|
1
|
Valdivia-Silva J, Chinney-Herrera A. Chemokine receptors and their ligands in breast cancer: The key roles in progression and metastasis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:124-161. [PMID: 39260935 DOI: 10.1016/bs.ircmb.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.
Collapse
Affiliation(s)
- Julio Valdivia-Silva
- Centro de Investigación en Bioingenieria (BIO), Universidad de Ingenieria y Tecnologia-UTEC, Barranco, Lima, Peru.
| | - Alberto Chinney-Herrera
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico-UNAM, Ciudad Universitaria, Coyoacan, Ciudad de Mexico, Mexico
| |
Collapse
|
|
2
|
Cabioglu N, Onder S, Karatay H, Bayram A, Oner G, Tukenmez M, Muslumanoglu M, Igci A, Dinccag A, Ozmen V, Aydiner A, Saip P, Yavuz E. New Emerging Chemokine Receptors: CCR5 or CXCR5 on Tumor Is Associated with Poor Response to Chemotherapy and Poor Prognosis in Locally Advanced Triple-Negative Breast Cancer. Cancers (Basel) 2024; 16:2388. [PMID: 39001456 PMCID: PMC11240792 DOI: 10.3390/cancers16132388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND We aim to investigate any possible associations between chemokine receptor expression and responses to neoadjuvant chemotherapy (NAC) along with outcomes in patients with triple-negative breast cancer (TNBC) with locally advanced disease. METHOD Expressions of chemokine receptors were examined immunohistochemically after staining archival tissue of surgical specimens (n = 63) using specific antibodies for CCR5, CCR7, CXCR4, and CXCR5. RESULTS Patients with high CCR5, CCR7, CXCR4, and CXCR5 expression on tumors and high CXCR4 expression on tumor-infiltrating lymphocytes (TILs) were less likely to have a pathological complete response (pCR) or Class 0-I RCB-Index compared to others. Patients with residual lymph node metastases (ypN-positive), high CCR5TM(tumor), and high CXCR4TM expressions had an increased hazard ratio (HR) compared to others (DFS: HR = 2.655 [1.029-6.852]; DSS: HR = 2.763 [1.008-7.574]), (DFS: HR = 2.036 [0.805-5.148]; DSS: HR = 2.689 [1.020-7.090]), and (DFS: HR = 2.908 [1.080-7.829]; DSS: HR = 2.132 (0.778-5.846)), respectively. However, patients without CXCR5TIL expression had an increased HR compared to those with CXCR5TIL (DFS: 2.838 [1.266-6.362]; DSS: 4.211 [1.770-10.016]). CONCLUSIONS High expression of CXCR4TM and CCR5TM was found to be associated with poor prognosis, and CXCR5TM was associated with poor chemotherapy response in the present cohort with locally advanced TNBC. Our results suggest that patients with TNBC could benefit from a chemokine receptor inhibitor therapy containing neoadjuvant chemotherapy protocols.
Collapse
Affiliation(s)
- Neslihan Cabioglu
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Semen Onder
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Hüseyin Karatay
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Aysel Bayram
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| | - Gizem Oner
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Mustafa Tukenmez
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Mahmut Muslumanoglu
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Abdullah Igci
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Ahmet Dinccag
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Vahit Ozmen
- Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (G.O.); (M.T.); (M.M.); (A.I.); (A.D.); (V.O.)
| | - Adnan Aydiner
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul 34452, Turkey; (A.A.); (P.S.)
| | - Pınar Saip
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul 34452, Turkey; (A.A.); (P.S.)
| | - Ekrem Yavuz
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey; (S.O.); (H.K.); (A.B.); (E.Y.)
| |
Collapse
|
|
3
|
Biodetection Techniques for Quantification of Chemokines. CHEMOSENSORS 2022. [DOI: 10.3390/chemosensors10080294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Chemokines are a class of cytokine whose special properties, together with their involvement and relevant role in various diseases, make them a restricted group of biomarkers suitable for diagnosis and monitoring. Despite their importance, biodetection techniques dedicated to the selective determination of one or more chemokines are very scarce. For some years now, the critical diagnosis of inflammatory diseases by detecting both cytokine and chemokine biomarkers, has had a strong impact on the development of multiple detection platforms. However, it would be desirable to implement methodologies with a higher degree of selectivity for chemokines, in order to provide more precise information. In addition, better development of biosensor technology applied to this specific field would make it possible to address the main challenges of detection methods for several diseases with a high incidence in the population, avoiding high costs and low sensitivity. Taking this into account, this review aims to present the state of the art of chemokine biodetection techniques and emphasize the role of these systems in the prevention, monitoring and treatment of various diseases associated with chemokines as a starting point for future developments that are also analyzed throughout the article.
Collapse
|
|
4
|
Prognostic and Predictive Role of CXC Chemokine Receptor 4 in Metastatic Colorectal Cancer Patients. Appl Immunohistochem Mol Morphol 2021; 28:755-760. [PMID: 31985548 DOI: 10.1097/pai.0000000000000828] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. About 30% of patients present with metastatic disease involving predominantly the liver and a similar percentage will develop distant metastases later after removal of the primary tumor. In metastatic CRC, chemotherapies and biological drugs have prolonged survival for up to 30 months. However, there is a great need for biomarkers predictive of response and prognosis to optimize treatments. CXC chemokine receptor 4 (CXCR4) is a chemokine receptor; it binds to CXCL12 and plays a central role in colon cancer cells' growth and dissemination. MATERIALS AND METHODS CXCR4 was evaluated in CRC primary tissues by immunohistochemistry. Formalin-fixed, paraffin-embedded 4-μm tissue sections were immunostained using a biotin-streptavidin-peroxidase method and categorized into 2 semiquantitative classes: (i) absence of staining, ≤50% positive cells (negative/low) and (ii) >50% positive cells (high). Associations between clinic-pathologic variables and CXCR4 expression were evaluated using the χ test. The Kaplan-Meier product-limit method was applied to graph overall survival (OS). OS was defined as the time elapsed from diagnosis to death from any cause. Univariate analysis was carried out using the log-rank test. Cox proportional hazards regression was used to analyze the effect of several risk factors on OS. RESULTS Seventy-eight primary adenocarcinomas were analyzed; 26 were categorized as negative/low and 52 as high. Age, sex, performance status, site of metastases, KRAS mutational status, type of first-line therapy, and a number of therapy lines did not correlate with CXCR4 expression. Although not significant (P=0.0533), high CXCR4 expression was more frequently localized on the right side of the colon. Significant correlations were detected with grading (P=0.0041) and response to first-line anti-epidermal growth factor receptors agents (P<0.0001), bevacizumab (P=0.0029), and chemotherapy alone (P=0.0260). At a median follow-up of 53 months, 77 deaths have been registered. Grading [hazard ratio (HR): 1.42; confidence interval (CI): 0.89-2.28; P<0.0001], KRAS mutational status (HR: 1.73; CI: 1.03-290; P=0.0133), response to first-line chemotherapy (HR: 3.39; CI: 2.10-5.48; P<0.0001), and CXCR4 expression (HR: 3.18; CI: 2.01-5.02; P<0.0001) showed prognostic power at univariate and multivariate analyses. CONCLUSION In the present report, we show that CXCR4 expression on the primary tumor is an independent prognostic factor and correlates with response to first-line chemotherapy in metastatic CRC patients.
Collapse
|
|
5
|
Saxena S, Singh RK. Chemokines orchestrate tumor cells and the microenvironment to achieve metastatic heterogeneity. Cancer Metastasis Rev 2021; 40:447-476. [PMID: 33959849 PMCID: PMC9863248 DOI: 10.1007/s10555-021-09970-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/22/2021] [Indexed: 01/26/2023]
Abstract
Chemokines, a subfamily of the cell cytokines, are low molecular weight proteins known to induce chemotaxis in leukocytes in response to inflammatory and pathogenic signals. A plethora of literature demonstrates that chemokines and their receptors regulate tumor progression and metastasis. With these diverse functionalities, chemokines act as a fundamental link between the tumor cells and their microenvironment. Recent studies demonstrate that the biology of chemokines and their receptor in metastasis is complex as numerous chemokines are involved in regulating site-specific tumor growth and metastasis. Successful treatment of disseminated cancer is a significant challenge. The most crucial problem for treating metastatic cancer is developing therapy regimes capable of overcoming heterogeneity problems within primary tumors and among metastases and within metastases (intralesional). This heterogeneity of malignant tumor cells can be related to metastatic potential, response to chemotherapy or specific immunotherapy, and many other factors. In this review, we have emphasized the role of chemokines in the process of metastasis and metastatic heterogeneity. Individual chemokines may not express the full potential to address metastatic heterogeneity, but chemokine networks need exploration. Understanding the interplay between chemokine-chemokine receptor networks between the tumor cells and their microenvironment is a novel approach to overcome the problem of metastatic heterogeneity. Recent advances in the understanding of chemokine networks pave the way for developing a potential targeted therapeutic strategy to treat metastatic cancer.
Collapse
Affiliation(s)
- Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
| |
Collapse
|
|
6
|
Conversion of AML-blasts to leukemia-derived dendritic cells (DCleu) in 'DC-culture-media' shifts correlations of released chemokines with antileukemic T-cell reactions. Immunobiology 2021; 226:152088. [PMID: 33838552 DOI: 10.1016/j.imbio.2021.152088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 02/21/2021] [Accepted: 03/10/2021] [Indexed: 11/22/2022]
Abstract
Dendritic cells (DC) and T-cells are mediators of CTL-responses. Autologous (from patients with acute myeloid leukaemia (AML) or myelodysplasia (MDS)) or allogeneic (donor)-T-cells stimulated by DCleu, gain an efficient lysis of naive blasts, although not in every case. CXCL8, -9, -10, CCL2, -5 and Interleukin (IL-12) were quantified by Cytometric Bead Array (CBA) in supernatants from 5 DC-generating methods and correlated with AML-/MDS-patients' serum-values, DC-/T-cell-interactions/antileukemic T-cell-reactions after mixed lymphocyte culture (MLC) and patients' clinical course. The blast-lytic activity of T-cells stimulated with DC or mononuclear cells (MNC) was quantified in a cytotoxicity assay. Despite great variations of chemokine-levels, correlations with post-stimulation (after stimulating T-cells with DC in MLC) improved antileukemic T-cell activity were seen: higher released chemokine-values correlated with improved T-cells' antileukemic activity (compared to stimulation with blast-containing MNC) - whereas with respect to the corresponding serum values higher CXCL8-, -9-, and -10- but lower CCL5- and -2-release correlated with improved antileukemic activity of DC-stimulated (vs. blast-stimulated) T-cells. In DC-culture supernatants higher chemokine-values correlated with post-stimulation improved antileukemic T-cell reactivity, whereas higher serum-values of CXCL8, -9, and -10 but lower serum-values of CCL5 and -2 correlated with post-stimulation improved antileukemic T-cell-reactivity. In a context of 'DC'-stimulation (vs serum) this might point to a change of (CCL5 and -2-associated) functionality from a more 'inflammatory' or 'tumor-promoting' to a more 'antitumor'-reactive functionality. This knowledge could contribute to develop immune-modifying strategies that promote antileukemic (adaptive) immune-responses.
Collapse
|
|
7
|
Smith NC, Goulart C, Hayward JA, Kupz A, Miller CM, van Dooren GG. Control of human toxoplasmosis. Int J Parasitol 2020; 51:95-121. [PMID: 33347832 DOI: 10.1016/j.ijpara.2020.11.001] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/12/2020] [Accepted: 11/15/2020] [Indexed: 12/21/2022]
Abstract
Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal. Toxoplasma gondii infects around 2 billion people and, whilst only a small percentage of infected people will suffer serious disease, the prevalence of the parasite makes it one of the most damaging zoonotic diseases in the world. Toxoplasmosis is a disease with multiple manifestations: it can cause a fatal encephalitis in immunosuppressed people; if first contracted during pregnancy, it can cause miscarriage or congenital defects in the neonate; and it can cause serious ocular disease, even in immunocompetent people. The disease has a complex epidemiology, being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops, or by consumption of intracellular cysts in undercooked meat from intermediate hosts. In this review we examine current and future approaches to control toxoplasmosis, which encompass a variety of measures that target different components of the life cycle of T. gondii. These include: education programs about the parasite and avoidance of contact with infectious stages; biosecurity and sanitation to ensure food and water safety; chemo- and immunotherapeutics to control active infections and disease; prophylactic options to prevent acquisition of infection by livestock and cyst formation in meat; and vaccines to prevent shedding of oocysts by definitive feline hosts.
Collapse
Affiliation(s)
- Nicholas C Smith
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; Research School of Biology, Australian National University, Canberra, ACT 0200, Australia.
| | - Cibelly Goulart
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; Research School of Biology, Australian National University, Canberra, ACT 0200, Australia
| | - Jenni A Hayward
- Research School of Biology, Australian National University, Canberra, ACT 0200, Australia
| | - Andreas Kupz
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia
| | - Catherine M Miller
- College of Public Health, Medical and Veterinary Science, James Cook University, Cairns, QLD 4878, Australia
| | - Giel G van Dooren
- Research School of Biology, Australian National University, Canberra, ACT 0200, Australia
| |
Collapse
|
|
8
|
Aru B, Günay A, Şenkuytu E, Yanıkkaya Demirel G, Gürek AG, Atilla D. A Translational Study of a Silicon Phthalocyanine Substituted with a Histone Deacetylase Inhibitor for Photodynamic Therapy. ACS OMEGA 2020; 5:25854-25867. [PMID: 33073111 PMCID: PMC7558005 DOI: 10.1021/acsomega.0c03180] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 09/22/2020] [Indexed: 06/11/2023]
Abstract
In this study, we synthesized and characterized a silicon phthalocyanine substituted with 3-hydroxypyridin-2-thione (SiPc-HDACi), designed to be a chemophotodynamic therapy agent acting as a histone deacetylase inhibitor, and we determined its photophysical, photochemical, and photobiological properties. Next, we evaluated its anticancer efficacy on MCF-7, double positive and MDA-MB-231, triple negative breast cancer cell lines, as well as on a healthy human endothelial cell line (HUVEC). Our results indicate that SiPc-HDACi can target nucleoli of cells, effectively inducing apoptosis while promoting cell cycle arrest thanks to its high singlet oxygen yield and its histone deacetylase downregulating properties, suggesting a powerful anticancer effect on breast cancer in vitro. Our further studies will be conducted with primary breast cancer cell culture to give a better insight into the anticancer mechanism of the compound.
Collapse
Affiliation(s)
- Başak Aru
- Department
of Molecular Biology and Genetics, Gebze
Technical University, 41400 Gebze, Kocaeli, Turkey
- Faculty
of Medicine, Immunology Department, Yeditepe University, 34755 Ataşehir, İstanbul, Turkey
| | - Aysel Günay
- Department
of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
| | - Elif Şenkuytu
- Faculty
of Science, Department of Chemistry, Atatürk
University, 25240 Erzurum, Turkey
| | | | - Ayşe Gül Gürek
- Department
of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
| | - Devrim Atilla
- Department
of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
| |
Collapse
|
|
9
|
Yuan X, Nie W, He Z, Yang J, Shao B, Ma X, Zhang X, Bi Z, Sun L, Liang X, Tie Y, Liu Y, Mo F, Xie D, Wei Y, Wei X. Carbon black nanoparticles induce cell necrosis through lysosomal membrane permeabilization and cause subsequent inflammatory response. Theranostics 2020; 10:4589-4605. [PMID: 32292516 PMCID: PMC7150486 DOI: 10.7150/thno.34065] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 01/29/2020] [Indexed: 02/05/2023] Open
Abstract
Rationale: The adverse health effects of nano-particulate pollutants have attracted much attention in recent years. Carbon nanomaterials are recognized as risk factors for prolonged inflammatory responses and diffuse alveolar injury. Previous research indicated a central role of alveolar macrophages in the pathogenesis of particle-related lung disease, but the underlying mechanism remains largely unknown. Methods: C57BL/6 mice were intratracheally instilled with carbon black nanoparticles (CBNPs). Cell necrosis and the infiltrated neutrophils in the lungs were detected by flow cytometry. Release of mitochondria was observed with Mito Tracker and mitochondrial DNA (mtDNA) was quantified by qPCR via Taqman probes. TLR9-p38 MAPK signaling pathway was detected by Western blotting. The production of lipid chemoattractant leukotriene B4 (LTB4) in the supernatant and bronchoalveolar lavage fluid (BALF) was quantitated using an enzyme immunoassay (EIA). Results: In the present study, we found that a single instillation of CBNPs induced neutrophil influx in C57BL/6 mice as early as 4 h post-exposure following the rapid appearance of cell damage indicators in BALF at 30 min. Macrophages exposed to CBNPs showed necrotic features and were characterized by lysosome rupture, cathepsin B release, reactive oxygen species generation, and reduced intracellular ATP level. Necrosis was partly inhibited by a specific lysosomal cathepsin B inhibitor CA074 Me. Further analyses suggested that the resulting leakage of mtDNA from the necrotic cells activated neutrophils and triggered severe inflammation in vivo. Pulmonary neutrophilic inflammation induced by mtDNA was reduced in TLR9-/- mice. Additionally, mtDNA induced LTB4 production from macrophages, which may contribute to neutrophil recruitment. Conclusion: We demonstrated here that CBNPs induce acute cell necrosis through lysosomal rupture and that mtDNA released from necrotic cells functions as a key event mediating pulmonary neutrophilic inflammation. This study described a novel aspect of the pathogenesis of particle-induced inflammatory response and provided a possible therapeutic target for the regulation of inflammation.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China
| |
Collapse
|
|
10
|
Merle M, Fischbacher D, Liepert A, Grabrucker C, Kroell T, Kremser A, Dreyssig J, Freudenreich M, Schuster F, Borkhardt A, Kraemer D, Koehne CH, Kolb HJ, Schmid C, Schmetzer HM. Serum Chemokine-release Profiles in AML-patients Might Contribute to Predict the Clinical Course of the Disease. Immunol Invest 2019; 49:365-385. [PMID: 31535582 DOI: 10.1080/08820139.2019.1661429] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In cancer or hematologic disorders, chemokines act as growth- or survival factors, regulating hematopoiesis and angiogenesis, determining metastatic spread and controlling leukocyte infiltration into tumors to inhibit antitumor immune responses. The aim was to quantify the release of CXCL8, -9, -10, CCL2, -5, and IL-12 in AML/MDS-pts' serum by cytometric bead array and to correlate data with clinical subtypes and courses. Minimal differences in serum-levels subdivided into various groups (e.g. age groups, FAB-types, blast-proportions, cytogenetic-risk-groups) were seen, but higher release of CXCL8, -9, -10 and lower release of CCL2 and -5 tendentially correlated with more favorable subtypes (<50 years of age, <80% blasts in PB). Comparing different stages of the disease higher CCL5-release in persisting disease and a significantly higher CCL2-release at relapse were found compared to first diagnosis - pointing to a change of 'disease activity' on a chemokine level. Correlations with later on achieved response to immunotherapy and occurrence of GVHD were seen: Higher values of CXCL8, -9, -10 and CCL2 and lower CCL5-values correlated with achieved response to immunotherapy. Predictive cut-off-values were evaluated separating the groups in 'responders' and 'non-responders'. Higher levels of CCL2 and -5 but lower levels of CXCL8, -9, -10 correlated with occurrence of GVHD. We conclude, that in AML-pts' serum higher values of CXCL8, -9, -10 and lower values of CCL5 and in part of CCL2 correlate with more favorable subtypes and improved antitumor'-reactive function. This knowledge can contribute to develop immune-modifying strategies that promote antileukemic adaptive immune responses.
Collapse
Affiliation(s)
- M Merle
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - D Fischbacher
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - A Liepert
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - C Grabrucker
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - T Kroell
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - A Kremser
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - J Dreyssig
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - M Freudenreich
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany
| | - F Schuster
- Department for Pediatric Hematology and Oncology, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - A Borkhardt
- Department for Pediatric Hematology and Oncology, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - D Kraemer
- Department for Hematology, Municipal Hospital Oldenburg, Oldenburg, Germany
| | - C-H Koehne
- Department for Hematology, Municipal Hospital Oldenburg, Oldenburg, Germany
| | - H J Kolb
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany.,Helmholtz Center, Clinical Cooperative Group Human Cell Transplantation (CCG-HCT), Munich, Germany
| | - C Schmid
- Department for Hematology, University Hospital Augsburg, Augsburg, Germany
| | - H M Schmetzer
- Department for Hematopoietic Transplantations, Med III, University Hospital of Munich, Munich, Germany.,Helmholtz Center, Clinical Cooperative Group Human Cell Transplantation (CCG-HCT), Munich, Germany
| |
Collapse
|
|
11
|
Bi H, Zhang Y, Wang S, Fang W, He W, Yin L, Xue Y, Cheng Z, Yang M, Shen J. Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer. Oncol Lett 2019; 18:4176-4184. [PMID: 31516616 PMCID: PMC6732969 DOI: 10.3892/ol.2019.10735] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 07/03/2019] [Indexed: 01/10/2023] Open
Abstract
Liver cancer (LC), which is one of the most common types of cancer worldwide, is notorious for its high morbidity and mortality rates. Interleukin-8 (IL-8), an important member of the CXC chemokine family that was originally classified as a potent neutrophil chemoattractant, has been shown to serve an important role in inflammation, tumor growth, invasion and metastasis through interactions with its receptors. However, the expression and functional roles of IL-8 and its receptors, CXC chemokine receptor (CXCR) 1 and CXCR2 in the progression of liver cancer remain to be fully elucidated. In the present study, it was shown that the mRNA levels of IL-8, CXCR1 and CXCR2 were increased in peripheral blood mononuclear cells from patients with liver cancer compared with those from patients with cirrhosis or normal controls (P<0.05). Higher levels of CXCR1, CXCR2 and IL-8 were associated with advanced tumor stage and increased risk of lymph node or distant metastasis. Immunohistochemistry showed that the IL-8, CXCR1 and CXCR2 proteins were expressed in the cytoplasm of hepatoma cells at higher intensities than those of normal controls (P<0.05). The semi-quantitative analysis revealed that the relative mean density of hepatic IL-8, CXCR1 and CXCR2 staining in liver cancer was significantly increased compared with that in normal liver tissues (P<0.05). The analysis revealed that the mRNA expression of IL-8 was positively associated with that of CXCR1 (r=0.618; P<0.05) and CXCR2 (r=0.569; P<0.05). The mRNA levels of CXCR1 and CXCR2 gradually increased with elevated expression of IL-8 in liver cancer. Experiments were performed using human Huh-7 and HepG2 cell lines, incubating cells with IL-8 and conducting in vitro migration and invasion assays. The results showed that the wound healing activity and migration of Huh-7 and HepG2 cells were increased by IL-8. Pretreatment of the cells with anti-CXCR1 or anti-CXCR2 (5 µM) for 30 min markedly inhibited IL-8-directed cell migration. Taken together, these results indicated that IL-8 promotes liver cancer cell migration via CXCR1 and CXCR2 and that targeting the CXCR1/2 may be a potential strategy for liver cancer treatment.
Collapse
Affiliation(s)
- Huijuan Bi
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Yu Zhang
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Shanshan Wang
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Wenhao Fang
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Wenjun He
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Lina Yin
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Ying Xue
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Zhixiang Cheng
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Minghui Yang
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Jilu Shen
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| |
Collapse
|
|
12
|
Omran OM. EGFR and CXCR1 expression in thyroid carcinoma in Qassim Region-Saudi Arabia: Correlation with clinicopathological parameters. ACTA ACUST UNITED AC 2019; 26:145-151. [PMID: 31031057 DOI: 10.1016/j.pathophys.2019.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 04/03/2019] [Accepted: 04/17/2019] [Indexed: 12/25/2022]
Abstract
AIMS Recent evidence indicates an increased incidence of thyroid carcinoma, especially papillary thyroid carcinoma (PTC), in Saudi Arabia. EGFR and CXCR1 were reported to have increased expression in several human neoplasms. The goals of the present research was to investigate EGFR and CXCR1 expression in thyroid carcinoma and correlate the results to the established prognostic factors. METHODS Immunohistochemical study for both EGFR and CXCR1 was performed on formalin-fixed paraffin-embedded thyroid carcinomas tissues sections applying Labeled Streptavidin-biotin method (LSAB). RESULTS Remarkable high expression of EGFR and CXCR1 were observed in PTC cases (56% and 63% respectively). There was association between EGFR expression in PTC and each of histologic subtype, lymph node metastasis (LNM), distant metastasis (DM), TNM staging and tumor relapse. There was statistical significant correlation between CXCR1 expression in PTC and each of histologic subtype, LNM, and tumor relapse. A significant correlation was detected between concomitant EGFR and CXCR expression and LNM, DM, increasing stage and tumor relapse. CONCLUSIONS The results of the present study demonstrated, a statistically positive correlation of EGFR and CXCR1 expression in PTC compared to normal thyroid tissues and nodular hyperplasia in Qassim Region- Saudi Arabia. Concomitant high expression of both receptors were strongly correlated with LNM, DM, TNM stage and tumor relapse than did each alone. These findings suggest that EGFR and CXCR1 play crucial roles in PTC and serve as predictors of poor prognosis, biomarkers of tumor diagnosis, and potential targets of cancer therapeutics.
Collapse
Affiliation(s)
- Ola M Omran
- Department of Pathology, College of Medicine, Qassim University, Saudi Arabia; Department of Pathology, Faculty of Medicine, Assiut University, Egypt.
| |
Collapse
|
|
13
|
Yin X, Liu Z, Zhu P, Wang Y, Ren Q, Chen H, Xu J. CXCL12/CXCR4 promotes proliferation, migration, and invasion of adamantinomatous craniopharyngiomas via PI3K/AKT signal pathway. J Cell Biochem 2018; 120:9724-9736. [PMID: 30582214 DOI: 10.1002/jcb.28253] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 10/22/2018] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Adamantinomatous craniopharyngiomas (adaCP) accounts for 5.6% to 15% of intracranial tumors. High expression of chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal cell-derived factor 1 [SDF1]) and its receptor CXC receptor type 4 (CXCR4) are widespread in various malignancy via multiple signal transduction pathways. This study aims to investigate the mechanism of CXCL12/CXCR4 promoting proliferation, migration, and invasion of adaCP. METHODS Quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry were used to evaluate the expression of CXCL12/CXCR4 mRNA and protein in 10 human adaCP tissues. Three successfully primary cell lines were obtained from native mainly solid tumor specimens, and confirmed by the means of inverted contrast microscope directly and following hematoxylin and eosin staining. Immunofluorescence was used to detect protein expression in vivo for the verification of primary cell line. Proliferation, migration, and invasion assays were performed to assess the biological functional role of CXCL12/CXCR4 in adaCP. The signal pathways involved in the action of CXCL12/CXCR4 in adaCP were also evaluated. RESULTS CXCL12 and CXCR4 were highly expressed in human adaCP samples. Primary adaCP cells were isolated and detected by the means of immunofluorescence for the detection of pan cytokeratin (pan-CK) and vimentin (VIM). Overexpression of CXCL12/CXCR4 significantly promoted the proliferation, migration, and invasion of primary adaCP cells. Moreover, cancer-promoting activity of CXCL12/CXCR4 is partially through its facilitation of PI3K/AKT signal pathway. CONCLUSIONS Our data showed that CXCL12/CXCR4 promotes adaCP proliferation, migration, and invasion through PI3K/AKT signal pathway. These findings suggested that therapeutic strategies regulating CXCL12/CXCR4 expression may provide an effective treatment of adaCP.
Collapse
Affiliation(s)
- Xiaohong Yin
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Zhiyong Liu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Pan Zhu
- Department of Clinical Laboratory, Taihe Hospital (Affiliated Hubei University of Medicine), Shiyan, Hubei, People's Republic of China
| | - Yuelong Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qingqing Ren
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hongxu Chen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | | |
Collapse
|
|
14
|
The Correlation Between Serum Chemokines and Clinical Outcome in Patients with Advanced Biliary Tract Cancer. Transl Oncol 2018; 11:353-357. [PMID: 29448202 PMCID: PMC5852407 DOI: 10.1016/j.tranon.2018.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 01/16/2018] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Biliary tract cancers (BTCs) are known to have a dismal prognosis. A number of chemokines play important roles in the progress of BTCs. However, the serum levels of chemokines in BTCs have not yet been explored. METHODS The sera of healthy donors (n = 8) and patients with BTCs who were enrolled in second line sunitinib trials (n = 27) were collected. The concentrations of three kinds of chemokines (CXCL5, CXCL8 and CXCL12) were measured using ELISA assay. The median concentrations of chemokines were compared between healthy donors and BTC patients and the role of chemokines as a prognostic biomarker was examined. RESULTS BTC patients generally had higher serum levels of CXCL5 and CXCL12 compared to healthy donors. Patients with cholangiocarcinoma showed significantly higher levels of serum CXCL12 than patients with gallbladder cancer. In survival analysis, only CXCL12 level showed a prognostic impact on overall survival (median OS: 6.9 vs. 0.9 months in low CXCL12 vs. high CXCL12, respectively; P = .008). High CXCL5 levels were also correlated with poor survival without statistical insignificance (median OS: 6.2 vs. 2.0 months in low CXCL5 vs. high CXCL5, respectively; P = .070). CONCLUSIONS There was a significant difference in OS according to the level of CXCL12, suggesting that serum CXCL12 levels may be a useful surrogate marker for clinical outcome in advanced BTCs.
Collapse
|
|
15
|
Khan NU, He H, Wang X, Ge B, Wang Q, Liu X, Lao J, Wang Y, Li J, Wang Z, Zhou S, Huang F. A two-color fluorescence enhanced dot-blot assay for revealing co-operative expression of chemokine receptors in cells. Chem Commun (Camb) 2018; 54:778-781. [DOI: 10.1039/c7cc08167g] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A highly sensitive two-color dot-blot assay has been developed to simultaneously detect co-operative expression of chemokine receptors in cells.
Collapse
|
|
16
|
Nakayama R, Arikawa K, Bhawal UK. The epigenetic regulation of CXCL14 plays a role in the pathobiology of oral cancers. J Cancer 2017; 8:3014-3027. [PMID: 28928893 PMCID: PMC5604453 DOI: 10.7150/jca.21169] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 07/09/2017] [Indexed: 02/07/2023] Open
Abstract
Background: Chemokines selectively attract and activate leukocytes and play roles in a variety of homeostatic and disease processes. Explore the biological properties of CXCL14 seems complicated due to unknown functional characteristics of CXCL14 in cancer. Methods: To study the multistep process of oral cancer development, we analyzed oral samples spanning normalcy, dysplasia and cancer from multiple perspectives, revealing a cascade of progressive changes. Results: CXCL14 protein was expressed in the cytoplasm adjacent to tumors. T classification (P<0.001), clinical stage (P=0.0013) and nodal metastasis (P=0.0035) were significantly associated with CXCL14 in relationships between CXCL14 expression levels and tumor and patient characteristics. Compared with non-tumor tissue, expression of the epidermal growth factor receptor (EGFR) gene was increased in dysplasia and was further sustained in cancer. Our data show an inverse relationship between CXCL14 and EGFR expression levels in tumor cells indicating that CXCL14 expression is beneficial for tumor suppression. To explore epigenetic regulation and the impact of CXCL14 on oral cancer, analysis of CpG islands methylation in the CXCL14 promoter region indicated that the abnormal hypermethylation of that promoter region in tumor cells and tissues is one of the mechanisms causing the reduced expression. Restoration of CXCL14 expression was induced by treatment with 5-aza-2'-deoxycytidine. Using in vivo mouse models, we demonstrate that the restoration of CXCL14 expression in irradiation-induced oral carcinoma cells induces the expression of Late Cornified Envelope (LCE) genes. Conclusions: Our data suggest that LCE genes are a novel target of CXCL14 and are likely to have a tumor suppressor function through the modulation of CXCL14 expression. In conclusion, CXCL14 might play a pivotal role in the pathobiology of oral cancer, probably by regulating DNA methylation and leukocyte migration. The level of CXCL14 expression may be a valuable adjuvant parameter to predict the prognosis of patients with oral carcinoma and may be a potential therapeutic target.
Collapse
Affiliation(s)
- Ryuji Nakayama
- Department of Preventive and Public Oral Health, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271-8587, Japan
| | - Kazumune Arikawa
- Department of Preventive and Public Oral Health, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271-8587, Japan.,Research Institute of Oral Health, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271-8587, Japan
| | - Ujjal K Bhawal
- Research Institute of Oral Health, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271-8587, Japan.,Department of Oral Health, Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa 238-8580, Japan.,Department of Biochemistry and Molecular Biology, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271-8587, Japan
| |
Collapse
|
|
17
|
Ma JC, Sun XW, Su H, Chen Q, Guo TK, Li Y, Chen XC, Guo J, Gong ZQ, Zhao XD, Qi JB. Fibroblast-derived CXCL12/SDF-1α promotes CXCL6 secretion and co-operatively enhances metastatic potential through the PI3K/Akt/mTOR pathway in colon cancer. World J Gastroenterol 2017; 23:5167-5178. [PMID: 28811711 PMCID: PMC5537183 DOI: 10.3748/wjg.v23.i28.5167] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/13/2017] [Accepted: 05/09/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the underlying mechanism by which CXCL12 and CXCL6 influences the metastatic potential of colon cancer and internal relation of colon cancer and stromal cells.
METHODS Western blotting was used to detect the expression of CXCL12 and CXCL6 in colon cancer cells and stromal cells. The co-operative effects of CXCL12 and CXCL6 on proliferation and invasion of colon cancer cells and human umbilical vein endothelial cells (HUVECs) were determined by enzyme-linked immunosorbent assay, and proliferation and invasion assays. The angiogenesis of HUVECs through interaction with cancer cells and stromal cells was examined by angiogenesis assay. We eventually investigated activation of PI3K/Akt/mTOR signaling by CXCL12 involved in the metastatic process of colon cancer.
RESULTS CXCL12 was expressed in DLD-1 cancer cells and fibroblasts. The secretion level of CXCL6 by colon cancer cells and HUVECs were significantly promoted by fibroblasts derived from CXCL12. CXCL6 and CXCL2 could significantly enhance HUVEC proliferation and migration (P < 0.01). CXCL6 and CXCL2 enhanced angiogenesis by HUVECs when cultured with fibroblast cells and colon cancer cells (P < 0.01). CXCL12 also enhanced the invasion of colon cancer cells. Stromal cell-derived CXCL12 promoted the secretion level of CXCL6 and co-operatively promoted metastasis of colon carcinoma through activation of the PI3K/Akt/mTOR pathway.
CONCLUSION Fibroblast-derived CXCL12 enhanced the CXCL6 secretion of colon cancer cells, and both CXCL12 and CXCL6 co-operatively regulated the metastasis via the PI3K/Akt/mTOR signaling pathway. Blocking this pathway may be a potential anti-metastatic therapeutic target for patients with colon cancer.
Collapse
|
|
18
|
Zhang Z, Liu F, Li Z, Wang D, Li R, Sun C. Jak3 is involved in CCR7-dependent migration and invasion in metastatic squamous cell carcinoma of the head and neck. Oncol Lett 2017; 13:3191-3197. [PMID: 28521425 PMCID: PMC5431255 DOI: 10.3892/ol.2017.5861] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 01/06/2017] [Indexed: 12/21/2022] Open
Abstract
Patients with cervical lymph node metastasis in squamous cell carcinoma of the head and neck (SCCHN) exhibit a poor prognosis and low 5-year survival rate. It has been proven that chemokine receptor 7 (CCR7) promotes cellular migration and invasion in metastatic SCCHN. In the present study, the metastatic SCCHN PCI-37B cell line was utilized to explore the role of Janus activated kinase-3 (Jak3) in the CCR7-mediated signaling pathway in metastatic SCCHN cells. It was observed that phospho-Jak3 was expressed in SCCHN tissues. In addition, when the PCI-37B cells were analyzed in response to chemokine ligand 19 (CCL19), the ligand of CCR7, at the indicated time points, the results of the present study demonstrated that CCR7 induced Jak3 activation, and inhibition of Jak3 activity using a specific inhibitor, ZM39923, significantly attenuated CCR7-induced Jak3 phosphorylation. Migration and invasion assays and immunofluorescence staining experiments demonstrated that CCL19 promoted cell migration, invasion and F-actin rearrangment in CCR7-expressing SCCHN cells partially due to the activation of the Jak3 signaling pathway. These results demonstrate that the Jak3 signaling pathway is important for the CCR7-induced malignant biological behavior of SCCHN cells.
Collapse
Affiliation(s)
- Zhongti Zhang
- Department of Prosthodontics, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China
| | - Fayu Liu
- Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China
| | - Zhenning Li
- Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China
| | - Dan Wang
- Department of Prosthodontics, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China
| | - Ruiwu Li
- Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China
| | - Changfu Sun
- Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China
| |
Collapse
|
|
19
|
Liu L, Nie S, Xie M. Tumor Microenvironment as a New Target for Tumor Immunotherapy of Polysaccharides. Crit Rev Food Sci Nutr 2017; 56 Suppl 1:S85-94. [PMID: 26463881 DOI: 10.1080/10408398.2015.1077191] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Many researches show that polysaccharides derived from fungi and plants have strong pharmacological activities such as enhancing the organism immune and anti-tumor function, and have few toxic and side effects. So the polysaccharides show a wide application prospect in the prevention and therapy of tumor. The tumor microenvironment consists of tumor cells and tumor cells' surrounding environment. The tumor microenvironment not only plays a key role in the development of tumor, but also is a potential treasure for searching new ways to treat tumor. In this review, we summarized polysaccharides' regulation effects on tumor microenvironment progression and tried to give a new theoretical basis for the exploitation of polysaccharides with anti-tumor activity.
Collapse
Affiliation(s)
- Liqiao Liu
- a State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang , Jiangxi , China
| | - Shaoping Nie
- a State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang , Jiangxi , China
| | - Mingyong Xie
- a State Key Laboratory of Food Science and Technology, Nanchang University , Nanchang , Jiangxi , China
| |
Collapse
|
|
20
|
Jao HY, Yu FS, Yu CS, Chang SJ, Liu KC, Liao CL, Ji BC, Bau DT, Chung JG. Suppression of the migration and invasion is mediated by triptolide in B16F10 mouse melanoma cells through the NF-kappaB-dependent pathway. ENVIRONMENTAL TOXICOLOGY 2016; 31:1974-1984. [PMID: 26420756 DOI: 10.1002/tox.22198] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 09/10/2015] [Accepted: 09/13/2015] [Indexed: 06/05/2023]
Abstract
Melanoma cancer is one of the major causes of death in humans worldwide. Triptolide is one of the active components of Tripterygium wilfordii Hook F, and has biological activities including induced cell cycle arrest and induction of apoptosis but its antimetastatic effects on murine melanoma cells have not yet been elucidated. Herein, we investigated the effect of triptolide on the inhibition of migration and invasion and possible associated signal pathways in B16F10 murine melanoma cancer cells. Wound healing assay and Matrigel Cell Migration Assay and Invasion System demonstrated that triptolide marked inhibiting the migration and invasion of B16F10 cells. Gelatin zymography assay demonstrated that triptolide significantly inhibited the activities of matrix metalloproteinases-2 (MMP-2). Western blotting showed that triptolide markedly reduced CXCR4, SOS1, GRB2, p-ERK, FAK, p-AKT, Rho A, p-JNK, NF-κB, MMP-9, and MMP-2 but increased PI3K and p-p38 and COX2 after compared to the untreated (control) cells. Real time PCR indicated that triptolide inhibited the gene expression of MMP-2, FAK, ROCK-1, and NF-κB but did not significantly affect TIMP-1 and -2 gene expression in B16F10 cells in vitro. EMSA assay also showed that triptolide inhibited NF-κB DNA binding in a dose-dependent manner. Confocal laser microscopy examination also confirmed that triptolide inhibited the expression of NF-κB in B16F10 cells. Taken together, we suggest that triptolide inhibited B16F10 cell migration and invasion via the inhibition of NF-κB expression then led to suppress MMP-2 and -9 expressions. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1974-1984, 2016.
Collapse
Affiliation(s)
- Hui-Yu Jao
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan, ROC
| | - Fu-Shun Yu
- School of Dentistry, China Medical University, Taichung, 404, Taiwan, ROC
| | - Chun-Shu Yu
- School of Pharmacology, China Medical University, Taichung, 404, Taiwan, ROC
| | - Shu-Jen Chang
- School of Pharmacology, China Medical University, Taichung, 404, Taiwan, ROC
| | - Kuo-Ching Liu
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404, Taiwan, ROC
| | - Ching-Lung Liao
- Graduate Institute of Chinese Medicine, China Medical University, Taichung, 404, Taiwan, ROC
| | - Bin-Chuan Ji
- Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan, ROC
| | - Da-Tian Bau
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 404, Taiwan, ROC
- Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, 404, Taiwan, ROC
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan, ROC
- Department of Biotechnology, Asia University, Taichung, 413, Taiwan, ROC
| |
Collapse
|
|
21
|
Abstract
SUMMARYProtists are a diverse collection of eukaryotic organisms that account for a significant global infection burden. Often, the immune responses mounted against these parasites cause excessive inflammation and therefore pathology in the host. Elucidating the mechanisms of both protective and harmful immune responses is complex, and often relies of the use of animal models. In any immune response, leucocyte trafficking to the site of infection, or inflammation, is paramount, and this involves the production of chemokines, small chemotactic cytokines of approximately 8–10 kDa in size, which bind to specific chemokine receptors to induce leucocyte movement. Herein, the scientific literature investigating the role of chemokines in the propagation of immune responses against key protist infections will be reviewed, focussing onPlasmodiumspecies,Toxoplasma gondii, Leishmaniaspecies andCryptosporidiumspecies. Interestingly, many studies find that chemokines can in fact, promote parasite survival in the host, by drawing in leucocytes for spread and further replication. Recent developments in drug targeting against chemokine receptors highlights the need for further understanding of the role played by these proteins and their receptors in many different diseases.
Collapse
|
|
22
|
Xie T, Ren HY, Lin HQ, Mao JP, Zhu T, Wang SD, Ye ZM. Sinomenine prevents metastasis of human osteosarcoma cells via S phase arrest and suppression of tumor-related neovascularization and osteolysis through the CXCR4-STAT3 pathway. Int J Oncol 2016; 48:2098-112. [PMID: 26983669 DOI: 10.3892/ijo.2016.3416] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 12/15/2015] [Indexed: 11/05/2022] Open
Abstract
Osteosarcoma is the most common primary malignant tumor of the bone. The long-term survivals continue to be unsatisfactory for patients with metastatic and recurrent disease. Metastasis is still a severe challenge in osteosarcoma treatment. Sinomenine, an alkaloid from traditional Chinese medicine, has been proved to possess potent antitumor and anti-invasion effect on various cancers. However, the effect of sinomenine on human osteosarcoma and the underlying mechanisms remains unknown. We report here that sinomenine inhibited proliferation by inducing S phase arrest and suppressing the clone formation. Significant inhibitory effects were found in invasion and metastasis in osteosarcoma, but little cytotoxicity was observed in tested concentrations. Exposure to sinomenine resulted in suppression of invasion and migration in osteosarcoma cells as well as tube formation ability in the human umbilical vein endothelial cells (HUVEC) and U2OS cells. Furthermore, it demonstrated that CXCR4 played a key role contributing to invasion in osteosarcoma which is considered to be a core target site in sinomenine treatment. Sinomenine inhibited invasion by suppressing CXCR4 and STAT3 phosphorylation then downregulating the expression of MMP-2, MMP-9, RANKL, VEGF downstream. In addition, then RANKL-mediated bone destruction stimulated by osteoclastogenesis and VEGF-related neovascularization were restrained. Importantly, in vivo, sinomenine suppressed proliferation, osteoclastogenesis and bone destruction. Through these various comprehensive means, sinomenine inhibits metastasis in osteosarcoma. Taken together, our results revealed that sinomenine caused S phase arrest, inhibited invasion and metastasis via suppressing the CXCR4-STAT3 pathway and then osteoclastogenesis-mediated bone destruction and neovascularization in osteosarcoma. Sinomenine is therefore a promising adjuvant agent for metastasis control in osteosarcoma.
Collapse
Affiliation(s)
- Tao Xie
- Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Hai-Yong Ren
- Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Hai-Qing Lin
- Department of Orthopedics, Second Jiaxing Hospital, Jiaxing, P.R. China
| | - Jin-Ping Mao
- Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Ting Zhu
- Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Sheng-Dong Wang
- Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Zhao-Ming Ye
- Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| |
Collapse
|
|
23
|
Rivas-Fuentes S, Salgado-Aguayo A, Pertuz Belloso S, Gorocica Rosete P, Alvarado-Vásquez N, Aquino-Jarquin G. Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation. J Cancer 2015; 6:938-52. [PMID: 26316890 PMCID: PMC4543754 DOI: 10.7150/jca.12286] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 06/23/2015] [Indexed: 12/12/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in development, activation of the immune response, and physiological angiogenesis. Chemokines have emerged as important regulators in the pathophysiology of cancer. These molecules are involved in the angiogenesis/angiostasis balance and in the recruitment of tumor infiltrating hematopoietic cells. In addition, chemokines promote tumor cell survival, as well as the directing and establishment of tumor cells to metastasis sites. The findings summarized here emphasize the central role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in the inflammatory process of NSCLC angiogenesis.
Collapse
Affiliation(s)
- Selma Rivas-Fuentes
- 1. Department of Biochemistry Research, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - Alfonso Salgado-Aguayo
- 2. Laboratory of Research on Rheumatic Diseases, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - Silvana Pertuz Belloso
- 3. Department of Comparative Biology, Faculty of Sciences, National Autonomous University of Mexico, Mexico City, Mexico
| | - Patricia Gorocica Rosete
- 1. Department of Biochemistry Research, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - Noé Alvarado-Vásquez
- 1. Department of Biochemistry Research, National Institute of Respiratory Diseases “Ismael Cosío Villegas”, Mexico City, Mexico
| | - Guillermo Aquino-Jarquin
- 4. Laboratory of Research on Genomics, Genetics and Bioinformatics. Tower of Haemato-oncology, Children´s Hospital of Mexico “Federico Gomez”, Mexico City, Mexico
| |
Collapse
|
|
24
|
Hu SCS. Mycosis fungoides and Sézary syndrome: Role of chemokines and chemokine receptors. World J Dermatol 2015; 4:69-79. [DOI: 10.5314/wjd.v4.i2.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/16/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (CTCL), and is characterized by a clonal expansion of malignant CD4+ T lymphocytes with skin-homing properties. Clinically and pathologically, mycosis fungoides can be categorized into patch, plaque and tumor stages. The clinical course of mycosis fungoides is usually chronic and indolent, but a proportion of patients may develop progressive disease with peripheral blood, lymph node and visceral organ involvement. Sézary syndrome is an aggressive leukemic form of CTCL characterized by a clonal population of malignant T cells in the peripheral blood. Various forms of skin-directed and systemic treatments are available for mycosis fungoides and Sézary syndrome. However, current treatments are generally not curative, and can only control the disease. Currently, the etiology and pathogenesis of mycosis fungoides and Sézary syndrome are not well defined. Proposed mechanisms include chronic antigenic stimulation by infectious agents, expression of specific adhesion molecules, altered cytokine production, mutations of oncogenes and tumor suppressor genes, and avoidance of apoptosis. In recent years, a number of chemokine receptors and their corresponding chemokine ligands have been found to contribute to the migration and survival of lymphoma cells in mycosis fungoides and Sézary syndrome, including CC chemokine receptor 4 (CCR4), CCR10, C-X-C chemokine receptor type 4 (CXCR4), CCR7, CCR3 and CXCR3. Since chemokines and chemokine receptors have been found to play important roles in the pathophysiology of mycosis fungoides and Sézary syndrome, they may be potentially useful targets for the development of new treatments for these diseases in the future.
Collapse
|
|
25
|
Crystalline silica-induced leukotriene B4-dependent inflammation promotes lung tumour growth. Nat Commun 2015; 6:7064. [PMID: 25923988 PMCID: PMC4418220 DOI: 10.1038/ncomms8064] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 03/27/2015] [Indexed: 12/26/2022] Open
Abstract
Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer. In this study, we demonstrate that in K-ras(LA1) mice, CS exposure markedly enhances the lung tumour burden and genetic deletion of leukotriene B4 receptor-1 (BLT1(-/-)) attenuates this increase. Pulmonary neutrophilic inflammation induced by CS is significantly reduced in BLT1(-/-)K-ras(LA1) mice. CS exposure induces LTB4 production by mast cells and macrophages independent of inflammasome activation. In an air-pouch model, CS-induced neutrophil recruitment is dependent on LTB4 production by mast cells and BLT1 expression on neutrophils. In an implantable lung tumour model, CS exposure results in rapid tumour growth and decreased survival that is attenuated in the absence of BLT1. These results suggest that the LTB4/BLT1 axis sets the pace of CS-induced sterile inflammation that promotes lung cancer progression. This knowledge may facilitate development of immunotherapeutic strategies to fight silicosis and lung cancer.
Collapse
|
|
26
|
Zhao S, Wang J, Qin C. Blockade of CXCL12/CXCR4 signaling inhibits intrahepatic cholangiocarcinoma progression and metastasis via inactivation of canonical Wnt pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:103. [PMID: 25471741 PMCID: PMC4265318 DOI: 10.1186/s13046-014-0103-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/21/2014] [Indexed: 12/25/2022]
Abstract
Background Intrahepatic cholangiocarcinoma (IHCC) is the second most frequent primary malignant liver tumor following hepatocellular carcinoma. It is a highly fatal disease and has few therapeutics. The CXC chemokine ligand-12 (CXCL12)/CXC chemokine receptor type 4 (CXCR4) axis has been shown to be involved in tumorgenesis, proliferation, and angiogenesis in a variety of cancers including IHCC. However, its prognostic significance in IHCC is unclear. The purpose of this study was to examine the functional role of CXCR4 in the progression and metastasis of IHCC and explore the underlying mechanism. Methods The CXCR4 expression, overall survival, and the clinical characteristics including age, sex, differentiation degree, tumor size, vascular invasion, lymph node metastasis, TNM stage, and T stage were analyzed for 122 IHCC patients. Short hairpin RNA (shRNA) against CXCR4 was used to disrupt the CXCL12/CXCR4 signal transduction pathways in IHCC cell lines. In vitro assays, including CCK-8 assay, flow cytometry, and colony formation assay, and in vivo tumor formation assay were utilized to detect the cell phenotype of CXCR4 knockdown cells. Transwell and wound healing assays were used to examine the IHCC cell invasion and migration ability. The Wnt pathway was assessed by Western blot and β-Catenin/Tcf transcription reporter assay. Results We demonstrated that CXCR4 expression was closely correlated with IHCC progression and metastasis characteristics. The overall survival of patients with high CXCR4 expression was significantly lower than that of patients with low CXCR4 expression. Furthermore, we showed that the abrogation of CXCR4 had significantly negative influence on the IHCC cell phenotype, including in vitro cell proliferation, cell cycle, colony formation, cell invasion, and in vivo tumorigenicity. In addition, CXCR4 knockdown downregulated Wnt target genes and mesenchymal markers such as Vimentin and Slug. Conclusions In conclusion, our result shows that high CXCR4 expression is associated with IHCC progression and metastasis via the canonical Wnt pathway, suggesting that CXCR4 may serve as a promising therapeutic target for IHCC.
Collapse
Affiliation(s)
- Shengqiang Zhao
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, China.
| | - Jing Wang
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, China.
| | - Chengyong Qin
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, China.
| |
Collapse
|
|
27
|
Lin K, Zou R, Lin F, Zheng S, Shen X, Xue X. Expression and effect of CXCL14 in colorectal carcinoma. Mol Med Rep 2014; 10:1561-8. [PMID: 24938992 DOI: 10.3892/mmr.2014.2343] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 05/30/2014] [Indexed: 11/06/2022] Open
Abstract
Chemokines are important in the proliferation and metastasis of tumors. CXCL14 is a member of the CXCL chemokine family and exhibits various expression patterns in different types of tumor, even those tumors that occur in the same type of tissue. The expression of CXCL14 and its clinical significance in colorectal carcinoma are unclear. In the present study, the expression levels of CXCL14 in colorectal carcinoma and adjacent normal tissues were detected using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Kaplan‑Meier survival curves and the Cox regression model were applied to evaluate the clinical significance of the expression levels of CXCL14 in colorectal carcinoma compared with those in normal tissues. To investigate the effects at a cellular level, a replication‑defective lentivirus overexpressing CXCL14 was constructed and transfected into HT29 colorectal carcinoma cells. The effect of CXCL14 on the proliferation of colorectal carcinoma cells and the change in cell cycle distributions were investigated using a cell counting kit‑8 assay and flow cytometry, respectively. Results of the current study indicated that the expression levels of CXCL14 mRNA and protein in colorectal carcinoma were markedly reduced compared with levels in normal tissues (P<0.05). The clinical correlation analysis suggested that downregulation of CXCL14 expression in tumors was associated with lymph metastasis, tumor location, and clinicopathological stage (P<0.05). Kaplan‑Meier survival analysis revealed that downregulation of CXCL14 expression was correlated with a poor prognosis (P<0.01). Overexpression of CXCL14 by lentiviral transfection produced an inhibitory effect on cell proliferation by arresting the cell cycle in the G1 stage. The data of the current study suggest that CXCL14 may be involved in the development and progression of colorectal carcinoma, and may act directly as a potential cancer suppressor gene. The level of CXCL14 expression may be a valuable adjuvant parameter in predicting the prognosis of colorectal carcinoma and may be a potential therapeutic target.
Collapse
Affiliation(s)
- Kezhi Lin
- Experimental Teaching Center, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Ruanmin Zou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Feng Lin
- Department of General Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
| | - Shuang Zheng
- Department of General Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
| | - Xian Shen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| |
Collapse
|
|
28
|
Yao Y, Tsirka SE. Monocyte chemoattractant protein-1 and the blood-brain barrier. Cell Mol Life Sci 2014; 71:683-97. [PMID: 24051980 PMCID: PMC3946874 DOI: 10.1007/s00018-013-1459-1] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Revised: 07/20/2013] [Accepted: 08/19/2013] [Indexed: 12/17/2022]
Abstract
The blood-brain barrier (BBB) is a dynamic structure that maintains the homeostasis of the brain and thus proper neurological functions. BBB compromise has been found in many pathological conditions, including neuroinflammation. Monocyte chemoattractant protein-1 (MCP1), a chemokine that is transiently and significantly up-regulated during inflammation, is able to disrupt the integrity of BBB and modulate the progression of various diseases, including excitotoxic injury and hemorrhage. In this review, we first introduce the biochemistry and biology of MCP1, and then summarize the effects of MCP1 on BBB integrity as well as individual BBB components.
Collapse
Affiliation(s)
- Yao Yao
- Program in Molecular and Cellular Pharmacology, Department of Pharmacological Sciences, BST8-192, Stony Brook University, Stony Brook, NY 11794-8651 USA
- Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065 USA
| | - Stella E. Tsirka
- Program in Molecular and Cellular Pharmacology, Department of Pharmacological Sciences, BST8-192, Stony Brook University, Stony Brook, NY 11794-8651 USA
| |
Collapse
|
|
29
|
Sueoka H, Hirano T, Uda Y, Iimuro Y, Yamanaka J, Fujimoto J. Blockage of CXCR2 suppresses tumor growth of intrahepatic cholangiocellular carcinoma. Surgery 2014; 155:640-9. [PMID: 24582495 DOI: 10.1016/j.surg.2013.12.037] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 12/31/2013] [Indexed: 01/18/2023]
Abstract
BACKGROUND/AIMS Complete operative resection is the only approach to cure for intrahepatic cholangiocellular carcinoma (ICC), but the disease's prognosis is notably poor. A novel therapeutic approach is urgently required. CXC chemokine receptor 2 (CXCR2) has been associated with tumorigenesis and metastasis in human cancers. In this study, we investigated the suppressive effect of ICC growth by blocking CXCR2. MATERIAL AND METHODS The role of CXCR2 was estimated using the human ICC cell lines, RBE and SSP25. CXCR2 small interfering RNA (siRNA) and an antagonist (SB225002) were used to block CXCR2. Proliferation assays, migration assays, and invasion assays were performed to confirm the suppressive effect of blocking CXCR2. Subcutaneous SSP25 tumors were established in athymic nude mice, and the mice were given SB225002. The expression of CXCR2 in ICC was determined by immunohistochemical staining of 34 ICC specimens. We investigated the relationship between CXCR2 expression and prognosis in ICC. RESULTS The prognosis of patients who had higher CXCR2 expression in ICC was significantly poor (P = .004). CXCR2 siRNA treatment significantly suppressed CXCR2 expression in both RBE and SSP25. Cell proliferation, migration, and invasion were significantly suppressed by both CXCR2 siRNA and SB225002 compared with the control group. SB225002 also suppressed the growth of transplanted subcutaneous tumors (P = .02) CONCLUSION: Our results demonstrated that blocking CXCR2 clearly suppressed the development of ICC. Blocking CXCR2 may be a promising therapeutic approach for ICC.
Collapse
Affiliation(s)
- Hideaki Sueoka
- Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Tadamichi Hirano
- Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yugo Uda
- Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yuji Iimuro
- Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Junichi Yamanaka
- Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Jiro Fujimoto
- Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
| |
Collapse
|
|
30
|
Chemokines and cytokines as salivary biomarkers for the early diagnosis of oral cancer. Int J Dent 2013; 2013:813756. [PMID: 24376459 PMCID: PMC3860143 DOI: 10.1155/2013/813756] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 10/31/2013] [Indexed: 01/19/2023] Open
Abstract
Chemokines have been shown to be important in both inflammation and carcinogenesis and are able to be measured in saliva with relatively robust methods including enzyme-linked immunosorbent assays (ELISA). Thus it has been hypothesized that patients with oral cancer and oral potentially malignant lesions will have elevated levels of specific chemokines in oral fluids and that this may be used as a marker of both the early detection of malignant disease and progression to malignancy. The concept that salivary biomarkers can be easily measured and indicate disease states has profound consequences for clinical practice and may open up new strategies for the diagnosis, prognosis, and potential therapy of oral squamous cell carcinoma (OSCC). This review focuses on our understanding of cytokines and chemokines and the potential role that they may have in clinical practice.
Collapse
|
|
31
|
Study on characteristics of chemokine CXCL10 gene cloned from cDNA expression library of Ujumqin sheep. BIOMED RESEARCH INTERNATIONAL 2013; 2013:217942. [PMID: 24187661 PMCID: PMC3804364 DOI: 10.1155/2013/217942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 08/26/2013] [Indexed: 01/20/2023]
Abstract
Chemokines were a major regulator of body's inflammatory and immune responses. In this study, the cDNA fragment of chemokine CXC ligand 10 (CXCL10) was cloned from the Ujumqin sheep ear marginal tissue cDNA expression library; the CXCL10 gene had 103 amino acids and a molecular weight of 11.47 kDa, and it shared a high homology among cattle, sheep, and goat, while a low homology compared with mouse. The CXCL10 protein had 4 conservative cysteine residues, located in 28, 30, 55, and 72 sites. The expression pattern and intracellular distribution of recombinant CXCL10 proteins in Ujumqin sheep fibroblast cells showed that there were green fluorescence signals both in cytoplasm and nucleolus after 24 h of transfection, the number of positive cells was increased with time, the peak level of fluorescence signal was reached after 48 h of transfection and the transfection efficiency was 33.3%; there was a significant decrease in fluorescence intensity after 72 h of transfection. Expression of recombinant CXCL10 gene in Escherichia coli had a time- and temperature-dependency on the amount of protein expression, and a small quantity of inducer was needed.
Collapse
|
|
32
|
Discovery and computer aided potency optimization of a novel class of small molecule CXCR4 antagonists. PLoS One 2013; 8:e78744. [PMID: 24205302 PMCID: PMC3800133 DOI: 10.1371/journal.pone.0078744] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 09/22/2013] [Indexed: 01/07/2023] Open
Abstract
Amongst the chemokine signalling axes involved in cancer, chemokine CXCL12 acting on chemokine receptor CXCR4 is particularly significant since it orchestrates migration of cancer cells in a tissue-specific metastatic process. High CXCR4 tumour expression is associated with poor prognosis of lung, brain, CNS, blood and breast cancers. We have identified a new class of small molecule CXCR4 antagonists based on the use of computational modelling studies in concert with experimental determination of in vitro activity against CXCL12-induced intracellular calcium mobilisation, proliferation and chemotaxis. Molecular modelling proved to be a useful tool in rationalising our observed potencies, as well as informing the direction of the synthetic efforts aimed at producing more potent compounds.
Collapse
|
|
33
|
Zambra FMB, Biolchi V, Brum IS, Chies JAB. CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer. Hum Immunol 2013; 74:1003-8. [DOI: 10.1016/j.humimm.2013.04.031] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 03/18/2013] [Accepted: 04/10/2013] [Indexed: 01/24/2023]
|
|
34
|
Miyazaki H, Takabe K, Yeudall WA. Chemokines, chemokine receptors and the gastrointestinal system. World J Gastroenterol 2013; 19:2847-2863. [PMID: 23704819 PMCID: PMC3660811 DOI: 10.3748/wjg.v19.i19.2847] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 11/13/2012] [Accepted: 04/27/2013] [Indexed: 02/06/2023] Open
Abstract
The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors, which include epidermal growth factor receptor agonists and members of the transforming growth factor β family. Furthermore, the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches. In this review, we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract.
Collapse
|
|
35
|
Meester I, Solis-Soto JM. Cytokines: monitors of disease severity for the clinic. ACTA ACUST UNITED AC 2013; 3:143-55. [PMID: 23485161 DOI: 10.1517/17530050802708999] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Cytokines communicate between the cells of the immune system and its targets to maintain homeostasis after injury or pathogenic events. They are involved in almost any pathological situation imaginable. OBJECTIVE To verify the importance of cytokines as biomarkers in current preclinical (aetiopathogenic, development of new therapies) and clinical studies (diagnosis, disease severity, prognosis and response to therapy). METHOD/RESULTS A Medline search with the query 'cytokine' AND 'biomarker' AND a variable for a variety of biomedical fields, followed by deeper-level searches, demonstrated the immense popularity of cytokines as biomarkers in almost any biomedical field. CONCLUSION As cytokines are not disease-specific they do not serve as single diagnostic biomarkers. The strength of the cytokines resides in monitoring disease severity, prognosis and response to treatment.
Collapse
Affiliation(s)
- Irene Meester
- Faculty of Medicine Department of Immunology, UANL, Gonzalitos 235, Mitras Centro, Monterrey, NL, Mexico, CP64460
| | | |
Collapse
|
|
36
|
Andalib A, Doulabi H, Maracy MR, Rezaei A, Hasheminia SJ. CCR3, CCR4, CCR5, and CXCR3 expression in peripheral blood CD4+ lymphocytes in gastric cancer patients. Adv Biomed Res 2013; 2:31. [PMID: 23977659 PMCID: PMC3748641 DOI: 10.4103/2277-9175.108770] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2012] [Accepted: 04/14/2012] [Indexed: 01/01/2023] Open
Abstract
Background: CD4+(TH1, and TH2) cell groups in the point of view of chemokine receptor expression were considered in blood of stomach cancer patients. Materials and Methods: The percentage of blood CD4+ T cells expressing chemokine receptors (before and after gastrectomy) was determined by flow cytometry (Becton Dickinson, USA) using the following chemokine receptor antibodies: anti-CCR5, anti-CXCR3, anti-CCR3 and anti-CCR4. Results: The means of CD4+ CCR5+ expressing cells was 1.23% ± 0.90, 0.83% ± 0.34 and 1.34% ± 0.74 in control, pre- and post-operation groups, respectively. CD4+ CXCR3+ expressing cells were 19.09% ± 8.4, 16.95% ± 5.71 and 25.08% ± 9.31, respectively. Similar pattern was seen for CD4+ CCR3+ and CD4+ CCR4+ expressing cells. Pearson correlation analysis shows no relationship between CCR3 and CCR4 expressions on TCD4 cells (r = 0.211, P = 0.126). The complex expression TH1 (CD4+ CXCR3+ CCR5+) receptors determined 1.14% ± 0.54 for control group, 0.86% ± 0.49 for pre-T and 1.57% ± 0.67 for post-T group. Moreover, the TH2 (CD4+ CCR3+ CCR4+) expression was 1.60% ± 1.05 for control group, 1.57% ± 0.83 for pre-T and 1.27% ± 0.66 for post-treatment group. Pearson correlation analysis shows that only the CCR3 and CCR5 expression was statistically correlated (r = 0.321, P = 0.018). Conclusion: Due to low expression of CCR5 in TH1 and CCR3 in TH2 cells, it seems that utility of these is extremely limited for clinical evaluation, but not scientific purpose. Moreover, considering the CXCR3 for TH1 cells and CCR4 expression for TH2 cells, due to considerable expression, may be practical.
Collapse
Affiliation(s)
- Alireza Andalib
- Department of Immunology, Isfahan Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | | | | | | |
Collapse
|
|
37
|
Wang JP, Hu WM, Wang KS, Yu J, Luo BH, Wu C, Chen ZH, Luo GQ, Liu YW, Liu QL, Xiao Y, Zhou HY, Yang XJ, Jiang HY, Li JH, Wen JF. Expression of C-X-C chemokine receptor types 1/2 in patients with gastric carcinoma: Clinicopathological correlations and significance. Oncol Lett 2012; 5:574-582. [PMID: 23420470 PMCID: PMC3573142 DOI: 10.3892/ol.2012.1043] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 11/08/2012] [Indexed: 01/08/2023] Open
Abstract
C-X-C chemokine receptor types 1/2 (CXCR1/2) may play multiple roles in the development and progression of a number of types of tumor. The abnormal expression of CXCR1/2 in various types of malignant tumors has been reported, but less is known with regard to gastric carcinoma. The present study was preliminarily conducted to elucidate the correlation between clinicopathological factors and the immunohistochemical expression of CXCR1/2 in patients with gastric carcinoma. The expression of CXCR1/2 in 69 specimens of sporadic gastric carcinoma and their corresponding non-neoplastic mucosa obtained by gastrectomy was assayed by immunohistochemistry (IHC) using a polyclonal anti-CXCR1/2 antibody. ERK1/2 and AKT phosphorylation and the expression of indicators of proliferation, growth and apoptosis (Bcl-2 and Bax, Cyclin D1, EGFR and Ki-67), angiogenesis (VEGF and CD34), invasion and metastasis (MMP-9, MMP-2, TIMP-2 and E-cadherin) were also detected by IHC. A total of 68 (98.6%) of the 69 patients with gastric carcinoma were found to have positive CXCR1/2 expression, which appeared to be significantly higher in gastric carcinoma compared with corresponding non-neoplastic mucosa tissues. The expression of CXCR1/2 in gastric carcinoma was significantly associated with invasion, metastasis and TNM staging (P<0.001). Correlation analysis between CXCR1/2 and pAKT (P=0.032), pERK (P<0.001), Cyclin D1 (P=0.049), EGFR (P=0.013), Bcl-2 (P=0.003), microvessel density (P=0.001), MMP-9 (P=0.013) and MMP-2 (P=0.027) expression using the Spearman test showed significant correlation in gastric carcinoma. Univariate and multivariate logistic regression analysis showed that, compared with negative or weak expression, overexpression of CXCR1/2 protein was a significant risk factor for TNM stage (P<0.001). These results preliminarily suggest that CXCR1/2 may be a useful maker for progression of the tumors and a promising target for gastric carcinoma therapy.
Collapse
Affiliation(s)
- Jun Pu Wang
- Department of Pathology, School Of Basic Medicine; Central South University, Hunan, Changsha 410013, P.R. China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Association between SDF1-3′A or CXCR4 gene polymorphisms with predisposition to and clinicopathological characteristics of prostate cancer with or without metastases. Mol Biol Rep 2012; 39:11073-9. [DOI: 10.1007/s11033-012-2010-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 10/01/2012] [Indexed: 11/30/2022]
|
|
39
|
Abstract
Chemokines and their receptors have a multifaceted role in tumor biology and are implicated in nearly all aspects of cancer growth, survival and dissemination. Modulation of the interaction between chemokines and their cell surface receptor is, therefore, a promising area for the development of new cancer medicines. In this review, we look at the compelling evidence that is emerging to support targeting CXC chemokines, also known as family α chemokines, as novel therapeutic strategies in the treatment of cancer.
Collapse
|
|
40
|
Inflammatory pathways as promising targets to increase chemotherapy response in bladder cancer. Mediators Inflamm 2012; 2012:528690. [PMID: 22811589 PMCID: PMC3395159 DOI: 10.1155/2012/528690] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Revised: 05/22/2012] [Accepted: 05/22/2012] [Indexed: 12/21/2022] Open
Abstract
While more and more physicians are choosing chemotherapy for patients with bladder cancer, the current treatment is still far from satisfactory due to low response rate and severe side effects. Emerging evidence indicates that inflammatory microenvironment is involved in the pathogenesis of bladder cancer. Recent studies have also provided ample evidence that chemotherapy response is influenced by activation of major inflammatory mediators, including transcription factors, cytokines, chemokines, and COX-2. We reviewed all published literature addressing the roles of inflammatory microenvironment in bladder cancer and evaluating emerging evidence that inflammatory pathways represent potential therapeutic targets to enhance chemotherapy of bladder cancer.
Collapse
|
|
41
|
Wang JP, Hu WM, Wang KS, Luo BH, Wu C, Chen ZH, Luo GQ, Liu YW, Liu QL, Yu J, Li JH, Wen JF. Upregulation of C-X-C chemokine receptor type 1 expression is associated with late-stage gastric adenocarcinoma. Exp Ther Med 2012; 4:55-60. [PMID: 23060922 DOI: 10.3892/etm.2012.568] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 04/30/2012] [Indexed: 12/31/2022] Open
Abstract
Chemokine receptors play multiple roles in the development and progression of various tumor types. The aim of this study was to examine C-X-C chemokine receptor type 1 (CXCR1) protein expression in gastric adenocarcinoma and to investigate the clinical implications of CXCR1 upregulation. Expression of CXCR1 protein in 83 specimens of sporadic gastric adenocarcinoma and their corresponding non-neoplastic mucosa obtained by gastrectomy was assayed using immunohistochemistry. The intensity of immunostaining in tumor tissue was considered strong when tumor tissue staining was more intense than in the corresponding non-neoplastic mucosa; the intensity was null when staining was weaker in the tumor than in the corresponding non-neoplastic mucosa; and the intensity was weak when staining was similar in both tissues. Microvascular density in tumor tissue and its corresponding non-neoplastic mucosa was measured using monoclonal antibody against CD34. A strong correlation was observed between elevated CXCR1 protein expression and tumor stage (P<0.05). T stage, N stage and overall stage positively correlated with CXCR1 protein expression. Microvascular density was higher in tumors with strong CXCR1 protein expression, but the correlation with CXCR1 was not linear (P=0.07). Multiple logistic regression analyses showed that, compared to no or weak expression, overexpression of CXCR1 protein was a significant risk factor for high N stage (N2, N3). These results indicate that CXCR1 may be considered as a new and promising target for gastric adenocarcinoma therapy.
Collapse
Affiliation(s)
- Jun Pu Wang
- Department of Pathology, School of Basic Medicine
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Wang Y, Ma Y, Fang Y, Wu S, Liu L, Fu D, Shen X. Regulatory T cell: a protection for tumour cells. J Cell Mol Med 2012; 16:425-36. [PMID: 21895966 PMCID: PMC3822920 DOI: 10.1111/j.1582-4934.2011.01437.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Accepted: 08/04/2011] [Indexed: 12/21/2022] Open
Abstract
Characterized by immunosuppression regulatory T cells (Tregs) play a key role in maintaining immune tolerance. A growing number of tumours have been found with Tregs accumulating in microenvironment and patients with high density of Tregs in tumour stroma get a worse prognosis, which suggests that Tregs may inhibit anti-tumour immunity in stroma, resulting in a poor prognosis. In this paper, we demonstrate the accumulation of Tregs in tumour stroma and the possible suppressive mechanisms. We also state the immunotherapy that has being used in animal and clinical trials.
Collapse
Affiliation(s)
- Yi Wang
- *Correspondence to: Fu DA, Ph.D., Xizhong SHEN, M.D., The Department of Gastroenterology of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Tel.: +86-21-54230545, +86-21-64041990 Fax: +86-21-54230545, +86-21-64038038 E-mail: ,
| | | | - Ying Fang
- The Department of Gastroenterology of Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Shengdi Wu
- The Department of Gastroenterology of Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Lili Liu
- The Department of Gastroenterology of Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Da Fu
- The Department of Gastroenterology of Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Xizhong Shen
- The Department of Gastroenterology of Zhongshan Hospital, Fudan UniversityShanghai, China
| |
Collapse
|
|
43
|
Knight JC, Hallett AJ, Brancale A, Paisey SJ, Clarkson RWE, Edwards PG. Evaluation of a fluorescent derivative of AMD3100 and its interaction with the CXCR4 chemokine receptor. Chembiochem 2011; 12:2692-8. [PMID: 21998043 DOI: 10.1002/cbic.201100441] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Indexed: 11/06/2022]
Abstract
AMD3100 is a potent and selective antagonist of the CXCR4 receptor; it has been shown to block the route of entry of HIV into host T-cells. This compound and its analogues have since been found to act as haematopoietic stem cell mobilisation agents and, more recently, as anti-cancer agents. Here, we have examined a fluorescent derivative of AMD3100, L(1), which offered the potential to assess the behaviour of AMD3100 at the cell surface by using optical imaging modalities. The binuclear Zn(II) , Cu(II) and Ni(II) complexes of L(1) have also been investigated as these metals have been previously shown to enhance the binding properties of AMD3100. Furthermore, Zn(II) and Cu(II) are known to enhance and quench, respectively, the fluorescence of similar anthracenyl-based ligands. Whilst L(1) demonstrates an ability to inhibit the binding of the anti-CXCR4 monoclonal antibody 12G5 (IC(50) =0.25-0.9 μM), the incorporation of an anthracenyl moiety resulted in a significantly reduced affinity for CXCR4 compared to AMD3100 (IC(50) =10 nM). We observed no significant increase in fluorescence intensity following incubation with murine pre-B cells overexpressing CXCR4 compared to a control cell line. This limits the usefulness of L(1) as a fluorescent imaging probe. Interestingly, the Zn(II) complex, which carries an overall +4 charge, revealed marginally higher specificity and reduced toxicity in vitro compared to the free ligand, albeit with reduced affinity for CXCR4 (IC(50) =1.8-5 μM). We suggest that the incorporation of an anthracenyl group contributes to the lipophilic character of the free ligand, thereby resulting in transport across the plasma membrane. This effect is seemingly diminished when the ligand is complexed to charged metal ions.
Collapse
Affiliation(s)
- James C Knight
- Department of Oncology, University of Alberta, Edmonton T6G 1Z2, Canada
| | | | | | | | | | | |
Collapse
|
|
44
|
Oh SM, Oh K, Lee DS. Intratumoral administration of secondary lymphoid chemokine and unmethylated cytosine-phosphorothioate-guanine oligodeoxynucleotide synergistically inhibits tumor growth in vivo. J Korean Med Sci 2011; 26:1270-6. [PMID: 22022177 PMCID: PMC3192336 DOI: 10.3346/jkms.2011.26.10.1270] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Accepted: 08/29/2011] [Indexed: 11/20/2022] Open
Abstract
Secondary lymphoid tissue chemokine (SLC), which is expressed in T cell zones of secondary lymphoid organs, including the spleen and lymph nodes, strongly recruits both T lymphocytes and mature dendritic cells. As appropriate interaction of tumor-specific T cells and mature dendritic cells, equipped with tumor antigens, is a prerequisite for effective T cell immunity against established tumors, we mobilized lymphocytes and dendritic cells to tumor sites by intratumoral injection of secondary lymphoid tissue chemokine-Fc (SLC-Fc) fusion protein using the B16F10 murine melanoma model. Activation of dendritic cells, another prerequisite for the effective activation of naïve tumor-specific T cells, was achieved by the addition of immunostimulatory cytosine-phosphorothioate-guanine oligodeoxynucleotide (CpG-ODN) into the tumor site. Intratumoral administration of SLC-Fc or CpG-ODN revealed antitumor effects against B16F10 murine melanoma grown in the subcutaneous space. Co-treatment of SLC-Fc and CpG-ODN displayed synergistic effects in reducing the tumor size. The synergistic antitumor effect in co-treatment group was correlated with the synergistic/additive increase in the infiltration of CD4(+) T cells and CD11c(+) dendritic cells in the tumor mass compared to the single treatment groups. These results suggest that the combined use of chemokines and adjuvant molecules may be a possible strategy in clinical tumor immunotherapy.
Collapse
Affiliation(s)
- So Mi Oh
- Laboratory of Immunology, Transplantation Research Institute, Seoul, Korea
| | - Keunhee Oh
- Laboratory of Immunology, Transplantation Research Institute, Seoul, Korea
- Interdisciplinary Program of Tumor Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Dong-Sup Lee
- Laboratory of Immunology, Transplantation Research Institute, Seoul, Korea
- Interdisciplinary Program of Tumor Biology, Seoul National University College of Medicine, Seoul, Korea
| |
Collapse
|
|
45
|
Abedini F, Ismail M, Hosseinkhani H, Ibrahim TAT, Omar AR, Chong PP, Bejo MH, Domb AJ. Effects of CXCR4 siRNA/dextran-spermine nanoparticles on CXCR4 expression and serum LDH levels in a mouse model of colorectal cancer metastasis to the liver. Cancer Manag Res 2011; 3:301-9. [PMID: 21931504 PMCID: PMC3173020 DOI: 10.2147/cmr.s11678] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Liver metastasis is the main cause of mortality related to colorectal cancer. CXCR4 is necessary for the outgrowth of colon cancer micrometastases. In oncology, it has been demonstrated that several human tumors release lactate dehydrogenase (LDH) into the circulation. CXCR4 gene expression and serum LDH levels are often increased in patients with colorectal cancer. Despite technological advances in cancer therapy, five-year overall survival is still around 50%. Therefore, better treatment needs to be developed. RNA interference (RNAi) is a modern and powerful tool for inhibition of gene expression. However, the rate-limiting step in this technology is effective delivery of RNAi agents. We have investigated a novel strategy of CXCR4 siRNA therapy and its effect on serum LDH levels in a BALB/C mouse model of colorectal cancer metastasis to the liver. Hepatic metastasis was established by injecting a CT26.WT mouse colon carcinoma cell line via the tail vein. Our results demonstrated that CXCR4 siRNA/ dextran-spermine nanoparticles achieved high silencing efficiency with low toxicity. Favorable localization of the nanoparticles was confirmed with CXCR4 gene expression in the liver, that was correlated with serum LDH levels. More research will be needed to determine the effect of CXCR4 silencing on serum LDH levels, which may be a useful marker for predicting liver metastasis in colorectal cancer.
Collapse
Affiliation(s)
- Fatemeh Abedini
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Selangor Darul Ehsan, Malaysia
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Capietto AH, Martinet L, Fournié JJ. How tumors might withstand γδ T-cell attack. Cell Mol Life Sci 2011; 68:2433-42. [PMID: 21547501 PMCID: PMC11115001 DOI: 10.1007/s00018-011-0705-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Revised: 04/19/2011] [Accepted: 04/20/2011] [Indexed: 01/13/2023]
Abstract
Several clinical trials are currently assessing the therapeutic activity of human TCRVγ9Vδ2(+) lymphocytes in cancer. Growing tumors usually follow a triphasic "Elimination, Equilibrium, Escape" evolution in patients. Thus, at diagnostic, most tumors have already developed some means to escape to immune protection. We review here the conventional immunoescape mechanisms which might also protect against cytolytic TCRVγ9Vδ2(+) lymphocytes activated by phosphoantigens. Neutralization of these deleterious processes might prove highly valuable to improve the efficacy of ongoing γδ cell-based cancer immunotherapies.
Collapse
Affiliation(s)
- Aude-Hélène Capietto
- INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France
- CNRS ERL5294, BP3028, CHU Purpan, 31300 Toulouse, France
- Université Toulouse III Paul-Sabatier, 31300 Toulouse, France
- Present Address: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Ludovic Martinet
- Université Toulouse III Paul-Sabatier, 31300 Toulouse, France
- Institut De Pharmacologie et de Biologie Structurale, Unité Mixte de Recherches (UMR) 5089, 31077 Toulouse, France
| | - Jean-Jacques Fournié
- INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France
- CNRS ERL5294, BP3028, CHU Purpan, 31300 Toulouse, France
- Université Toulouse III Paul-Sabatier, 31300 Toulouse, France
| |
Collapse
|
|
47
|
Abstract
Hundreds of G protein coupled receptor (GPCR) isotypes integrate and coordinate the function of individual cells mediating signaling between different organs in our bodies. As an aberration of the normal relationships that organize cells' coexistence, cancer has to deceive cell-cell communication in order to grow and spread. GPCRs play a critical role in this process. Despite the fact that GPCRs represent one of the most common drug targets, current medical practice includes only a few anticancer compounds directly acting on their signaling. Many approaches can be envisaged to target GPCRs involved in oncology. Beyond interfering with GPCRs signaling by using agonists or antagonists to prevent cell proliferation, favor apoptosis, induce maturation, prevent migration, etc., the high specificity of the interaction between the receptors and their ligands can be exploited to deliver toxins, antineoplastic drugs or isotopes to transformed cells. In this review we describe the strategies that are in use, or appear promising, to act directly on GPCRs in the fight against neoplastic transformation and tumor progression.
Collapse
|
|
48
|
Abstract
Chemokines (ie, chemoattractant cytokines) are a family of small secreted molecules that mediate leukocyte migration. It is becoming increasingly more evident that chemokines play an integral role in the initiation of a specific immune response. With respect to cancer, chemokines are being studied for both their role in tumor biology and as promising immunotherapy candidates. We review several areas of chemokine importance in tumor immunity and discuss the experimental evidence that is leading to the clinical use of this cytokine family in new treatment approaches for patients with cancer.
Collapse
|
|
49
|
Allavena P, Germano G, Marchesi F, Mantovani A. Chemokines in cancer related inflammation. Exp Cell Res 2010; 317:664-73. [PMID: 21134366 DOI: 10.1016/j.yexcr.2010.11.013] [Citation(s) in RCA: 154] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Revised: 11/29/2010] [Accepted: 11/29/2010] [Indexed: 12/11/2022]
Abstract
Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis. Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies.
Collapse
Affiliation(s)
- Paola Allavena
- Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | | | | | | |
Collapse
|
|
50
|
Varney ML, Singh S, Li A, Mayer-Ezell R, Bond R, Singh RK. Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases. Cancer Lett 2010; 300:180-8. [PMID: 21035946 DOI: 10.1016/j.canlet.2010.10.004] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2009] [Revised: 09/28/2010] [Accepted: 10/04/2010] [Indexed: 12/12/2022]
Abstract
CXCR1 and CXCR2 are G-protein coupled receptors, that have been shown to play important role in tumor growth and metastasis, and are prime targets for the development of novel therapeutics. Here, we report that targeting CXCR2 and CXCR1 activity using orally active small molecule antagonist (SCH-527123, SCH-479833) inhibits human colon cancer liver metastasis mediated by decreased neovascularization and enhanced malignant cell apoptosis. There were no differences in primary tumor growth. These studies demonstrate the important role of CXCR2/1 in colon cancer metastasis and that inhibition of CXCR2 and CXCR1, small molecule antagonists provides a novel therapeutic strategy.
Collapse
Affiliation(s)
- Michelle L Varney
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, USA
| | | | | | | | | | | |
Collapse
|