MMP-11 (63.58±8.48 ng/ml) were elevated in the patients. Similarly, the levels of various cytokines TNF-α and IL-1α were also increased in the patients of ovarian cancer (32.17±3.52 pg/ml and 7.04±0.85 pg/ml respectively). CONCLUSION MMPs are commonly expressed in ovarian cancer which are potential extrapolative biomarkers and have a major role in metastasis. Due to oxidative stress, different cytokines are released by tumor associated macrophages (TAMs) that result in the cancer progression. Consequently, tissue inhibitors of matrix metalloproteinases (TIMPs) are the valuable therapeutic approaches to complement conservative anticancer strategies.
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Affiliation(s)
- Mahmood Rasool
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan
| | | | - Gulshan Parveen
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan
| | - Shazia Iqbal
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan
| | - Irfan Ali
- Akhuwat-Faisalabad Institute of Research Science and Technology, Faisalabad, Pakistan
| | - Mahmood Husain Qazi
- Centre for Research in Molecular Medicine (CRIMM), The University of Lahore, Lahore, Pakistan
| | - Muhammad Asif
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
| | - Kashif Kamran
- Faculty of Life Sciences, University of Balochistan, Quetta, Pakistan
| | - Asim Iqbal
- Faculty of Life Sciences, University of Balochistan, Quetta, Pakistan
| | - Saima Iram
- Bolan Medical Hospital, Quetta, Pakistan
| | - Sami Ullah Khan
- Department of Botany, Women University of Azad Jammu & Kashmir, Bagh, Pakistan
| | | | - Ahmad Zaheer
- National Institute for Biotechnology & Genetic Engineering, Faisalabad, Pakistan
| | | | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, Center of Innovation in Personalized Medicine, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
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Wang Y, Yang Y, Zhu Y, Li L, Chen F, Zhang L. Polymorphisms and expression of IL-32: impact on genetic susceptibility and clinical outcome of lung cancer. Biomarkers 2016; 22:165-170. [PMID: 27775437 DOI: 10.1080/1354750x.2016.1252956] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Yanwen Wang
- Laboratory of Pathology, Department of Pathology, West China Hospital Sichuan University, Chengdu, P.R. China
| | - Yongfeng Yang
- Laboratory of Pathology, Department of Pathology, West China Hospital Sichuan University, Chengdu, P.R. China
| | - Yihan Zhu
- Laboratory of Pathology, Department of Pathology, West China Hospital Sichuan University, Chengdu, P.R. China
| | - Li Li
- Laboratory of Pathology, Department of Pathology, West China Hospital Sichuan University, Chengdu, P.R. China
| | - Fei Chen
- Laboratory of Pathology, Department of Pathology, West China Hospital Sichuan University, Chengdu, P.R. China
| | - Li Zhang
- Laboratory of Pathology, Department of Pathology, West China Hospital Sichuan University, Chengdu, P.R. China
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Craig ER, Londoño AI, Norian LA, Arend RC. Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review. Gynecol Oncol 2016; 143:674-683. [PMID: 27751590 DOI: 10.1016/j.ygyno.2016.10.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/26/2016] [Accepted: 10/03/2016] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Epithelial ovarian cancer continues to be the deadliest gynecologic malignancy. Patients with both diabetes mellitus and obesity have poorer outcomes, yet research correlating metabolic abnormalities, such as metabolic syndrome, to ovarian cancer risk and outcomes is lacking. This article reviews the literature regarding metabolic derangements and their relationship to epithelial ovarian cancer, with a focus on potential mechanisms behind these associations. METHODS PubMed and Google Scholar were searched for articles in the English language regarding epithelial ovarian cancer, obesity, diabetes mellitus, and metabolic syndrome, with a focus on studies conducted since 1990. RESULTS Obesity, type II diabetes mellitus, and metabolic syndrome have been associated with poor outcomes in epithelial ovarian cancer. More studies investigating the relationship between metabolic syndrome and epithelial ovarian cancer are needed. A variety of pathologic factors may contribute to cancer risk in patients with metabolic derangements, including altered adipokine and cytokine expression, altered immune responses to tumor cells, and changes in pro-tumorigenic signaling pathways. CONCLUSION More research is needed to examine the effects of metabolic syndrome on epithelial ovarian cancer risk and mortality, as well as the underlying pathophysiologies in patients with obesity, diabetes mellitus, and metabolic syndrome that may be targeted for therapeutic intervention.
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Affiliation(s)
- Eric R Craig
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Angelina I Londoño
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lyse A Norian
- Department of Nutrition Sciences and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rebecca C Arend
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA.
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33
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Abstract
The human body combats infection and promotes wound healing through the remarkable process of inflammation. Inflammation is characterized by the recruitment of stromal cell activity including recruitment of immune cells and induction of angiogenesis. These cellular processes are regulated by a class of soluble molecules called cytokines. Based on function, cell target, and structure, cytokines are subdivided into several classes including: interleukins, chemokines, and lymphokines. While cytokines regulate normal physiological processes, chronic deregulation of cytokine expression and activity contributes to cancer in many ways. Gene polymorphisms of all types of cytokines are associated with risk of disease development. Deregulation RNA and protein expression of interleukins, chemokines, and lymphokines have been detected in many solid tumors and hematopoetic malignancies, correlating with poor patient prognosis. The current body of literature suggests that in some tumor types, interleukins and chemokines work against the human body by signaling to cancer cells and remodeling the local microenvironment to support the growth, survival, and invasion of primary tumors and enhance metastatic colonization. Some lymphokines are downregulated to suppress tumor progression by enhancing cytotoxic T cell activity and inhibiting tumor cell survival. In this review, we will describe the structure/function of several cytokine families and review our current understanding on the roles and mechanisms of cytokines in tumor progression. In addition, we will also discuss strategies for exploiting the expression and activity of cytokines in therapeutic intervention.
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Affiliation(s)
- M Yao
- University of Kansas Medical Center, Kansas City, KS, United States
| | - G Brummer
- University of Kansas Medical Center, Kansas City, KS, United States
| | - D Acevedo
- University of Kansas Medical Center, Kansas City, KS, United States
| | - N Cheng
- University of Kansas Medical Center, Kansas City, KS, United States.
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Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers. Int J Mol Sci 2016; 17:ijms17050717. [PMID: 27187365 PMCID: PMC4881539 DOI: 10.3390/ijms17050717] [Citation(s) in RCA: 144] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 05/05/2016] [Accepted: 05/09/2016] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease but the second cause of death among NAFLD patients are attributed to malignancies at both gastrointestinal (liver, colon, esophagus, stomach, and pancreas) and extra-intestinal sites (kidney in men, and breast in women). Obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers. NAFLD has an intertwined relationship with metabolic syndrome and significantly contributes to the risk of hepatocellular carcinoma (HCC), but recent evidence have fuelled concerns that NAFLD may be a new, and added, risk factor for extra-hepatic cancers, particularly in the gastrointestinal tract. In this review we critically appraise key studies on NAFLD-associated extra-hepatic cancers and speculate on how NAFLD may influence carcinogenesis at these sites.
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Gupta M, Babic A, Beck AH, Terry K. TNF-α expression, risk factors, and inflammatory exposures in ovarian cancer: evidence for an inflammatory pathway of ovarian carcinogenesis? Hum Pathol 2016; 54:82-91. [PMID: 27068525 DOI: 10.1016/j.humpath.2016.03.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 03/09/2016] [Accepted: 03/11/2016] [Indexed: 11/26/2022]
Abstract
Inflammatory cytokines, like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), are elevated in ovarian cancer. Differences in cytokine expression by histologic subytpe or ovarian cancer risk factors can provide useful insight into ovarian cancer risk and etiology. We used ribonucleic acid in situ hybridization to assess TNF-α and IL-6 expression on tissue microarray slides from 78 epithelial ovarian carcinomas (51 serous, 12 endometrioid, 7 clear cell, 2 mucinous, 6 other) from a population-based case-control study. Cytokine expression was scored semiquantitatively, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using polytomous logistic regression. TNF-α was expressed in 46% of the tumors, whereas sparse IL-6 expression was seen in only 18% of the tumors. For both markers, expression was most common in high-grade serous carcinomas followed by endometrioid carcinomas. Parity was associated with a reduced risk of TNF-α-positive (OR, 0.3; 95% CI, 0.1-0.7 for 3 or more children versus none) but not TNF-α-negative tumors (P heterogeneity=.02). In contrast, current smoking was associated with a nearly 3-fold increase in risk of TNF-α-negative (OR, 2.8; 95% CI, 1.2-6.6) but not TNF-α-positive tumors (P heterogeneity = .06). Our data suggest that TNF-α expression in ovarian carcinoma varies by histologic subtype and provides some support for the role of inflammation in ovarian carcinogenesis. The novel associations detected in our study need to be validated in a larger cohort of patients in future studies.
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Affiliation(s)
- Mamta Gupta
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
| | - Ana Babic
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215
| | - Andrew H Beck
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Kathryn Terry
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02215; Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215
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Abstract
Resistance to chemotherapy is among the most important issues in the management of ovarian cancer. Unlike cancer cells, which are heterogeneous as a result of remarkable genetic instability, stromal cells are considered relatively homogeneous. Thus, targeting the tumor microenvironment is an attractive approach for cancer therapy. Arguably, anti-vascular endothelial growth factor (anti-VEGF) therapies hold great promise, but their efficacy has been modest, likely owing to redundant and complementary angiogenic pathways. Components of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and other pathways may compensate for VEGF blockade and allow angiogenesis to occur despite anti-VEGF treatment. In addition, hypoxia induced by anti-angiogenesis therapy modifies signaling pathways in tumor and stromal cells, which induces resistance to therapy. Because of tumor cell heterogeneity and angiogenic pathway redundancy, combining cytotoxic and targeted therapies or combining therapies targeting different pathways can potentially overcome resistance. Although targeted therapy is showing promise, much more work is needed to maximize its impact, including the discovery of new targets and identification of individuals most likely to benefit from such therapies.
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Abstract
Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response.
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Affiliation(s)
- Shanthini M Crusz
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Frances R Balkwill
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Ozyalvacli G, Yesil C, Kargi E, Kizildag B, Kilitci A, Yilmaz F. Diagnostic and prognostic importance of the neutrophil lymphocyte ratio in breast cancer. Asian Pac J Cancer Prev 2015; 15:10363-6. [PMID: 25556476 DOI: 10.7314/apjcp.2014.15.23.10363] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The aim of this study was to determine diagnostic and prognostic roles of the neutrophil to lymphocyte ratio (NLR) in breast cancer patients. To date, data are limited on associations of primary breast carcinoma (PBC) and benign proliferative breast disease (BPBD) with preoperative NLR values. MATERIALS AND METHODS Our study covered of 120 female patients with PBC and 50 with BPBD. Diagnostic values of NLR were estimated using sensitivity, specificity and areas under receiver operating characteristic curves (AUC). RESULTS NLR values were significantly higher in the PBC patients than in those with BPBD, with an AUC of 0.668 in the PBC case. The optimal cut-off for NLR was 2.96 and this was validated in the testing set, giving a sensitivity and a specificity of 79.7% and 76.2%, respectively, in PBC patients. CONCLUSIONS Preoperative high NLR is a significant diagnostic predictor of distinction of breast cancer from BPBD and elevated NLR is also an important prognostic marker for primary invasive breast cancer.
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Affiliation(s)
- Gulzade Ozyalvacli
- Department of Pathology, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey E-mail :
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Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition. Cancer Metastasis Rev 2015; 33:17-39. [PMID: 24357056 DOI: 10.1007/s10555-013-9456-2] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ovarian adenocarcinoma is characterized by a late detection, dissemination of cancer cells into the whole peritoneum, and the frequent acquisition of chemoresistance. If these particularities can be explained in part by intrinsic properties of ovarian cancer cells, an increased number of studies show the importance of the tumor microenvironment in tumor progression. Ovarian cancer cells can regulate the composition of their stroma in promoting the formation of ascitic fluid, rich in cytokines and bioactive lipids, and in stimulating the differentiation of stromal cells into a pro-tumoral phenotype. In return, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, tumor-associated macrophages, or other peritoneal cells, such as adipocytes and mesothelial cells can regulate tumor growth, angiogenesis, dissemination, and chemoresistance. This review focuses on the current knowledge about the roles of stromal cells and the associated secreted factors on tumor progression. We also summarize the different studies showing that targeting the microenvironment represents a great potential for improving the prognosis of patients with ovarian adenocarcinoma.
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Cytokine profiling of ascites at primary surgery identifies an interaction of tumor necrosis factor-α and interleukin-6 in predicting reduced progression-free survival in epithelial ovarian cancer. Gynecol Oncol 2015; 138:352-7. [PMID: 26001328 DOI: 10.1016/j.ygyno.2015.05.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 05/13/2015] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Epithelial ovarian cancer (EOC) typically presents with advanced disease. Even with optimal debulking and response to adjuvant chemotherapy, the majority of patients will have disease relapse. We evaluated cytokine and chemokine profiles in ascites at primary surgery as biomarkers for progression-free survival (PFS) and overall survival (OS) in patients with advanced EOC. METHODS Retrospective analysis of patients (n =70) who underwent surgery at Roswell Park Cancer Institute between 2002 and 2012, followed by platinum-based chemotherapy. RESULTS The mean age at diagnosis was 61.8 years, 85.3% had serous EOC, and 95.7% had stage IIIB, IIIC, or IV disease. Univariate analysis showed that ascites levels of tumor necrosis factor (TNF)-α were associated with reduced PFS after primary surgery. Although the ascites concentration of interleukin (IL)-6 was not by itself predictive of PFS, we found that stratifying patients by high TNF-α and high IL-6 levels identified a sub-group of patients at high risk for rapid disease relapse. This effect was largely independent of clinical prognostic variables. CONCLUSIONS The combination of high TNF-α and high IL-6 ascites levels at primary surgery predicts worse PFS in patients with advanced EOC. These results suggest an interaction between ascites TNF-α and IL-6 in driving tumor progression and resistance to chemotherapy in advanced EOC, and raise the potential for pre-treatment ascites levels of these cytokines as prognostic biomarkers. This study involved a small sample of patients and was an exploratory analysis; therefore, findings require validation in a larger independent cohort.
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Abstract
While for a century therapeutics has been dominated by small molecules, i.e. organic chemicals of ~400Da absorbable via the gut, this is no longer the case. There are now a plethora of important medicines which are proteins and injectable, which have dramatically improved the therapy of many inflammatory diseases and of cancer. Most of these are monoclonal antibodies, some are receptor Ig Fc fusion proteins, others are cytokines or enzymes. The key to this new aspect of therapeutics has been the filling of unmet needs, and the consequent commercial success, which promoted further research and development. The first 'biologic' for a common disease, rheumatoid arthritis (RA), was a monoclonal antibody, infliximab, to human tumour necrosis factor (TNF). This was based on our work, which is described in this review, summarizing how TNF was defined as a good target in RA, how it was developed is described here, as well as future indications for anti-TNF and related agents. Biologics are now the fastest growing sector of therapeutics.
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Affiliation(s)
- Claudia Monaco
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK
| | - Jagdeep Nanchahal
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK
| | - Peter Taylor
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK
| | - Marc Feldmann
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK
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Tumor Necrosis Factor Alpha (-238 / -308) and TNFRII-VNTR (-322) Polymorphisms as Genetic Biomarkers of Susceptibility to Develop Cervical Cancer Among Tunisians. Pathol Oncol Res 2014; 21:339-45. [PMID: 25113639 DOI: 10.1007/s12253-014-9826-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Accepted: 07/24/2014] [Indexed: 10/24/2022]
Abstract
Host genetic factors may confer susceptibility to Cervical Cancer. TNF-α as pro-inflammatory cytokine participates in the maintenance of immune homeostasis. Allelic variation of immuno-modulatory genes is associated with alteration in immune function. This study investigated the associations between TNF-α-308G>A, -238G>A, and TNFRII - VNTR-322 and cervical cancer in Tunisian women. Genotypes of those polymorphisms were detected in 130 cases and 260 controls. The variant heterozygote -308 G/A was associated with a 41% decreased risk of cervical cancer (GG vs A/A; p = 0.002; OR = 0.41; 95% CI =0.23-0.76). Furthermore, compared with dominant variant G/G, the (G/A+A/A) genotypes was significantly associated with a decreased risk of CC (GG vs G/A+A/A; p = 0.026; OR = 0.62; 95% CI = 0.40-0.97). The FIGO stratified analysis showed that the minor variant A/A and combined G/A+A/A of TNFα-238 G>A and TNFα-308 G>A increased the risk of the tumor evolution, respectively, (P = 0.011; OR = 2.98; 95% CI = 1.16-7.72) (P = 0.008; OR = 2.76; 95% CI = 1.20-6.41), (P = 0.000; OR = 16.33; 95% CI = (5.10-55.23) (P = 0.000; OR = 7.54; 95% CI = 2.68-22.29). There was statistically significant relationship between the incidence of the TNF-α mutations and the clinical progression of cancer according to the FIGO classification. In our study, the haploview analysis revealed no LD between rs1800629 and rs361525. TNF-α and TNFRII polymorphisms might be genetic risk factors for cervical cancer in Tunisian population.
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Lebeña A, Vegas O, Gómez-Lázaro E, Arregi A, Garmendia L, Beitia G, Azpiroz A. Melanoma tumors alter proinflammatory cytokine production and monoamine brain function, and induce depressive-like behavior in male mice. Behav Brain Res 2014; 272:83-92. [PMID: 24995613 DOI: 10.1016/j.bbr.2014.06.045] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 06/23/2014] [Accepted: 06/24/2014] [Indexed: 10/25/2022]
Abstract
Depression is a commonly observed disorder among cancer patients; however, the mechanisms underlying the relationship between these disorders are not well known. We used an animal model to study the effects of tumor development on depressive-like behavior manifestation, proinflammatory cytokine expression, and central monoaminergic activity. Male OF1 mice were inoculated with B16F10 melanoma tumor cells and subjected to a 21-day behavioral evaluation comprising the novel palatable food (NPF) test and tail suspension test (TST). The mRNA expression levels of proinflammatory cytokines, interleukin (IL)-1β and IL-6, and tumor necrosis factor-alpha (TNF-α), were measured in the hypothalamus and hippocampus and the levels of IL-6 and TNF-α were measured in the blood plasma. We similarly determined the monoamine turnover in various brain areas. The tumors resulted in increasing the immobility in TST and the expression level of IL-6 in the hippocampus. These increases corresponded with a decrease in dopaminergic activity in the striatum and a decrease in serotonin turnover in the prefrontal cortex. Similarly, a high level of tumor development produced increases in the brain expression levels of IL-6 and TNF-α and plasma levels of IL-6. Our findings suggest that these alterations in inflammatory cytokines and monoaminergic system function might be responsible for the manifestation of depressive-like behaviors in tumor-bearing mice.
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Affiliation(s)
- Andrea Lebeña
- Department of Basic Psychological Processes and Their Development, Basque Country University, Avda. Tolosa 70, 20018 San Sebastián, Spain
| | - Oscar Vegas
- Department of Basic Psychological Processes and Their Development, Basque Country University, Avda. Tolosa 70, 20018 San Sebastián, Spain
| | - Eneritz Gómez-Lázaro
- Department of Basic Psychological Processes and Their Development, Basque Country University, Avda. Tolosa 70, 20018 San Sebastián, Spain
| | - Amaia Arregi
- Department of Basic Psychological Processes and Their Development, Basque Country University, Avda. Tolosa 70, 20018 San Sebastián, Spain
| | - Larraitz Garmendia
- Department of Basic Psychological Processes and Their Development, Basque Country University, Avda. Tolosa 70, 20018 San Sebastián, Spain
| | - Garikoitz Beitia
- Department of Basic Psychological Processes and Their Development, Basque Country University, Avda. Tolosa 70, 20018 San Sebastián, Spain
| | - Arantza Azpiroz
- Department of Basic Psychological Processes and Their Development, Basque Country University, Avda. Tolosa 70, 20018 San Sebastián, Spain.
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Zhu G, Du Q, Wang X, Tang N, She F, Chen Y. TNF-α promotes gallbladder cancer cell growth and invasion through autocrine mechanisms. Int J Mol Med 2014; 33:1431-40. [PMID: 24676340 PMCID: PMC4055436 DOI: 10.3892/ijmm.2014.1711] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 03/11/2014] [Indexed: 12/13/2022] Open
Abstract
Tumor necrosis factor-α (TNF-α) has been suggested to be a putative tumor promoter gene, and autocrine of TNF-α expression has been found in colon cancer and ovarian cancer. As the role of autocrine TNF-α in human gallbladder cancer has not yet been elucidated, the present study examined the expression of TNF-α in gallbladder cancer-derived cell lines. Based on the data, TNF-α mRNA and TNF-α protein expression differed significantly different between the cell lines. In addition, using siRNA targeting TNF-α, the vector, pGPU-GFP-siTNF-α, was constructed and then transfected into the SGC-996 cells (gallbladder cancer cell line) which express high levels of endogenous TNF-α. In vitro experiments indicated that the silencing of TNF-α in the SGC-996 cells significantly suppressed proliferation and invasion. However, apoptosis was not induced by the silencing of TNF-α. Furthermore, we traced the mechanisms underlying these effects and found that the silencing of TNF-α affected the TNF-α-AKT-NF-κB-Bcl-2 pathway in the SGC-996 cells. Our data provide evidence that autocrine TNF-α plays a role as a tumor promoter gene in gallbladder cancer cells, possibly by promoting proliferation and invasion through autocrine mechanisms.
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Affiliation(s)
- Guangwei Zhu
- Department of Hepatobiliary Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Qiang Du
- Department of Hepatobiliary Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Xiaoqian Wang
- Department of Hepatobiliary Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Nanhong Tang
- Department of Hepatobiliary Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Feifei She
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Yanling Chen
- Department of Hepatobiliary Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, P.R. China
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Evaluating the role of substance P in the growth of brain tumors. Neuroscience 2014; 261:85-94. [DOI: 10.1016/j.neuroscience.2013.12.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 12/09/2013] [Accepted: 12/11/2013] [Indexed: 01/11/2023]
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Pérez-Hernández AI, Catalán V, Gómez-Ambrosi J, Rodríguez A, Frühbeck G. Mechanisms linking excess adiposity and carcinogenesis promotion. Front Endocrinol (Lausanne) 2014; 5:65. [PMID: 24829560 PMCID: PMC4013474 DOI: 10.3389/fendo.2014.00065] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 04/15/2014] [Indexed: 12/17/2022] Open
Abstract
Obesity constitutes one of the most important metabolic diseases being associated to insulin resistance development and increased cardiovascular risk. Association between obesity and cancer has also been well established for several tumor types, such as breast cancer in post-menopausal women, colorectal, and prostate cancer. Cancer is the first death cause in developed countries and the second one in developing countries, with high incidence rates around the world. Furthermore, it has been estimated that 15-20% of all cancer deaths may be attributable to obesity. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment. In this sense, obesity may lead to cancer development through dysfunctional adipose tissue and altered signaling pathways. In this review, three main pathways relating obesity and cancer development are examined: (i) inflammatory changes leading to macrophage polarization and altered adipokine profile; (ii) insulin resistance development; and (iii) adipose tissue hypoxia. Since obesity and cancer present a high prevalence, the association between these conditions is of great public health significance and studies showing mechanisms by which obesity lead to cancer development and progression are needed to improve prevention and management of these diseases.
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Affiliation(s)
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
- *Correspondence: Gema Frühbeck, Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Avda. Pío XII 36, Pamplona 31008, Spain e-mail:
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Saussurea lappa Clarke-Derived Costunolide Prevents TNF α -Induced Breast Cancer Cell Migration and Invasion by Inhibiting NF- κ B Activity. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:936257. [PMID: 23997800 PMCID: PMC3755433 DOI: 10.1155/2013/936257] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 05/03/2013] [Indexed: 12/13/2022]
Abstract
Saussurea lappa Clarke (SLC) has been used as a traditional medicine in Korea, China, and Japan for the treatment of abdominal pain and tenesmus. Costunolide, a sesquiterpene lactone isolated from SLC, has diverse medicinal effects. However, the anticancer effects of costunolide are still unclear in breast cancer. In this study, we demonstrate that costunolide suppresses tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNFα-induced NF-κB activation. Costunolide inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in the in vivo mouse orthotopic tumor growth assays. In addition, costunolide inhibited in vitro TNFα-induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNFα-induced NF-κB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-κB-dependent gene to mediate breast cancer cell growth and metastases. Therefore, we conclude that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNFα-induced NF-κB activation, suggesting that costunolide as well as SLC may be promising anticancer drugs, especially for metastatic breast cancer.
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Spies NP, Takabayashi M. Expression of galaxin and oncogene homologs in growth anomaly in the coral Montipora capitata. DISEASES OF AQUATIC ORGANISMS 2013; 104:249-256. [PMID: 23759562 DOI: 10.3354/dao02603] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Growth anomaly (GA) is a coral disease characterized by enlarged skeletal lesions. Although negative effects of GA on several of coral's biological functions have been determined, the etiology and molecular pathology of this disease is very poorly understood. We studied the expression of 5 genes suspected to play a role in pathological development of GA in the endemic Hawaiian coral Montipora capitata, which is particularly susceptible to this disease. Transcript abundances of the 5 target genes in healthy tissue, GA-affected tissue, and unaffected tissue (apparently healthy tissue adjacent to GA) relative to 3 internal control genes (actin, NADH, and rpS3) were compared using quantitative reverse transcriptase PCR. Galaxin, which codes for a protein suspected to be involved in calcification and thus hypothesized to be differentially expressed in GA, was up-regulated in unaffected tissue but remained at baseline levels in GA tissue. The gene expressions of murine double minute 2 (MDM2) and tumor necrosis factor (TNF) remained unchanged in GA tissue. The expression of tyrosine protein kinase (TPK) and βγ-crystallin (BGC) were both down-regulated. These expression patterns were all inconsistent with the expression patterns of homologous genes in neoplastic diseases featuring similar morphological symptoms in humans. These expression data therefore suggest that the calcification mechanism is likely not enhanced in coral GA and that coral GA is not a malignant neoplasia.
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Affiliation(s)
- Narrissa P Spies
- Tropical Conservation Biology & Environmental Science Department, University of Hawaii, Hilo, HI 96720, USA.
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Ardestani S, Li B, Deskins DL, Wu H, Massion PP, Young PP. Membrane versus soluble isoforms of TNF-α exert opposing effects on tumor growth and survival of tumor-associated myeloid cells. Cancer Res 2013; 73:3938-50. [PMID: 23704210 DOI: 10.1158/0008-5472.can-13-0002] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
TNF-α, produced by most malignant cells, orchestrates the interplay between malignant cells and myeloid cells, which have been linked to tumor growth and metastasis. Although TNF-α can exist as one of two isoforms, a 26-kDa membrane tethered form (mTNF-α) or a soluble 17-kDa cytokine (sTNF-α), the vast majority of published studies have only investigated the biologic effects of the soluble form. We show for the first time that membrane and soluble isoforms have diametrically opposing effects on both tumor growth and myeloid content. Mouse lung and melanoma tumor lines expressing mTNF-α generated small tumors devoid of monocytes versus respective control lines or lines expressing sTNF-α. The lack of myeloid cells was due to a direct effect of mTNF-α on myeloid survival via induction of cell necrosis by increasing reactive oxygen species. Human non-small cell lung carcinoma expressed varying levels of both soluble and membrane TNF-α, and gene expression patterns favoring mTNF-α were predictive of improved lung cancer survival. These data suggest that there are significant differences in the role of different TNF-α isoforms in tumor progression and the bioavailability of each isoform may distinctly regulate tumor progression. This insight is critical for effective intervention in cancer therapy with the available TNF-α inhibitors, which can block both TNF-α isoforms.
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Affiliation(s)
- Shidrokh Ardestani
- Department of Pathology, Vanderbilt Ingram Cancer Center/Cancer Biostatistics Center, Nashville, Tennessee, USA
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Balasubramanian P, Longo VD. Aging, nutrient signaling, hematopoietic senescence, and cancer. Crit Rev Oncog 2013; 18:559-71. [PMID: 24579735 DOI: 10.1615/critrevoncog.2013010596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
It is well known that cancer is one of the main causes of mortality in the aged population. Recent studies suggest that oncogenic pathways, such as the insulin-like growth factor-1 (IGF-I), Ras, and Akt/PKB, can contribute to both aging and cancer not only by promoting growth and preventing apoptosis, but also by promoting DNA damage and genomic instability. Epidemiological studies suggest that the chronic, low-grade inflammation that accompanies aging also contributes to tissue damage and tumor progression. Coupled with the accumulation of senescent cells and declining immune function, this leads to the generation and survival of cancer cells, possibly explaining why advanced age is the primary risk factor for cancer.
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Affiliation(s)
- Priya Balasubramanian
- Andrus Gerontology Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089-0191, USA
| | - Valter D Longo
- Andrus Gerontology Center, the Molecular and Computational Biology Department, and the Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089-0191, USA
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