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Sampaio-Ribeiro G, Ruivo A, Silva A, Santos AL, Oliveira RC, Gama J, Cipriano MA, Tralhão JG, Paiva A. Innate Immune Cells in the Tumor Microenvironment of Liver Metastasis from Colorectal Cancer: Contribution to a Comprehensive Therapy. Cancers (Basel) 2023; 15:3222. [PMID: 37370832 DOI: 10.3390/cancers15123222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/07/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent type of cancer, and liver metastasis is the most common site of metastatic development. In the tumor microenvironment (TME), various innate immune cells are known to influence cancer progression and metastasis occurrence. CD274 (PD-L1) and CD206 (MRC1) are proteins that have been associated with poor prognosis and disease progression. We conducted a study on tumoral and non-tumoral biopsies from 47 patients with CRC liver metastasis, using flow cytometry to phenotypically characterize innate immune cells. Our findings showed an increase in the expression of CD274 on classical, intermediate, and non-classical monocytes when comparing tumor with non-tumor samples. Furthermore, tumor samples with a desmoplastic growth pattern exhibited a significantly decreased percentage of CD274- and CD206-positive cells in all monocyte populations compared to non-desmoplastic samples. We found a correlation between a lower expression of CD206 or CD274 on classical, intermediate, and non-classical monocytes and increased disease-free survival, which points to a better prognosis for these patients. In conclusion, our study has identified potential new targets and biomarkers that could be incorporated into a personalized medicine approach to enhance the outcome for colorectal cancer patients.
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Affiliation(s)
- Gabriela Sampaio-Ribeiro
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ana Ruivo
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ana Silva
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
| | - Ana Lúcia Santos
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
| | - Rui Caetano Oliveira
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Germano de Sousa-Centro de Diagnóstico Histopatológico CEDAP, 3000-377 Coimbra, Portugal
- Centre of Investigation on Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical and Academic Center of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - João Gama
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
| | - Maria Augusta Cipriano
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
| | - José Guilherme Tralhão
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Centre of Investigation on Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical and Academic Center of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - Artur Paiva
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Ciências Biomédicas Laboratoriais, ESTESC-Coimbra Health School, Instituto Politécnico de Coimbra, 3046-854 Coimbra, Portugal
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Gómez-Melero S, Caballero-Villarraso J. CCR6 as a Potential Target for Therapeutic Antibodies for the Treatment of Inflammatory Diseases. Antibodies (Basel) 2023; 12:30. [PMID: 37092451 PMCID: PMC10123731 DOI: 10.3390/antib12020030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023] Open
Abstract
The CC chemokine receptor 6 (CCR6) is a G protein-coupled receptor (GPCR) involved in a wide range of biological processes. When CCR6 binds to its sole ligand CCL20, a signaling network is produced. This pathway is implicated in mechanisms related to many diseases, such as cancer, psoriasis, multiple sclerosis, HIV infection or rheumatoid arthritis. The CCR6/CCL20 axis plays a fundamental role in immune homeostasis and activation. Th17 cells express the CCR6 receptor and inflammatory cytokines, including IL-17, IL-21 and IL-22, which are involved in the spread of inflammatory response. The CCL20/CCR6 mechanism plays a crucial role in the recruitment of these pro-inflammatory cells to local tissues. To date, there are no drugs against CCR6 approved, and the development of small molecules against CCR6 is complicated due to the difficulty in screenings. This review highlights the potential as a therapeutic target of the CCR6 receptor in numerous diseases and the importance of the development of antibodies against CCR6 that could be a promising alternative to small molecules in the treatment of CCR6/CCL20 axis-related pathologies.
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Affiliation(s)
- Sara Gómez-Melero
- Maimonides Biomedical Research Institute of Cordoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - Javier Caballero-Villarraso
- Maimonides Biomedical Research Institute of Cordoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Medicine and Nursing, University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
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Jia SN, Han YB, Yang R, Yang ZC. Chemokines in colon cancer progression. Semin Cancer Biol 2022; 86:400-407. [PMID: 35183412 DOI: 10.1016/j.semcancer.2022.02.007] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 01/27/2023]
Abstract
Colon cancer is a major human cancer accounting for about a tenth of all cancer cases thus making it among the top three cancers in terms of incidence as well as mortality. Metastasis to distant organs, particularly to liver, is the primary reason for associated mortality. Chemokines, the chemo-attractants for various immune cells, have increasingly been reported to be involved in cancer initiation and progression, including in colon cancer. Here we discuss the available knowledge on the role of several chemokines, such as, CCL2, CCL3, CCL5, CXCL1, CXCL2, CXCL8 in colon cancer progression. CCL20 is one chemokine with emerging evidence for its role in influencing colon cancer tumor microenvironment through the documents effects on fibroblasts, macrophages and immune cells. We focus on CCL20 and its receptor CCR6 as promising factors that affect multiple levels of colon cancer progression. They interact with several cytokines and TLR receptors leading to increased aggressiveness, as supported by multitude of evidence from in vitro, in vivo studies as well as human patient samples. CCL20-CCR6 bring about their biological effects through regulation of several signaling pathways, including, ERK and NF-κB pathways, in addition to the epithelial-mesenchymal transition. Signaling involving CCL20-CCR6 has profound effect on colon cancer hepatic metastasis. Combined with elevated CCL20 levels in colon tumors and metastatic patients, the above information points to a need for further evaluation of chemokines as diagnostic and/or prognostic biomarkers.
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Affiliation(s)
- Sheng-Nan Jia
- Department of HepatoPancreatoBiliary Medicine, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Ying-Bo Han
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Rui Yang
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Ze-Cheng Yang
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, 130000, China.
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Yu L, Zhang MM, Hou JG. Molecular and cellular pathways in colorectal cancer: apoptosis, autophagy and inflammation as key players. Scand J Gastroenterol 2022; 57:1279-1290. [PMID: 35732586 DOI: 10.1080/00365521.2022.2088247] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal carcinogenesis (CRC) is one of the most aggressive forms of cancer, particularly in developing countries. It accounts for the second and third-highest reason for cancer-induced lethality in women and men respectively. CRC involves genetic and epigenetic modifications in colonic epithelium, leading to colon adenocarcinoma. The current review highlights the pathogenic mechanisms and multifactorial etiology of CRC, influenced by apoptosis, inflammation, and autophagy pathways. METHODS We have carried out a selective literature review on mechanisms contributing to the pathogenesis of CRC. RESULTS Resistance to senescence and apoptosis of the mesenchymal cells, which play a key role in intestinal organogenesis, morphogenesis and homeostasis, appears important for sporadic CRC. Additionally, inflammation-associated tumorigenesis is a key incident in CRC, supported by immune disruptors, adaptive and innate immune traits, environmental factors, etc. involving oxidative stress, DNA damage and epigenetic modulations. The self-digesting mechanism, autophagy, also plays a twin role in CRC through the participation of LC3/LC3-II, Beclin-1, ATG5, other autophagy proteins, and Inflammatory Bowel Disease (IBD) susceptibility genes. It facilitates the promotion of effective surveillance pathways and stimulates the generation of malignant tumor cells. The autophagy and apoptotic pathways undergo synergistic or antagonistic interactions in CRC and bear a critical association with IBD that results from the pro-neoplastic effects of persistent intestinal inflammation. Conversely, pro-inflammatory factors stimulate tumor growth and angiogenesis and inhibit apoptosis, suppressing anti-tumor activities. CONCLUSION Hence, research attempts for the development of potential therapies for CRC are in progress, primarily based on combinatorial approaches targeting apoptosis, inflammation, and autophagy.
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Affiliation(s)
- Lei Yu
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Miao-Miao Zhang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Ji-Guang Hou
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
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Braoudaki M, Ahmad MS, Mustafov D, Seriah S, Siddiqui MN, Siddiqui SS. Chemokines and chemokine receptors in colorectal cancer; multifarious roles and clinical impact. Semin Cancer Biol 2022; 86:436-449. [PMID: 35700938 DOI: 10.1016/j.semcancer.2022.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022]
Abstract
Colorectal cancer (CRC) is considered the second cause of cancer death worldwide. The early diagnosis plays a key role in patient prognosis and subsequently overall survival. Similar to several types of cancer, colorectal cancer is also characterised by drug resistance and heterogeneity that contribute to its complexity -especially at advanced stages. However, despite the extensive research related to the identification of biomarkers associated to early diagnosis, accurate prognosis and the management of CRC patients, little progress has been made thus far. Therefore, the mortality rates, especially at advanced stages, remain high. A large family of chemoattractant cytokines called chemokines are known for their significant role in inflammation and immunity. Chemokines released by the different tumorous cells play a key role in increasing the complexity of the tumour's microenvironment. The current review investigates the role of chemokines and chemokine receptors in colorectal cancer and their potential as clinical molecular signatures that could be effectively used as a personalised therapeutic approach. We discussed how chemokine and chemokine receptors regulate the microenvironment and lead to heterogeneity in CRC. An important aspect of chemokines is their role in drug resistance which has been extensively discussed. This review also provides an overview of the current advances in the search for chemokines and chemokine receptors in CRC.
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Affiliation(s)
- Maria Braoudaki
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Mohammed Saqif Ahmad
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Denis Mustafov
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Sara Seriah
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Mohammad Naseem Siddiqui
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Shoib Sarwar Siddiqui
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK.
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de la Pinta C, Castillo ME, Collado M, Galindo-Pumariño C, Peña C. Radiogenomics: Hunting Down Liver Metastasis in Colorectal Cancer Patients. Cancers (Basel) 2021; 13:5547. [PMID: 34771709 PMCID: PMC8582778 DOI: 10.3390/cancers13215547] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 02/07/2023] Open
Abstract
Radiomics is a developing new discipline that analyzes conventional medical images to extract quantifiable data that can be mined for new biomarkers that show the biology of pathological processes at microscopic levels. These data can be converted into image-based signatures to improve diagnostic, prognostic and predictive accuracy in cancer patients. The combination of radiomics and molecular data, called radiogenomics, has clear implications for cancer patients' management. Though some studies have focused on radiogenomics signatures in hepatocellular carcinoma patients, only a few have examined colorectal cancer metastatic lesions in the liver. Moreover, the need to differentiate between liver lesions is fundamental for accurate diagnosis and treatment. In this review, we summarize the knowledge gained from radiomics and radiogenomics studies in hepatic metastatic colorectal cancer patients and their use in early diagnosis, response assessment and treatment decisions. We also investigate their value as possible prognostic biomarkers. In addition, the great potential of image mining to provide a comprehensive view of liver niche formation is examined thoroughly. Finally, new challenges and current limitations for the early detection of the liver premetastatic niche, based on radiomics and radiogenomics, are also discussed.
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Affiliation(s)
- Carolina de la Pinta
- Radiation Oncology Department, Ramón y Cajal University Hospital, IRYCIS, Alcalá University, 28034 Madrid, Spain
| | - María E. Castillo
- Medical Oncology Department, Ramón y Cajal University Hospital, IRYCIS, Alcalá University, 28034 Madrid, Spain; (M.E.C.); (M.C.); (C.G.-P.)
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain
| | - Manuel Collado
- Medical Oncology Department, Ramón y Cajal University Hospital, IRYCIS, Alcalá University, 28034 Madrid, Spain; (M.E.C.); (M.C.); (C.G.-P.)
| | - Cristina Galindo-Pumariño
- Medical Oncology Department, Ramón y Cajal University Hospital, IRYCIS, Alcalá University, 28034 Madrid, Spain; (M.E.C.); (M.C.); (C.G.-P.)
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain
| | - Cristina Peña
- Medical Oncology Department, Ramón y Cajal University Hospital, IRYCIS, Alcalá University, 28034 Madrid, Spain; (M.E.C.); (M.C.); (C.G.-P.)
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain
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Tumor Microenvironment in Metastatic Colorectal Cancer: The Arbitrator in Patients' Outcome. Cancers (Basel) 2021; 13:cancers13051130. [PMID: 33800796 PMCID: PMC7961499 DOI: 10.3390/cancers13051130] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Colorectal cancer accounts for approximately 10% of all annually diagnosed cancers worldwide being liver metastasis, the most common cause of death in patients with colorectal cancer. The interplay between tumor and stromal cells in the primary tumor microenvironment and at distant metastases are rising in importance as potential mechanisms of the tumor progression. In this review we discuss the new biomarkers derived from tumor microenvironment and liquid biopsy as emerging prognostic and treatments response markers for metastatic colorectal cancer. We also review the developing new clinical strategies based on tumor microenvironmental cells to tackle metastatic disease in metastatic colorectal cancer patients. Abstract Colorectal cancer (CRC) is one of the most common cancers in western countries. Its mortality rate varies greatly, depending on the stage of the disease. The main cause of CRC mortality is metastasis, which most commonly affects the liver. The role of tumor microenvironment in tumor initiation, progression and metastasis development has been widely studied. In this review we summarize the role of the tumor microenvironment in the liver pre-metastatic niche formation, paying attention to the distant cellular crosstalk mediated by exosomes. Moreover, and based on the prognostic and predictive capacity of alterations in the stromal compartment of tumors, we describe the role of tumor microenvironment cells and related liquid biopsy biomarkers in the delivery of precise medication for metastatic CRC. Finally, we evaluate the different clinical strategies to prevent and treat liver metastatic disease, based on the targeting of the tumor microenvironment. Specifically, targeting angiogenesis pathways and regulating immune response are two important research pipelines that are being widely developed and promise great benefits.
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Pączek S, Łukaszewicz-Zając M, Mroczko B. Chemokines-What Is Their Role in Colorectal Cancer? Cancer Control 2020; 27:1073274820903384. [PMID: 32103675 PMCID: PMC7066593 DOI: 10.1177/1073274820903384] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death. It
is the second most frequently diagnosed malignancy in Europe and third
worldwide. Colorectal malignancies diagnosed at an early stage offer a promising
survival rate. However, advanced tumors often present distant metastases even
after the complete resection of a primary tumor. Therefore, novel biomarkers of
CRC are sorely needed in the diagnosis and prognosis of this common malignancy.
A family of chemokines are composed of small, secreted proteins. They are best
known for their ability to stimulate the migration of several cell types. Some
investigations have indicated that chemokines are involved in cancer
development, including CRC. This article presents current knowledge regarding
chemokines and their specific receptors in CRC progression. Moreover, the prime
aim of this review is to summarize the potential role of these proteins as
biomarkers in the diagnosis and prognosis of CRC.
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Affiliation(s)
- Sara Pączek
- Department of Biochemical Diagnostics, Medical University of Bialystok, Poland
| | | | - Barbara Mroczko
- Department of Biochemical Diagnostics, Medical University of Bialystok, Poland.,Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Poland
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Korbecki J, Grochans S, Gutowska I, Barczak K, Baranowska-Bosiacka I. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. Int J Mol Sci 2020; 21:ijms21207619. [PMID: 33076281 PMCID: PMC7590012 DOI: 10.3390/ijms21207619] [Citation(s) in RCA: 225] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/05/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4+ and CD8+ lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In this review, we discuss human CC motif chemokine ligands: CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 (CC motif chemokine receptor CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands). We present their functioning in human physiology and in neoplasia, including their role in the proliferation, apoptosis resistance, drug resistance, migration, and invasion of cancer cells. We discuss the significance of chemokine receptors in organ-specific metastasis, as well as the influence of each chemokine on the recruitment of various cells to the tumor niche, such as cancer-associated fibroblasts (CAF), Kupffer cells, myeloid-derived suppressor cells (MDSC), osteoclasts, tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and regulatory T cells (Treg). Finally, we show how the effect of the chemokines on vascular endothelial cells and lymphatic endothelial cells leads to angiogenesis and lymphangiogenesis.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; (J.K.); (S.G.)
| | - Szymon Grochans
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; (J.K.); (S.G.)
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University, Powstańców Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; (J.K.); (S.G.)
- Correspondence: ; Tel.: +48-914661515
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Do HTT, Lee CH, Cho J. Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers. Cancers (Basel) 2020; 12:E287. [PMID: 31991604 PMCID: PMC7072521 DOI: 10.3390/cancers12020287] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/14/2020] [Accepted: 01/19/2020] [Indexed: 12/19/2022] Open
Abstract
Chemokines are chemotactic cytokines that mediate immune cell chemotaxis and lymphoid tissue development. Recent advances have indicated that chemokines and their cognate receptors play critical roles in cancer-related inflammation and cancer progression. On the basis of these findings, the chemokine system has become a new potential drug target for cancer immunotherapy. In this review, we summarize the essential roles of the complex network of chemokines and their receptors in cancer progression. Furthermore, we discuss the potential value of the chemokine system as a cancer prognostic marker. The chemokine system regulates the infiltration of immune cells into the tumor microenvironment, which induces both pro- and anti-immunity and promotes or suppresses tumor growth and proliferation, angiogenesis, and metastasis. Increasing evidence indicates the promising prognostic value of the chemokine system in cancer patients. While CCL2, CXCL10, and CX3CL1/CX3CR1 can serve as favorable or unfavorable prognostic factors depending on the cancer types, CCL14 and XCL1 possess good prognostic value. Other chemokines such as CXCL1, CXCL8, and CXCL12 are poor prognostic markers. Despite vast advances in our understanding of the complex nature of the chemokine system in tumor biology, knowledge about the multifaceted roles of the chemokine system in different types of cancers is still limited. Further studies are necessary to decipher distinct roles within the chemokine system in terms of cancer progression and to validate their potential value in cancer prognosis.
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Affiliation(s)
| | | | - Jungsook Cho
- College of Pharmacy, Dongguk University-Seoul, Goyang, Gyeonggi 10326, Korea; (H.T.T.D.); (C.H.L.)
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Borroni EM, Qehajaj D, Farina FM, Yiu D, Bresalier RS, Chiriva-Internati M, Mirandola L, Štifter S, Laghi L, Grizzi F. Fusobacterium nucleatum and the Immune System in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2019. [DOI: 10.1007/s11888-019-00442-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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12
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Jiao X, Shu G, Liu H, Zhang Q, Ma Z, Ren C, Guo H, Shi J, Liu J, Zhang C, Wang Y, Gao Y. The Diagnostic Value of Chemokine/Chemokine Receptor Pairs in Hepatocellular Carcinoma and Colorectal Liver Metastasis. J Histochem Cytochem 2019; 67:299-308. [PMID: 30633620 DOI: 10.1369/0022155418824274] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chemokines and their receptors have been proposed to play important roles in tumor progression and metastasis. To investigate their roles in the progression of primary and metastatic malignant liver tumors and their prognosis, we compared expression profiles of CXCL12/CXCR4, CCL20/CCR6, and CCL21/CCR7 in hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM). Immunohistochemistry was used to analyze the expression levels of the chemokine/chemokine receptor pairs in 29 HCC and 11 CRLM specimens and adjacent non-cancerous tissues, and correlations with clinicopathological variables and overall survival were determined. CCL20/CCR6 expression was higher in HCC than in adjacent non-cancerous tissues. High CCR6 expression in HCC was negatively associated with 5-year survival rate and was an independent prognostic factor for overall survival of HCC patients, whereas differences were not observed between CRLM and adjacent tissues. Furthermore, significantly higher expression of CCL21/CCR7 was found in CRLM than in HCC. In summary, the CCL20/CCR6 axis was elevated in HCC but not in CRLM, whereas the CCL21/CCR7 axis was elevated in CRLM but not in HCC.
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Affiliation(s)
- Xiaolei Jiao
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin Key Laboratory of Artificial Cells, Tianjin Institute for Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin, China
| | - Guiming Shu
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Hui Liu
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin Key Laboratory of Artificial Cells, Tianjin Institute for Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin, China
| | - Qin Zhang
- Department of Pathology, Tianjin Third Central Hospital, Tianjin, China
| | - Zhe Ma
- Department of Pathology, Tianjin Third Central Hospital, Tianjin, China
| | - Chaoyi Ren
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Hongsheng Guo
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Jingxiang Shi
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Junguo Liu
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Chuanshan Zhang
- Department of Pathology, Tianjin Third Central Hospital, Tianjin, China
| | - Yijun Wang
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Yingtang Gao
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin Key Laboratory of Artificial Cells, Tianjin Institute for Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin, China
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Mytar B, Stec M, Szatanek R, Węglarczyk K, Szewczyk K, Szczepanik A, Drabik G, Baran J, Siedlar M, Baj-Krzyworzeka M. Characterization of human gastric adenocarcinoma cell lines established from peritoneal ascites. Oncol Lett 2018; 15:4849-4858. [PMID: 29552124 PMCID: PMC5840753 DOI: 10.3892/ol.2018.7995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 12/28/2017] [Indexed: 01/01/2023] Open
Abstract
The three cell lines, designated as gastric cancer (GC)1401, GC1415 and GC1436 were derived from peritoneal effusions from patients with gastric adenocarcinoma. Cell lines were established in tissue culture and in immunodeficient, non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. All cell lines were cultured in Dulbecco's modified Eagle's medium supplemented with 5% fetal bovine serum. These cell lines were grown as an adherent monolayer with doubling time ranging between 25 h (GC1436 cell line) and 30–34 h (GC1401 and GC1415, respectively). All cells showed morphological features of epithelial-like cells, forming sheets of polygonal cells. Chromosomal analysis showed that the modal numbers ranged from 52 (GC1401), 51–56 (GC1415) and 106 (GC1436). High heterogeneity, resulting from several structural and numerical chromosomal abnormalities were evident in all cell lines. The surface marker expression suggested a tumor origin of the cells, and indicated the intestinal phenotype of a GC (CD10+, MUC1). All three cell lines were tumorigenic but not metastatic, in vivo, in NOD/SCID mice. The lack of metastatic potential was suggested by the lack of aldehyde dehydrogenase 1A1 activity. In conclusion, these newly established GC cell lines widen the feasibility of the functional studies on biology of GC as well as drug testing for potential therapeutic purposes.
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Affiliation(s)
- Bożenna Mytar
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Małgorzata Stec
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Rafał Szatanek
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Kazimierz Węglarczyk
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Katarzyna Szewczyk
- Department of Medical Genetics Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Antoni Szczepanik
- First Department of General Gastrointestinal and Oncology Surgery, Jagiellonian University Medical College, 30-001 Krakow, Poland
| | - Grażyna Drabik
- Department of Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Jarek Baran
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland
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Ignacio RMC, Dong YL, Kabir SM, Choi H, Lee ES, Wilson AJ, Beeghly-Fadiel A, Whalen MM, Son DS. CXCR2 is a negative regulator of p21 in p53-dependent and independent manner via Akt-mediated Mdm2 in ovarian cancer. Oncotarget 2018. [PMID: 29515768 PMCID: PMC5839399 DOI: 10.18632/oncotarget.24231] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Ovarian cancer (OC) has the highest rate of mortality among gynecological malignancy. Chemokine receptor CXCR2 in OC is associated with poor outcomes. However, the mechanisms by which CXCR2 regulates OC proliferation remain poorly understood. We generated CXCR2-positive cells from parental p53 wild-type (WT), mutant and null OC cells, and assessed the roles of CXCR2 on proliferation of OC cells in p53-dependent and independent manner. CXCR2 promoted cell growth rate: p53WT > mutant = null cells. Nutlin-3, a p53 stabilizer, inhibited cell proliferation in p53WT cells, but had little effect in p53-mutant or null cells, indicating p53-dependence of CXCR2-mediated proliferation. CXCR2 decreased p53 protein, a regulator of p21, and downregulated p21 promoter activity only in p53WT cells. The p53 responsive element (RE) of p21 promoter played a critical role in this CXCR2-mediated p21 downregulation. Moreover, CXCR2-positive cells activated more Akt than CXCR2-negative cells followed by enhanced murine double minute (Mdm2). Silencing Mdm2 or Akt1 upregulated p21 expression, whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells. Cell cycle analysis revealed that CXCR2 decreased p21 gene in p53-null cells. Interestingly, romidepsin (histone deacetylase inhibitor)-induced p21 upregulation did not involve the p53 RE in the p21 promoter in p53-null cells. Romidepsin decreased the protein levels of Akt1 and Mdm2, leading to induction of p21 in p53-null cells. CXCR2 reduced romidepsin-induced p21 upregulation by activating Akt-induced Mdm2. Taken together, CXCR2 enhances cell proliferation by suppressing p21 through Akt-Mdm2 signaling in p53-dependent and independent manner.
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Affiliation(s)
- Rosa Mistica C Ignacio
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Yuan-Lin Dong
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Syeda M Kabir
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Hyeongjwa Choi
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Eun-Sook Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, USA
| | - Andrew J Wilson
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.,Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA
| | - Alicia Beeghly-Fadiel
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA.,Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA
| | - Margaret M Whalen
- Department of Chemistry, Tennessee State University, Nashville, TN 37209, USA
| | - Deok-Soo Son
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
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15
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Human antigen R-regulated CCL20 contributes to osteolytic breast cancer bone metastasis. Sci Rep 2017; 7:9610. [PMID: 28851919 PMCID: PMC5575024 DOI: 10.1038/s41598-017-09040-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 07/14/2017] [Indexed: 12/19/2022] Open
Abstract
Breast cancer mainly spreads to bone, causing decreased survival of patient. Human antigen R (HuR) and chemokines are important molecules associated with mRNA stability and cell-cell interaction in cancer biology. Here, HuR knockdown inhibited bone metastasis and osteolysis of metastatic breast cancer cells in mice and HuR expression promoted the metastatic ability of cancer cells via CCL20 and GM-CSF. In contrast with the findings for GM-CSF, ELAVL1 and CCL20 expressions were markedly increased in breast tumor tissues and ELAVL1 expression showed a strong positive correlation with CCL20 expression in breast cancer subtypes, particularly the basal-like subtype. Metastasis-free survival and overall survival were decreased in the breast cancer patients with high CCL20 expression. We further confirmed the role of CCL20 in breast cancer bone metastasis. Intraperitoneal administration of anti-CCL20 antibodies inhibited osteolytic breast cancer bone metastasis in mice. Treatment with CCL20 noticeably promoted cell invasion and the secretion of MMP-2/9 in the basal-like triple-negative breast cancer cell lines, not the luminal. Moreover, CCL20 elevated the receptor activator of nuclear factors kappa-B ligand/osteoprotegerin ratio in breast cancer and osteoblastic cells and mediated the crosstalk between these cells. Collectively, HuR-regulated CCL20 may be an attractive therapeutic target for breast cancer bone metastasis.
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16
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Ye X, Wang R, Bhattacharya R, Boulbes DR, Fan F, Xia L, Adoni H, Ajami NJ, Wong MC, Smith DP, Petrosino JF, Venable S, Qiao W, Baladandayuthapani V, Maru D, Ellis LM. Fusobacterium Nucleatum Subspecies Animalis Influences Proinflammatory Cytokine Expression and Monocyte Activation in Human Colorectal Tumors. Cancer Prev Res (Phila) 2017; 10:398-409. [PMID: 28483840 DOI: 10.1158/1940-6207.capr-16-0178] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 12/02/2016] [Accepted: 05/03/2017] [Indexed: 12/16/2022]
Abstract
Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical colorectal cancer specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical colorectal cancer specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human colorectal cancers. We also assessed inflammatory cytokines in colorectal cancer specimens using immunoassays and found that expression of the cytokines IL17A and TNFα was markedly increased but IL21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 protein expression in colorectal cancer cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote colorectal cancer development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for colorectal cancer prevention and treatment. Cancer Prev Res; 10(7); 398-409. ©2017 AACR.
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Affiliation(s)
- Xiangcang Ye
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Rui Wang
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rajat Bhattacharya
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Delphine R Boulbes
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fan Fan
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ling Xia
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Harish Adoni
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nadim J Ajami
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Matthew C Wong
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Daniel P Smith
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Joseph F Petrosino
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Susan Venable
- Texas Children's Microbiome Center, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
| | - Wei Qiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Dipen Maru
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lee M Ellis
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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17
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Li X, Nie J, Mei Q, Han WD. MicroRNAs: Novel immunotherapeutic targets in colorectal carcinoma. World J Gastroenterol 2016; 22:5317-5331. [PMID: 27340348 PMCID: PMC4910653 DOI: 10.3748/wjg.v22.i23.5317] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 04/23/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal carcinoma (CRC) is one of the most common types of cancer worldwide and the prognosis for CRC patients with recurrence or metastasis is extremely poor. Although chemotherapy and radiation therapy can improve survival, there are still numerous efforts to be performed. Immunotherapy is frequently used, either alone or in combination with other therapies, for the treatment of CRC and is a safe and feasible way to improve CRC treatment. Furthermore, the significance of the immune system in the biology of CRC has been demonstrated by retrospective assessments of immune infiltrates in resected CRC tumors. MicroRNAs (miRNAs) are short, non-coding RNAs that can regulate multiple target genes at the post-transcriptional level and play critical roles in cell proliferation, differentiation and apoptosis. MiRNAs are required for normal immune system development and function. Nevertheless, aberrant expression of miRNAs is often observed in various tumor types and leads to immune disorders or immune evasion. The immunomodulatory function of miRNAs indicates that miRNAs may ultimately be part of the portfolio of anti-cancer targets. Herein, we will review the potential roles of miRNAs in the regulation of the immune response in CRC and then move on to discuss how to utilize different miRNA targets to treat CRC. We also provide an overview of the major limitations and challenges of using miRNAs as immunotherapeutic targets.
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18
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Wagner M, Vicinus B, Muthra ST, Richards TA, Linder R, Frick VO, Groh A, Rubie C, Weichert F. Text mining, a race against time? An attempt to quantify possible variations in text corpora of medical publications throughout the years. Comput Biol Med 2016; 73:173-85. [PMID: 27208610 DOI: 10.1016/j.compbiomed.2016.03.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 03/19/2016] [Accepted: 03/21/2016] [Indexed: 11/29/2022]
Abstract
BACKGROUND The continuous growth of medical sciences literature indicates the need for automated text analysis. Scientific writing which is neither unitary, transcending social situation nor defined by a timeless idea is subject to constant change as it develops in response to evolving knowledge, aims at different goals, and embodies different assumptions about nature and communication. The objective of this study was to evaluate whether publication dates should be considered when performing text mining. METHODS A search of PUBMED for combined references to chemokine identifiers and particular cancer related terms was conducted to detect changes over the past 36 years. Text analyses were performed using freeware available from the World Wide Web. TOEFL Scores of territories hosting institutional affiliations as well as various readability indices were investigated. Further assessment was conducted using Principal Component Analysis. Laboratory examination was performed to evaluate the quality of attempts to extract content from the examined linguistic features. RESULTS The PUBMED search yielded a total of 14,420 abstracts (3,190,219 words). The range of findings in laboratory experimentation were coherent with the variability of the results described in the analyzed body of literature. Increased concurrence of chemokine identifiers together with cancer related terms was found at the abstract and sentence level, whereas complexity of sentences remained fairly stable. CONCLUSIONS The findings of the present study indicate that concurrent references to chemokines and cancer increased over time whereas text complexity remained stable.
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Affiliation(s)
- Mathias Wagner
- Department of Pathology, University of Saarland, Homburg Saar Campus, Homburg Saar, Germany
| | - Benjamin Vicinus
- Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg Saar Campus, Homburg Saar, Germany; Institute of Virology, University of Saarland, Homburg Saar Campus, Homburg Saar, Germany
| | - Sherieda T Muthra
- Lombardi Comprehensive Cancer Center, Georgetown University, 37th & O St NW, Washington, DC 20057, United States of America.
| | - Tereza A Richards
- The Medical Library, University of the West Indies, Mona, Kingston, Jamaica
| | - Roland Linder
- Institute of Medical Informatics, University of Luebeck, Luebeck, Germany
| | - Vilma Oliveira Frick
- Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg Saar Campus, Homburg Saar, Germany
| | - Andreas Groh
- Department of Mathematics, University of Saarland, Saarbrücken Campus, Saarbrücken, Germany
| | - Claudia Rubie
- Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg Saar Campus, Homburg Saar, Germany
| | - Frank Weichert
- Department of Computer Science VII, Technical University of Dortmund, Dortmund, Germany
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19
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Nandi B, Shapiro M, Samur MK, Pai C, Frank NY, Yoon C, Prabhala RH, Munshi NC, Gold JS. Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages. Oncoimmunology 2016; 5:e1189052. [PMID: 27622061 DOI: 10.1080/2162402x.2016.1189052] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 05/05/2016] [Accepted: 05/06/2016] [Indexed: 12/11/2022] Open
Abstract
Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers. Colon cancers adoptively transplanted into CCR6-deficient mice have decreased tumor-associated macrophages without alterations in the number of monocytes in blood or bone marrow. CCL20, the unique ligand for CCR6, promotes migration of monocytes in vitro and promotes accumulation of macrophages in vivo. Depletion of tumor-associated macrophages decreases the growth of tumors in the transplantable tumor model. Macrophages infiltrating the colon cancers in this model secrete the inflammatory mediators CCL2, IL-1α, IL-6 and TNFα. Ccl2, Il1α and Il6 are consequently downregulated in tumors from CCR6-deficient mice. CCL2, IL-1α and IL-6 also promote proliferation of colon cancer cells, linking the decreased macrophage migration into tumors mediated by CCL20-CCR6 interactions to the delay in tumor growth in CCR6-deficient hosts. The relevance of these findings in human colon cancer is demonstrated through correlation of CCR6 expression with that of the macrophage marker CD163 as well as that of CCL2, IL1α and TNFα. Our findings support the exploration of targeting the CCL20-CCR6 pathway for the treatment of colon cancer.
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Affiliation(s)
- Bisweswar Nandi
- Research Service, VA Boston Healthcare System, West Roxbury, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Mia Shapiro
- Research Service, VA Boston Healthcare System, West Roxbury, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Mehmet K Samur
- Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA
| | - Christine Pai
- Research Service, VA Boston Healthcare System , West Roxbury, MA, USA
| | - Natasha Y Frank
- Harvard Medical School, Boston, MA, USA; Medicine Service, VA Boston Healthcare System, West Roxbury, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
| | - Charles Yoon
- Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
| | - Rao H Prabhala
- Research Service, VA Boston Healthcare System, West Roxbury, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nikhil C Munshi
- Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Medicine Service, VA Boston Healthcare System, West Roxbury, MA, USA
| | - Jason S Gold
- Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA; Surgery Service, VA Boston Healthcare System, West Roxbury, MA, USA
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20
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CCR6 expression in colon cancer is associated with advanced disease and supports epithelial-to-mesenchymal transition. Br J Cancer 2016; 114:1343-51. [PMID: 27149649 PMCID: PMC4984452 DOI: 10.1038/bjc.2016.113] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/22/2016] [Accepted: 03/29/2016] [Indexed: 12/11/2022] Open
Abstract
Background: Adjuvant chemotherapy offered to treat colon cancer is based on the TNM staging system, which often fails due to molecular heterogeneity and undefined molecular mechanisms independent of TNM. Therefore, identification of markers to better predict therapeutic option and outcome is needed. In this study we have characterised the clinical association of CCR6 with colon cancer and defined CCR6-mediated molecular pathway. Methods: Immunohistochemistry, RT-qPCR, western blot and FACS were used to determine expression of CCR6 and/or EMT markers in colon tissues/cells. BrdU assay and trans-well system were used to determine cell proliferation, migration and invasion in response to CCL20. Results: CCR6 was higher in cancer cases compared to normal adjacent tissue and expression was associated with nodal status and distant metastasis. Similarly, CCR6 expression was higher in cells derived from node-positive cases and highest expression was in cells derived from metastatic cases. Significant changes in EMT markers, that is, E-cadherin, vimentin, β-catenin, N-cadherin, α-SMA, SNAILl and ZEB1 were observed in response to CCL20 along with decreased proliferation, increased migratory and invasive potential. Conclusions: Results suggest CCR6 as a potential therapeutic target as well as biomarker in addition to nodal status for predicting therapeutic option.
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21
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Stec M, Szatanek R, Baj-Krzyworzeka M, Baran J, Zembala M, Barbasz J, Waligórska A, Dobrucki JW, Mytar B, Szczepanik A, Siedlar M, Drabik G, Urbanowicz B, Zembala M. Interactions of tumour-derived micro(nano)vesicles with human gastric cancer cells. J Transl Med 2015; 13:376. [PMID: 26626416 PMCID: PMC4666152 DOI: 10.1186/s12967-015-0737-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 11/20/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tumour cells release membrane micro(nano)fragments called tumour-derived microvesicles (TMV) that are believed to play an important role in cancer progression. TMV suppress/modify antitumour response of the host, but there is also some evidence for their direct interaction with cancer cells. In cancer patients TMV are present in body fluid and tumour microenvironment. The present study aimed at characterization of whole types/subpopulations, but not only exosomes, of TMV from newly established gastric cancer cell line (called GC1415) and to define their interactions with autologous cells. METHODS TMV were isolated from cell cultures supernatants by centrifugation at 50,000×g and their phenotype was determined by flow cytometry. The size of TMV was analysed by dynamic light scattering and nanoparticle tracking analysis, while morphology by transmission electron microscopy and atomic force microscopy. Interactions of TMV with cancer cells were visualized using fluorescence-activated cell sorter, confocal and atomic force microscopy, biological effects by xenografts in NOD SCID mice. RESULTS Isolated TMV showed expression of CD44H, CD44v6 (hyaluronian receptors), CCR6 (chemokine receptor) and HER-2/neu molecules, exhibited different shapes and sizes (range 60-900 nm, highest frequency of particles with size range of 80-120 nm). TMV attached to autologous cancer cells within 2 h and then were internalized by them at 24 h. CD44H, CD44v6 and CCR6 molecules may play a role in attachment of TMV to cancer cells, while HER-2 associated with CD24 be involved in promoting cancer cells growth. Pre-exposure of cancer cells to TMV resulted in enhancement of tumour growth and cancer cell-induced angiogenesis in NOD SCID mice model. CONCLUSIONS TMV interact directly with cancer cells serving as macro-messengers and molecular cargo transfer between gastric cancer cells resulting in enhancement of tumour growth. TMV should be considered in future as target of anticancer therapy.
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Affiliation(s)
- Małgorzata Stec
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Rafał Szatanek
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Jarosław Baran
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Maria Zembala
- Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Kraków, Poland.
| | - Jakub Barbasz
- Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Kraków, Poland.
| | - Agnieszka Waligórska
- Division of Cell Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| | - Jurek W Dobrucki
- Division of Cell Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| | - Bożenna Mytar
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Antoni Szczepanik
- First Department of General and Gastrointestinal Surgery, Jagiellonian University Medical College, Kraków, Poland.
| | - Maciej Siedlar
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Grażyna Drabik
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Barbara Urbanowicz
- Electron Microscopy Laboratory, University Children's Hospital of Cracow, Kraków, Poland.
| | - Marek Zembala
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
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TNF-α increases the membrane expression of the chemokine receptor CCR6 in thyroid tumor cells, but not in normal thyrocytes: potential role in the metastatic spread of thyroid cancer. Tumour Biol 2015; 37:5569-75. [PMID: 26577851 DOI: 10.1007/s13277-015-4418-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 11/10/2015] [Indexed: 01/07/2023] Open
Abstract
The chemokine receptor CCR6, selectively bound by CCL20, is involved in the metastatic spread of cancer cells. Tumor necrosis factor-α (TNF-α) displays a complex pro-tumorigenic actions, but it is unknown whether this cytokine could modulate the expression of chemokine receptors in thyroid tumors. The membrane expression of CCR6 was assessed by flow cytometry and immunofluorescence, in primary cultures of normal human thyroid (NHT) cells and in thyroid cancer cell lines (TPC-1 and BCPAP), both in basal conditions and after stimulation with TNF-α. In basal conditions, CCR6+ cells were virtually absent in NHT cells (0.4 ± 0.4 %), while they were detected in TPC-1 (23.6 ± 6.6 %) and in BCPAP (12.9 ± 9.4 %) tumor cells (ANOVA F: 10.534; p < 0.005). The incubation with TNF-α significantly increased the percentage of CCR6+ cells in TPC-1 (23.6 ± 6.6 % vs. 33.1 ± 8.7; p < 0.033) and in BCPAP (12.9 ± 9.4 % vs. 18.1 ± 11.5; p < 0.030), but not in NHT (0.4 ± 0.4 % vs. 0.2 ± 0.3; NS) cells. The magnitude of the TNF-α effect was similar for TPC-1 and BCPAP (∼40 % vs. baseline) cells. TPC-1 cells were characterized by a greater amount of CCR6 per cell as compared with BCPAP cells, both in basal conditions (148.3 ± 33.7 fluorescence intensity vs. 102.5 ± 22.1 p < 0.016) and after TNF-α stimulation (147.8 ± 46.3 fluorescence intensity vs. 95.3 ± 18.5; p < 0.025). Cell migration assays showed that TNF-α treatment significantly increased the rate of migrated cells in those cells in which it also increased the membrane expression of CCR6 (TPC-1 and BCPAP) as compared to basal condition (p < 0.05 for both TPC-1 and BCPAP cells). No effect was observed in NHT cells in which TNF-α stimulation had no effect in terms of CCR6 expression. We first report that TNF-α enhances the expression of CCR6 in thyroid tumor cells, thus providing evidence that TNF-α increases the metastatic potential of thyroid tumors.
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Rubie C, Kauffels A, Kölsch K, Glanemann M, Justinger C. CXCL12/CXCR4 display an inverse mRNA expression profile in gastric carcinoma that correlates with tumor progression. Oncol Lett 2015; 11:360-364. [PMID: 26870218 DOI: 10.3892/ol.2015.3850] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 07/16/2015] [Indexed: 02/07/2023] Open
Abstract
Chemokines and their receptors have been shown to contribute to tumor growth and metastatic spread in various gastrointestinal cancer entities. In the present study, the mRNA expression profiles and clinical significance of chemokine ligand CXCL12 and its corresponding receptor CXCR4 were investigated in patients with gastric cancer (GC). Using quantitative polymerase chain reaction, the expression profile of CXCL12/CXCR4 was analyzed in resection specimens from the patients with GC (n=66) and in corresponding normal gastric tissues. Upon investigating CXCL12/CXCR4 mRNA expression levels in the GC tissues, significant downregulation of CXCL12 expression was demonstrated (P<0.05), whereas CXCR4 mRNA expression was shown to be significantly upregulated (P<0.05). Likewise, in gastric carcinoma patients undergoing neoadjuvant chemotherapy, CXCR4 expression was found to be significantly upregulated (P<0.05), whereas in GC patients with lymph and vein infiltration, CXCL12 mRNA expression was significantly downregulated (P<0.05). These results demonstrate a significant inverse association between the development and progress of GC and CXCL12/CXCR4 mRNA expression. CXCR4 mRNA upregulation was promoted under the effect of neoadjuvant chemotherapy prior to surgery in GC patients, whereas higher tumor stages with lymph and vein infiltration negatively affected CXCL12 mRNA expression.
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Affiliation(s)
- Claudia Rubie
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Anne Kauffels
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Kathrin Kölsch
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Mathias Glanemann
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Christoph Justinger
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
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Zhang XG, Song BT, Liu FJ, Sun D, Wang KX, Qu H. CCR6 overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer. Clin Transl Oncol 2015; 18:700-7. [DOI: 10.1007/s12094-015-1420-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 09/25/2015] [Indexed: 11/30/2022]
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Chin CC, Chen CN, Kuo HC, Shi CS, Hsieh MC, Kuo YH, Tung SY, Lee KF, Huang WS. Interleukin-17 induces CC chemokine receptor 6 expression and cell migration in colorectal cancer cells. J Cell Physiol 2015; 230:1430-7. [PMID: 25201147 DOI: 10.1002/jcp.24796] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 09/05/2014] [Indexed: 12/12/2022]
Abstract
The CC chemokine receptor 6 (CCR6) and its ligand CCL20 are involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. In addition, interleukin-17 (IL-17), produced by a T cell subset named "Th17," has been identified as an important player in inflammatory responses, and has emerged as a mediator in inflammation-associated cancer. However, the relevance of IL-17 in the development and progression of CRC still remains to be explored. This study aimed to investigate the effect of IL-17 on the cell migration of CRC cells. Human CRC HCT-116 cells were used to study the effect of IL-17 on CCR6 expression and cell migration in CRC cells. IL-17 treatment induced migration of HCT-116 cells across the Boyden chamber membrane and increased the expression level of the CCR6. Inhibition of CCR6 by small interfering RNA (siRNA) and neutralizing antibody inhibited IL-17-induced cell migration. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK and p38 pathways are critical for IL-17-induced CCR6 expression and cell migration. Promoter activity and transcription factor ELISA assays showed that IL-17 increased NF-κB-DNA binding activity in HCT-116 cells. Inhibition of NF-κB activation by specific inhibitors and siRNA blocked the IL-17-induced CCR6 expression. Our findings support the hypothesis that CCR6 up-regulation stimulated by IL-17 may play an active role in CRC cell migration.
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Affiliation(s)
- Chih-Chien Chin
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
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CrkL meditates CCL20/CCR6-induced EMT in gastric cancer. Cytokine 2015; 76:163-169. [PMID: 26044596 DOI: 10.1016/j.cyto.2015.05.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 05/05/2015] [Accepted: 05/07/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND In recent years, Crk-like adapter protein (CrkL) has been identified as a key regulator in the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms underlying the CC chemokine receptor 6 (CCR6) and chemokine (C-C motif) ligand 20 (CCL20)-induced EMT in gastric cancer are still unclear. METHODS We conducted the immunohistochemistry and immunoblotting to detect the expression of CCR6 and CrkL in 90 cases of gastric cancer tissues and five kinds of cell lines. And then, gastric cancer cells were subjected to small interfering RNA (siRNA) treatment and in vitro assay. RESULTS Both CCR6 and CrkL were aberrantly expressed in gastric cancer specimens and closely correlated with differentiation of cell lines. The expression of CCR6 and CrkL was also significantly associated with metastasis, stage, and poor prognosis of gastric cancer. In addition, we validated CCL20 activated the expression of p-CrkL, p-Erk1/2, p-Akt, vimentin, N-cadherin and MMP2 in MGC803 cells in a dose-dependent manner. However, si-CrkL abrogated the CCL20-induced p-Erk1/2, vimentin, N-cadherin and MMP2 expression. Most importantly, the knockdown of CrkL decreased migration and invasion of MGC803 cells. CONCLUSIONS CrkL mediates CCL20/CCR6-induced EMT via Akt pathway, instead of Erk1/2 pathway in development of gastric cancer, which indicated CCL20/CCR6-CrkL-Erk1/2-EMT pathway may be targeted to antagonize the progression of gastric cancer.
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Vela M, Aris M, Llorente M, Garcia-Sanz JA, Kremer L. Chemokine receptor-specific antibodies in cancer immunotherapy: achievements and challenges. Front Immunol 2015; 6:12. [PMID: 25688243 PMCID: PMC4311683 DOI: 10.3389/fimmu.2015.00012] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 01/07/2015] [Indexed: 12/22/2022] Open
Abstract
The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications.
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Affiliation(s)
- Maria Vela
- Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB/CSIC), Madrid, Spain
| | - Mariana Aris
- Centro de Investigaciones Oncológicas, Fundación Cáncer, Buenos Aires, Argentina
| | - Mercedes Llorente
- Protein Tools Unit, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB/CSIC), Madrid, Spain
| | - Jose A. Garcia-Sanz
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CIB/CSIC), Madrid, Spain
| | - Leonor Kremer
- Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB/CSIC), Madrid, Spain
- Protein Tools Unit, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB/CSIC), Madrid, Spain
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Abstract
OBJECTIVES Lactoferrin (Lf) is an iron-binding glycoprotein present in high concentration in human milk. It is a pleiotropic protein and is involved in diverse bioactivities, such as stimulation of cell proliferation and differentiation, immune competence, antimicrobial activities, anti-infection, and anticancer activities. Lf has been shown to be partly resistant to proteolysis in the gastrointestinal tract and may thus play important roles in the intestine and liver during infancy. Talactoferrin alfa (TLf) is a recombinant human Lf shown to protect against sepsis and necrotizing enterocolitis as well as cancer. Because bovine Lf (bLf) and human Lf have different amino acid composition and all 3 Lfs differ in glycosylation, they may have different functions/potency. The objective of the present study was to investigate and compare bioactivities of TLf and Lfs from human and bovine milk and thus to provide a better understanding of the bioactivities of different forms of Lf and their potential applications. METHODS In the present study, Caco-2 and C3A cells were used as intestine and liver models to evaluate internalization of Lfs by intestine and liver cells, effects of Lfs on cell proliferation and differentiation, growth of enteropathogenic Escherichia coli (EPEC), chemokine (C-C motif) ligand 20 (CCL20) secretion, and transforming growth factor (TGF)-β1 expression. In addition, HT-29 cells were used as a colon cancer cell model to examine the effects of Lfs on apoptosis. RESULTS All Lfs significantly enhanced cell proliferation and differentiation, apoptosis, CCL20 secretion, and TGF-β1 expression. They also markedly suppressed growth of EPEC. Compared with bLf, TLf showed stronger effects on suppression of EPEC growth and enhancement of TGF-β1 secretion, whereas bLf exhibited more potent effects on cell differentiation, apoptosis, and CCL20 secretion. CONCLUSIONS Our results demonstrate that TLf has several bioactivities similar to human Lf and bLf from milk and may play critical roles in immune and intestinal development in infants as well as having anti-cancer activities in adults. TLf and bLf may be used for different applications owing to their various potencies. TLf may preferentially be used for anti-bacterial applications, whereas bLf may be used for cancer therapy because it exhibits stronger effects on CCL20 secretion, cell differentiation, and apoptosis.
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Luddy KA, Robertson-Tessi M, Tafreshi NK, Soliman H, Morse DL. The role of toll-like receptors in colorectal cancer progression: evidence for epithelial to leucocytic transition. Front Immunol 2014; 5:429. [PMID: 25368611 PMCID: PMC4202790 DOI: 10.3389/fimmu.2014.00429] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 08/22/2014] [Indexed: 01/08/2023] Open
Abstract
Toll-like receptors (TLRs) are expressed by immune cells, intestinal epithelium, and tumor cells. In the homeostatic setting, they help to regulate control over invading pathogens and maintain the epithelial lining of the large and small intestines. Aberrant expression of certain TLRs by tumor cells can induce growth inhibition while others contribute to tumorigenesis and progression. Activation of these TLRs can induce inflammation, tumor cell proliferation, immune evasion, local invasion, and distant metastasis. These TLR-influenced behaviors have similarities with properties observed in leukocytes, suggesting that tumors may be hijacking immune programs to become more aggressive. The concept of epithelial to leucocytic-transition (ELT) is proposed, akin to epithelial to mesenchymal transition, in which tumors develop the ability to activate leucocytic traits otherwise inaccessible to epithelial cells. Understanding the mechanisms of ELT could lead to novel therapeutic strategies for inhibiting tumor metastasis.
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Affiliation(s)
- Kimberly A Luddy
- Department of Cancer Imaging and Metabolism, Imaging and Technology Center of Excellence, H. Lee Moffitt Cancer Center , Tampa, FL , USA
| | - Mark Robertson-Tessi
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center , Tampa, FL , USA
| | - Narges K Tafreshi
- Department of Cancer Imaging and Metabolism, Imaging and Technology Center of Excellence, H. Lee Moffitt Cancer Center , Tampa, FL , USA
| | - Hatem Soliman
- Don and Erika Wallace Comprehensive Breast Program, Center for Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL , USA
| | - David L Morse
- Department of Cancer Imaging and Metabolism, Imaging and Technology Center of Excellence, H. Lee Moffitt Cancer Center , Tampa, FL , USA
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Zhou J, Xiang Y, Yoshimura T, Chen K, Gong W, Huang J, Zhou Y, Yao X, Bian X, Wang JM. The role of chemoattractant receptors in shaping the tumor microenvironment. BIOMED RESEARCH INTERNATIONAL 2014; 2014:751392. [PMID: 25110692 PMCID: PMC4119707 DOI: 10.1155/2014/751392] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 06/17/2014] [Indexed: 12/13/2022]
Abstract
Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics.
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Affiliation(s)
- Jiamin Zhou
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Endoscopic Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yi Xiang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Teizo Yoshimura
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Keqiang Chen
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Jian Huang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ye Zhou
- Department of Gastric Cancer and Soft Tissue Surgery, Fudan University Cancer Center, Shanghai 200032, China
| | - Xiaohong Yao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ji Ming Wang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
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Liu J, Ke F, Xu Z, Liu Z, Zhang L, Yan S, Wang Z, Wang H, Wang H. CCR6 is a prognostic marker for overall survival in patients with colorectal cancer, and its overexpression enhances metastasis in vivo. PLoS One 2014; 9:e101137. [PMID: 24979261 PMCID: PMC4076197 DOI: 10.1371/journal.pone.0101137] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Accepted: 06/03/2014] [Indexed: 02/07/2023] Open
Abstract
The chemokine receptor CCR6 has been recently shown to be associated with colorectal cancer (CRC) progression. However, the direct evidence for whether CCR6 in tumors is a prognostic marker for the survival of patients with CRC and whether it plays a critical role in CRC metastasis in vivo is lacking. Here we show that the levels of CCR6 were upregulated in CRC cell lines and primary CRC clinical samples. CCR6 upregulation was closely correlated with disease stages and the survival time of CRC patients. Knockdown of CCR6 inhibited the migration of CRC cells in vitro. Overexpression of CCR6 in CRC cells increased their proliferation, migration, and colony formation in vitro and promoted their metastatic potential in vivo. CCR6 activated Akt signaling, upregulated metastasis genes and downregulated metastasis suppressor genes. Selective targeting of CCR6 in tumors dramatically inhibited the growth of CRC in mice. Thus, the tumor expression of CCR6 plays a critical role in CRC metastasis, upregulated CCR6 predicts poor survival in CRC patients, and targeting CCR6 expression in tumors may be a potential therapeutic strategy for CRC.
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Affiliation(s)
- Jinlin Liu
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Ke
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenyao Xu
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhaoyuan Liu
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingyun Zhang
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sha Yan
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhe Wang
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Wang
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Honglin Wang
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- * E-mail:
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Zeng W, Chang H, Ma M, Li Y. CCL20/CCR6 promotes the invasion and migration of thyroid cancer cells via NF-kappa B signaling-induced MMP-3 production. Exp Mol Pathol 2014; 97:184-90. [PMID: 24984269 DOI: 10.1016/j.yexmp.2014.06.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 06/27/2014] [Indexed: 01/01/2023]
Abstract
CCL20, an important member of the CC-chemokine family, is the only ligand that activates CCR6. The levels of CCL20 and CCR6 are elevated in many human cancers, and CCL20/CCR6 interaction participates in the development and progression of cancer. In this present study, we found that CCR6 was overexpressed in thyroid cancer cells. Activation of CCR6 by CCL20 promoted the invasion and migration of human thyroid cancer SW1736 cells, while knockdown of CCR6 repressed the effect of CCL20. Furthermore, CCL20/CCR6 interaction induced the activation of NF-κB, and stimulated the expression and secretion of MMP-3. In addition, BAY117082, a special inhibitor of NF-κB, suppressed the expression and secretion of MMP-3 stimulated by CCL20/CCR6. Together, these results suggest that CCL20/CCR6 enhances thyroid cancer cell invasion and migration. The possible molecular mechanisms involved NF-κB activation and NF-κB-dependent MMP-3 upregulation. Thus, molecular therapies that aim at CCL20 and CCR6 may offer promising intervention strategies for thyroid cancer.
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Affiliation(s)
- Wei Zeng
- Department of Otolaryngology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China
| | - Hao Chang
- Department of Otolaryngology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China
| | - Min Ma
- Department of Otolaryngology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China
| | - Yanwei Li
- Department of Ophthalmology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China.
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33
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Cheng XS, Li YF, Tan J, Sun B, Xiao YC, Fang XB, Zhang XF, Li Q, Dong JH, Li M, Qian HH, Yin ZF, Yang ZB. CCL20 and CXCL8 synergize to promote progression and poor survival outcome in patients with colorectal cancer by collaborative induction of the epithelial–mesenchymal transition. Cancer Lett 2014; 348:77-87. [DOI: 10.1016/j.canlet.2014.03.008] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 03/02/2014] [Accepted: 03/07/2014] [Indexed: 01/13/2023]
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Nandi B, Pai C, Huang Q, Prabhala RH, Munshi NC, Gold JS. CCR6, the sole receptor for the chemokine CCL20, promotes spontaneous intestinal tumorigenesis. PLoS One 2014; 9:e97566. [PMID: 24866282 PMCID: PMC4035256 DOI: 10.1371/journal.pone.0097566] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 04/21/2014] [Indexed: 12/12/2022] Open
Abstract
Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been associated with colorectal cancer growth and metastasis, however, a causal role for CCL20 signaling through CCR6 in promoting intestinal carcinogenesis has not been demonstrated in vivo. In this study, we aimed to determine the role of CCL20-CCR6 interactions in spontaneous intestinal tumorigenesis. CCR6-deficient mice were crossed with mice heterozygous for a mutation in the adenomatous polyposis coli (APC) gene (APCMIN/+ mice) to generate APCMIN/+ mice with CCR6 knocked out (CCR6KO-APCMIN/+ mice). CCR6KO-APCMIN/+ mice had diminished spontaneous intestinal tumorigenesis. CCR6KO-APCMIN/+ also had normal sized spleens as compared to the enlarged spleens found in APCMIN/+ mice. Decreased macrophage infiltration into intestinal adenomas and non-tumor epithelium was observed in CCR6KO-APCMIN/+ as compared to APCMIN/+ mice. CCL20 signaling through CCR6 caused increased production of CCL20 by colorectal cancer cell lines. Furthermore, CCL20 had a direct mitogenic effect on colorectal cancer cells. Thus, interactions between CCL20 and CCR6 promote intestinal carcinogenesis. Our results suggest that the intestinal tumorigenesis driven by CCL20-CCR6 interactions may be driven by macrophage recruitment into the intestine as well as proliferation of neoplastic epithelial cells. This interaction could be targeted for the treatment or prevention of malignancy.
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MESH Headings
- Animals
- Apoptosis
- Blotting, Western
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Chemokine CCL20/genetics
- Chemokine CCL20/metabolism
- Colonic Neoplasms/genetics
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- Female
- Fluorescent Antibody Technique
- Genes, APC
- Humans
- Immunoenzyme Techniques
- Intestinal Neoplasms/etiology
- Intestinal Neoplasms/metabolism
- Intestinal Neoplasms/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Receptors, CCR6/genetics
- Receptors, CCR6/metabolism
- Receptors, CCR6/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
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Affiliation(s)
- Bisweswar Nandi
- Research Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Christine Pai
- Research Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
| | - Qin Huang
- Harvard Medical School, Boston, Massachusetts, United States of America
- Pathology, Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
| | - Rao H. Prabhala
- Research Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- Dana-Farber Cancer Center, Boston, Massachusetts, United States of America
| | - Nikhil C. Munshi
- Harvard Medical School, Boston, Massachusetts, United States of America
- Dana-Farber Cancer Center, Boston, Massachusetts, United States of America
- Medicine Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
| | - Jason S. Gold
- Harvard Medical School, Boston, Massachusetts, United States of America
- Surgery Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
- Brigham and Women's Hospital, Boston, Massachusetts, United States of America
- * E-mail:
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35
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Rubie C, Kruse B, Frick VO, Kölsch K, Ghadjar P, Wagner M, Grässer F, Wagenpfeil S, Glanemann M. Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells. J Transl Med 2014; 12:48. [PMID: 24559209 PMCID: PMC3996063 DOI: 10.1186/1479-5876-12-48] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 02/13/2014] [Indexed: 02/07/2023] Open
Abstract
Background Recently, involvement of the chemokine/receptor system CCL20/CCR6 in colorectal cancer (CRC) progression was shown. Here, we analyzed the functional interaction of miRNA-518-5p (miR-518a-5p) with CCR6 and its impact on CCR6 expression in CRC cells. Methods MiR-518a-5p was identified by computer software to potentially interact with CCR6. Hence, functional implications of miR-518a-5p with the 3′UTR of CCR6 were analyzed using the Dual Luciferase Reporter assay system. Confirmation of the predicted target site for miR-518a-5p was achieved by site-directed mutagenesis of the seed sequence in the 3′UTR of CCR6 and subsequent application of the mutated seed sequence in a luciferase assay with miR-518a-5p mimics. Accordingly, two CRC cell lines (Caco-2 and HT-29) were transfected with miR-518a-5p miRNA mimics and gene and protein expression of CCR6 was monitored using qRT PCR and immunocytochemistry, respectively. Results Addition of miR-518a-5p led to significant down-regulation of luciferase activity (P < 0.05), which was significantly reversed in a reporter test system containing the mutated seed sequences in the 3′UTR of CCR6. Following transfection of CRC cell lines with miR-518a-5p mimics and subsequent monitoring of CCR6 expression showed significant down-regulation of CCR6 mRNA and CCR6 protein expression in both CRC cell lines under investigation (P < 0.05). Conclusions We have shown that miR-518a-5p functionally interacts with CCR6 and that transfection of CRC cells with miR-518a-5p leads to significant CCR6 down-regulation. Consequently, CCR6 expression is regulated by miR-518a-5p in CRC cells indicating that regulation of CCR6 expression by miR-518a-5p might be a regulatory mechanism involved in CRC pathogenesis.
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Affiliation(s)
- Claudia Rubie
- Department of General -, Visceral-, Vascular - and Paediatric Surgery, University of the Saarland, 66421 Homburg/Saar, Germany.
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Frick VO, Rubie C, Kölsch K, Wagner M, Ghadjar P, Graeber S, Glanemann M. CCR6/CCL20 chemokine expression profile in distinct colorectal malignancies. Scand J Immunol 2013; 78:298-305. [PMID: 23790181 DOI: 10.1111/sji.12087] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 06/07/2013] [Indexed: 12/12/2022]
Abstract
Originally, chemokines and their G-protein-coupled receptors were described to regulate multiple physiological functions, particularly tissue architecture and compartment-specific migration of white blood cells. Now, it is established that the chemokine/chemokine receptor system is also used by cancer cells for migration and metastatic spread. Here, we examined the relative levels of CC-chemokine CCL20 and its corresponding receptor CCR6 in resection specimens from patients with different malignant and non-malignant colorectal diseases as well as in colorectal liver metastases (CRLM). CCL20/CCR6 mRNA and protein expression profiles were assessed by quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in resection specimens from patients with ulcerative colitis (UC, n = 15), colorectal adenoma (CRA, n = 15), colorectal adenocarcinoma (CRC, n = 61) and colorectal liver metastases (CRLM, n = 16). Corresponding non-diseased tissues served as control. In contrast to UC tissues, the CCL20/CCR6 system showed a distinct upregulation in CRA, CRC and CRLM related to corresponding non-affected tissues (P < 0.05, respectively). Furthermore, CRA, CRC and CRLM tissue samples displayed significantly higher protein amounts of CCL20 in comparison with UC specimens (P < 0.05, respectively). Our results strongly suggest an association between CCL20/CCR6 expression and the induction of CRA, CRC and the development of CRLM. Therefore, CCL20 and CCR6 may provide potential targets for novel treatment strategies of CRC.
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Affiliation(s)
- V O Frick
- Department of General, Visceral, Vascular and Pediatric Surgery, University of the Saarland, Homburg/Saar, Germany
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Hashimoto K, Saigusa S, Araki T, Tanaka K, Okita Y, Fujikawa H, Kawamura M, Okugawa Y, Toiyama Y, Inoue Y, Uchida K, Mohri Y, Kusunoki M. Correlation of CCL20 expression in rectal mucosa with the development of ulcerative colitis-associated neoplasia. Oncol Lett 2013; 6:1271-1276. [PMID: 24179507 PMCID: PMC3813524 DOI: 10.3892/ol.2013.1528] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 07/16/2013] [Indexed: 12/30/2022] Open
Abstract
Chronic inflammation increases the risk of developing several gastrointestinal malignancies. Chemokines that are produced by colonic epithelial cells play significant roles in the maintenance and repair of the epithelial barrier. The present study aimed to clarify whether the expression of CCL20 and its receptor, CCR6, was correlated with the development of ulcerative colitis (UC)-associated neoplasia. A total of 93 patients with UC who underwent proctocolectomies were enrolled in the present study. Immunohistochemical analysis for CCL20 and CCR6 expression in the rectal mucosa was performed and the correlation between expression and the pathogenesis of UC-associated neoplasia was investigated. A total of 16 (17.2%) patients presented with UC-associated neoplasia. The immunohistochemistry (IHC) score for CCL20 was significantly increased in the patients with a mild form of the disease (P=0.0363). The IHC score for CCL20 expression in the patients with UC-associated neoplasia was higher compared with the patients without neoplasia (P=0.0294). In contrast, there was no significant correlation between CCR6 expression and the clinicopathological variables. The logistic regression analysis revealed that a high IHC score for CCL20 expression in the rectal mucosa and a disease duration of more than eight years were significantly correlated with the development of UC-associated neoplasia (P<0.05). The results suggest that an evaluation of CCL20 expression in the rectal mucosa may be useful to identify patients who are at a high risk for developing UC-associated neoplasia. However, a selection bias existed in the present study due to the fact that the patient population that was enrolled was not representative of a typical surveillance patient population.
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Affiliation(s)
- Kiyoshi Hashimoto
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
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38
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Vicinus B, Rubie C, Stegmaier N, Frick VO, Kölsch K, Kauffels A, Ghadjar P, Wagner M, Glanemann M. miR-21 and its target gene CCL20 are both highly overexpressed in the microenvironment of colorectal tumors: significance of their regulation. Oncol Rep 2013; 30:1285-92. [PMID: 23817679 DOI: 10.3892/or.2013.2580] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 06/12/2013] [Indexed: 02/07/2023] Open
Abstract
Recently, we reported a functional interaction between miR-21 and its identified chemokine target CCL20 in colorectal cancer (CRC) cell lines. Here, we investigated whether such functional interactions are permitted at the cellular level which would require an inverse correlation of expression and also co-expression of miR-21 and CCL20 in the same cell. Expression profiling was performed using qPCR, and ELISA, in situ hybridization and immunohistochemistry were applied for the presentation of their cellular localization. We demonstrated that miR-21 as well as CCL20 were both significantly upregulated in CRC tissues; thus, showing no antidromic expression pattern. This provided an initial clue that miR-21 and CCL20 may not be expressed in the same cell. In addition, we located miR-21 expression at the cellular level predominantly in stromal cells such as tumor-associated fibroblasts and to a minor degree in immune cells such as macrophages and lymphocytes. Likewise, CCL20 expression was primarily detected in tumor-infiltrating immune cells. Thus, investigating the cellular localization of miR-21 and its target CCL20 revealed that both molecules are expressed predominantly in the microenvironment of CRC tumors.
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Affiliation(s)
- Benjamin Vicinus
- Department of General, Visceral, Vascular and Paediatric Surgery, University of the Saarland, 66421 Homburg/Saar, Germany
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Hu D, Du C, Xue W, Dou F, Yao Y, Gu J. The expression of chemokine receptors CCR6, CXCR2 and CXCR4 is not organ-specific for distant metastasis in colorectal cancer: a comparative study. Histopathology 2013; 63:167-73. [PMID: 23758411 DOI: 10.1111/his.12127] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Accepted: 03/06/2013] [Indexed: 12/12/2022]
Abstract
AIMS The liver and lung are the organs most commonly affected by metastasis in colorectal cancer (CRC), and the interaction of chemokines and chemokine receptors (CKRs) plays an important role in the metastatic process. The aim of this study was to investigate the organ specificity of CKRs in CRC distant metastasis. METHODS AND RESULTS Surgical specimens of primary tumours from 46 patients with metachronous distant metastases were retrieved retrospectively (20 lung metastases; 26 liver metastases). As a control, the records of 29 patients without distant metastases were randomly retrieved from our database, and their specimens were reassessed. The expression rates of CKRs, including CCR6, CXCR2, and CXCR4, were determined by immunohistochemistry, and were compared among the groups. The expression rates of CCR6 and CXCR2 were both significantly higher in the metastasis group than in the non-metastasis group (P < 0.05), but there was no statistical difference between the lung metastasis and liver metastasis subgroups. The expression of CXCR4 was not significantly different between the metastasis and non-metastasis groups. Multivariable analysis suggested that preoperative serum carcinoembryonic antigen level, CCR6 and CXCR2 were independent factors associated with distant metastasis. CONCLUSIONS The expression of CCR6 and CXCR2 in CRC could predict metachronous distant metastasis, but they have no organ specificity for metastasis.
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Affiliation(s)
- Dongzhi Hu
- Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
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40
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Van den Eynden GG, Majeed AW, Illemann M, Vermeulen PB, Bird NC, Høyer-Hansen G, Eefsen RL, Reynolds AR, Brodt P. The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res 2013; 73:2031-43. [PMID: 23536564 DOI: 10.1158/0008-5472.can-12-3931] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, Kupffer, stellate, and inflammatory cells) determine their fate. The sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth. Adhesion molecules participate in these interactions and may affect their outcome. Bone marrow-derived cells and chemokines also play a part in the early battle for survival of the metastases. Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 distinct patterns, reflecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment.
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Robinson SM, White SA. Hepatic sinusoidal obstruction syndrome reduces the effect of oxaliplatin in colorectal liver metastases. Histopathology 2012; 61:1247-8. [DOI: 10.1111/j.1365-2559.2012.04358.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Iwata T, Tanaka K, Inoue Y, Toiyama Y, Hiro J, Fujikawa H, Okugawa Y, Uchida K, Mohri Y, Kusunoki M. Macrophage inflammatory protein-3 alpha (MIP-3a) is a novel serum prognostic marker in patients with colorectal cancer. J Surg Oncol 2012; 107:160-6. [PMID: 22926691 DOI: 10.1002/jso.23247] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 07/26/2012] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND OBJECTIVES A significant prognostic difference exists among metastatic colorectal cancer (CRC) patients despite of any treatments. We identify the specific cytokines related to prognosis of metastatic CRC and assess their prognostic significance. METHODS Stage IV CRC patients were divided into two groups according to their prognosis. Difference in serum cytokine level between these groups was determined by the cytokine array. Among the specific cytokines, macrophage inflammatory protein-3 alpha (MIP-3a) was measured using an enzyme-linked immunosorbent assay (ELISA) in the sera of 242 CRC patients. RESULTS Several cytokines related to prognostic difference in stage IV CRC were identified. The median MIP-3a level (28.2 pg/ml) was used as a cut-off value. Increased MIP-3a was significantly associated with synchronous liver metastases and age. In univariate analysis, high MIP-3a was correlated with poor prognosis (P < 0.001). Multivariate analysis showed that high MIP-3a was an independent prognostic factor in all CRC patients (P < 0.001). In subgroup analysis, high MIP-3a was significantly associated with poor survival in patients with stage II, II/III, and IV CRC, respectively. CONCLUSIONS Serum MIP-3a is not only an independent prognostic factor, but also an independent predictive factor for liver metastasis, which may guide the decision making of metastatic CRC patients.
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Affiliation(s)
- Takashi Iwata
- Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Mie, Japan
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43
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Cho YB, Lee WY, Choi SJ, Kim J, Hong HK, Kim SH, Choi YL, Kim HC, Yun SH, Chun HK, Lee KU. CC chemokine ligand 7 expression in liver metastasis of colorectal cancer. Oncol Rep 2012; 28:689-94. [PMID: 22614322 DOI: 10.3892/or.2012.1815] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 04/10/2012] [Indexed: 11/06/2022] Open
Abstract
The main cause of death for colorectal cancer (CRC) patients is the development of metastatic lesions at sites distant from the primary tumor. Therefore, it is important to find biomarkers that are related to the metastasis and to study the possible mechanisms. Recent data have shown that soluble attractant molecules called chemokines support the metastasis of certain cancers to certain organs. To identify molecular regulators that are differentially expressed in liver metastasis of CRC, PCR array analysis was performed and CC chemokine ligand 7 (CCL7) showed remarkable overexpression in liver metastatic tumor tissues. To validate the results of the PCR array, 30 patients with primary CRC and liver metastases were selected. Immunohistochemistry and real-time PCR analysis showed that CCL7 was expressed in normal colonic epithelium and the expression was higher in liver metastases compared to primary CRC (p<0.001). Real-time PCR showed that the expression of CCR1, CCR2 and CCR3 was also higher in liver metastases compared to primary CRC (p=0.001, p=0.033 and p<0.001, respectively). In conclusion, correlation of CCL7 overexpression and its receptor expression with colon cancer liver metastasis suggests that CCL7 as a novel target in liver metastasis of CRC may be of potential clinical value for the prevention of hepatic recurrences.
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Affiliation(s)
- Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul National University Hospital, Seoul 135-710, Republic of Korea
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Fusi A, Liu Z, Kümmerlen V, Nonnemacher A, Jeske J, Keilholz U. Expression of chemokine receptors on circulating tumor cells in patients with solid tumors. J Transl Med 2012; 10:52. [PMID: 22433180 PMCID: PMC3337808 DOI: 10.1186/1479-5876-10-52] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 03/20/2012] [Indexed: 12/31/2022] Open
Abstract
Background The study was performed to investigate the expression of chemokine receptors (CR) on circulating tumor cells (CTC), which may be of importance for organ-specific metastases and cancer treatment since CR are potential drug-targets. Methods Blood samples from patients with metastatic carcinoma (MC) or melanoma (MM) were enriched for CTC and expression of CR (CXCR4, CCR6, CCR7 and CCR9) was evaluated by flow cytometry. Results CTC were detected in 49 of 68 patients (72%) [28 MC; 21 MM] with a median number of 3 CTC (range: 1-94)/10 mL of blood. CXCR4 was expressed on CTC in 82% (40/49) of patients [median number 1 CTC/10 mL blood; range 1-14] and CCR6 in 29 patients (59%; median 1, range: 1-14). In MM patients, CCR7 was expressed on CTC in 6 (29%) samples and CCR9 in 12 (57%). A positive correlation between surface expression of CR and organ-specific metastatic pattern was not observed. Conclusions CR were expressed on CTC of patients with solid tumors. Along with our findings, the observation that CR could be involved in CTC proliferation and migration of tumor cells appoints CTC as potential CR-antagonist therapeutic target.
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Affiliation(s)
- Alberto Fusi
- Department of Hematology and Medical Oncology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
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45
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Vicinus B, Rubie C, Faust SK, Frick VO, Ghadjar P, Wagner M, Graeber S, Schilling MK. miR-21 functionally interacts with the 3'UTR of chemokine CCL20 and down-regulates CCL20 expression in miR-21 transfected colorectal cancer cells. Cancer Lett 2011; 316:105-12. [PMID: 22099878 DOI: 10.1016/j.canlet.2011.10.031] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Revised: 10/21/2011] [Accepted: 10/21/2011] [Indexed: 12/12/2022]
Abstract
As deregulation of miRNAs and chemokine CCL20 was shown to play a role in colorectal cancer (CRC) pathogenesis, we analyzed the functional interactions of candidate miRNAs with CCL20 mRNA. After target prediction software programs indicated a role for miR-21 in CCL20 regulation, we applied the luciferase reporter assay system to demonstrate that miR-21 functionally interacts with the 3'UTR of CCL20 mRNA and down-regulates CCL20 in miR-21 mimic transfected CRC cell lines (Caco-2, SW480 and SW620). Thus, regulation of CCL20 expression by miR-21 might be a regulatory mechanism involved in progression of CRC.
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Affiliation(s)
- Benjamin Vicinus
- Department of General, Visceral, Vascular and Paediatric Surgery, University of the Saarland, 66421 Homburg/Saar, Germany
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Jin K, Gao W, Lu Y, Lan H, Teng L, Cao F. Mechanisms regulating colorectal cancer cell metastasis into liver (Review). Oncol Lett 2011; 3:11-15. [PMID: 22740847 DOI: 10.3892/ol.2011.432] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 09/26/2011] [Indexed: 01/28/2023] Open
Abstract
The metastatic spread of tumor cells is one of the most common causes of mortality in cancer patients. The elucidation of the molecular mechanisms that underlie the formation of metastatic colonies has been one of the major objectives of cancer research. Organ-specific colonization of cancer cells is a significant and noteworthy feature of metastasis. Colorectal cancer (CRC) is one of the most common causes of cancer-related mortality. The liver is commonly the sole site of metastasis for CRC and represents a major cause of mortality in CRC patients. However, what regulates CRC cell metastasis into liver and the reasons for the liver-specific metastasis of CRC have yet to be adequately elucidated. Recent progress provides indications and a conceptual framework with which to investigate this issue. This review evaluated experimental and clinical evidence to support a mechanistic role for circulation patterns and microvessels in liver, metastasis-related genes, chemokines and their receptors, and cellular adhesion molecules in the process of CRC liver metastasis.
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Affiliation(s)
- Ketao Jin
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical College, Taizhou, Zhejian 317000
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Kawada K, Hasegawa S, Murakami T, Itatani Y, Hosogi H, Sonoshita M, Kitamura T, Fujishita T, Iwamoto M, Matsumoto T, Matsusue R, Hida K, Akiyama G, Okoshi K, Yamada M, Kawamura J, Taketo MM, Sakai Y. Molecular mechanisms of liver metastasis. Int J Clin Oncol 2011; 16:464-72. [PMID: 21847533 DOI: 10.1007/s10147-011-0307-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2011] [Indexed: 12/13/2022]
Abstract
Colorectal cancer is the second most common cancer, and is the third leading cause of cancer-related death in Japan. The majority of these deaths is attributable to liver metastasis. Recent studies have provided increasing evidence that the chemokine-chemokine receptor system is a potential mechanism of tumor metastasis via multiple complementary actions: (a) by promoting cancer cell migration, invasion, survival and angiogenesis; and (b) by recruiting distal stromal cells (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor invasion and metastasis. Here, we discuss recent preclinical and clinical data supporting the view that chemokine pathways are potential therapeutic targets for liver metastasis of colorectal cancer.
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Affiliation(s)
- Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
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Rubie C, Frick VO, Ghadjar P, Wagner M, Justinger C, Graeber S, Sperling J, Kollmar O, Schilling MK. Effect of preoperative FOLFOX chemotherapy on CCL20/CCR6 expression in colorectal liver metastases. World J Gastroenterol 2011; 17:3109-16. [PMID: 21912453 PMCID: PMC3158410 DOI: 10.3748/wjg.v17.i26.3109] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 12/17/2010] [Accepted: 12/24/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the influence of preoperative FOLFOX chemotherapy on CCL20/CCR6 expression in liver metastases of stage IV colorectal cancer (CRC) patients.
METHODS: Using Real Time-PCR, enzyme-linked immunosorbent assay, Western Blots and immunohistochemistry, we have analyzed the expression of CCL20, CCR6 and proliferation marker Ki-67 in colorectal liver metastasis (CRLM) specimens from stage IV CRC patients who received preoperative FOLFOX chemotherapy (n = 53) and in patients who did not receive FOLFOX chemotherapy prior to liver surgery (n = 29).
RESULTS: Of the 53 patients who received FOLFOX, time to liver surgery was ≤ 1 mo in 14 patients, ≤ 1 year in 22 patients and > 1 year in 17 patients, respectively. In addition, we investigated the proliferation rate of CRC cells in liver metastases in the different patient groups. Both CCL20 and CCR6 mRNA and protein expression levels were significantly increased in patients who received preoperative FOLFOX chemotherapy ≤ 12 mo before liver surgery (P < 0.001) in comparison to patients who did not undergo FOLFOX treatment. Further, proliferation of CRLM cells as measured by Ki-67 was increased in patients who underwent FOLFOX treatment. CCL20 and CCR6 expression levels were significantly increased in CRLM patients who had undergone preoperative FOLFOX chemotherapy.
CONCLUSION: This chemokine/receptor up-regulation could lead to increased proliferation/migration through an autocrine mechanism which might be used by surviving metastatic cells to escape cell death caused by FOLFOX.
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Rubie C, Frick VO, Ghadjar P, Wagner M, Justinger C, Faust SK, Vicinus B, Gräber S, Kollmar O, Schilling MK. CXC receptor-4 mRNA silencing abrogates CXCL12-induced migration of colorectal cancer cells. J Transl Med 2011; 9:22. [PMID: 21349176 PMCID: PMC3049756 DOI: 10.1186/1479-5876-9-22] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 02/24/2011] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Interactions between CXCR4 and its ligand CXCL12 have been shown to be involved in cancer progression in colorectal cancer (CRC). We performed a comparative CXCL12/CXCR4 expression analysis and assessed the effect of external CXCL12 stimulation on migration of CRC cells without and with CXCR4 inhibition. METHODS Expression of CXCL12/CXCR4 was assessed by quantitative real-time PCR, ELISA and immunohistochemistry in resection specimens of 50 CRC patients as well as in the corresponding normal tissues and in three human CRC cell lines with different metastatic potential (Caco-2, SW480 and HT-29). Migration assays were performed after stimulation with CXCL12 and CXCR4 was inhibited by siRNA and neutralizing antibodies. RESULTS In CRC tissues CXCL12 was significantly down-regulated and CXCR4 was significantly up-regulated compared to the corresponding normal tissues. In cell lines CXCR4 was predominantly expressed in SW480 and less pronounced in HT-29 cells. CXCL12 was only detectable in Caco-2 cells. CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells. This effect was significantly abrogated by neutralizing anti-CXCR4 antibody as well as by CXCR4 siRNAs (P < 0.05). CONCLUSIONS CXCR4 expression was up-regulated in CRC and CXCL12 stimulation increased migration in CXCR4 bearing cell lines. Migration was inhibited by both neutralizing CXCR4 antibodies and CXCR4 siRNAs. Thus, the expression and functionality of CXCR4 might be associated with the metastatic potential of CRC cells and CXCL12/CXCR4 interactions might therefore constitute a promising target for specific treatment interventions.
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Affiliation(s)
- Claudia Rubie
- Department of General -, Visceral-, Vascular - and Paediatric Surgery, University of the Saarland, 66421 Homburg/Saar, Germany.
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McLean MH, Murray GI, Stewart KN, Norrie G, Mayer C, Hold GL, Thomson J, Fyfe N, Hope M, Mowat NAG, Drew JE, El-Omar EM. The inflammatory microenvironment in colorectal neoplasia. PLoS One 2011; 6:e15366. [PMID: 21249124 PMCID: PMC3017541 DOI: 10.1371/journal.pone.0015366] [Citation(s) in RCA: 131] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 11/11/2010] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.
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Affiliation(s)
- Mairi H McLean
- Gastrointestinal Research Group, School of Medicine and Dentistry, Aberdeen University, Aberdeen, United Kingdom
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