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Kubera M, Arteta B, Grygier B, Curzytek K, Malicki S, Maes M. Stimulatory effect of fluoxetine and desipramine, but not mirtazapine on C26 colon carcinoma hepatic metastases formation: association with cytokines. Front Immunol 2023; 14:1160977. [PMID: 37409130 PMCID: PMC10318584 DOI: 10.3389/fimmu.2023.1160977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Due to the high prevalence of depression among cancer patients, antidepressant medications are frequently administered as adjuvant treatment. However, the safety of such medications in the development of metastasis is unclear. In this study, we investigated the effects of fluoxetine, desipramine, and mirtazapine on the liver metastasis of murine C26 colon carcinoma (cc). Balb/c male mice were administered these antidepressants intraperitoneally (i.p.) for 14 days following intrasplenic injections of C26 colon carcinoma cells. Desipramine and fluoxetine, but not mirtazapine, significantly increased the number of tumor foci and total volume of the tumor in liver tissue. This effect was associated with a decrease in the ability of splenocytes to produce interleukin (IL)-1β and interferon (IFN)-γ and an increase in their ability to produce interleukin (IL)-10. Similar changes were observed in plasma IL-1β, IFN-γ, and IL-10 levels. The current study demonstrates that the stimulatory effect of desipramine and fluoxetine, but not mirtazapine, on experimental colon cancer liver metastasis is associated with a suppression of immune defenses against the tumor.
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Affiliation(s)
- Marta Kubera
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
| | - Beatriz Arteta
- Department of Cell Biology and Histology, School of Medicine and Nursing, Tumor Microenvironment Group, Basque Country University, Leioa, Spain
| | - Beata Grygier
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
| | - Katarzyna Curzytek
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
| | - Stanisław Malicki
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
- IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia
- Kyung Hee University, Seoul, Republic of Korea
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Xiang J, Ding M, Lin J, Xue T, Ye Q, Yan B. Preoperative carcinoembryonic antigen to body mass index ratio contributes to prognosis prediction in colorectal cancer. Oncol Lett 2022; 24:416. [PMID: 36245819 PMCID: PMC9554958 DOI: 10.3892/ol.2022.13536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/16/2022] [Indexed: 11/05/2022] Open
Abstract
Both carcinoembryonic antigen (CEA) level and body mass index (BMI) are traditional prognostic markers in colorectal cancer (CRC); however, to the best of our knowledge, the value of the CEA to BMI ratio (CBR) has never been addressed. In the present study, 191 patients with CRC treated using radical resection were retrospectively included, and the significance of the CBR in predicting disease-free survival (DFS) or overall survival (OS) rates was calculated. The prognostic efficacy of the CBR in predicting OS was compared with individual CEA and BMI values. The survival differences of the subgroups were calculated by Kaplan-Meier analysis, and corresponding risk factors were then estimated by a Cox proportional hazards model. As a result, 29.84% (57/191) of the patients were assigned to the high CBR group (cut-off, ≥0.28); the CBR had a sensitivity of 56.50 and 68.90%, and a specificity of 80.60 and 80.10% for DFS and OS, respectively. Patients with a high CBR more commonly underwent laparotomy and exhibited advanced T stages, the presence of tumor deposits and advanced Tumor-Node-Metastasis stages (stage II or III). The CBR was more efficient than the CEA or BMI alone in predicting OS. In addition, patients with a high CBR presented with a significantly worse outcome than patients with a low CBR. Finally, the CBR was an independent risk factor for both DFS and OS. In conclusion, the CBR was a more robust prognostic factor in CRC, and patients with a relatively high CBR exhibited poorer survival.
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Affiliation(s)
- Jia Xiang
- Department of Oncology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, Hainan 572000, P.R. China
| | - Mengyao Ding
- Department of Otolaryngology Head and Neck Surgery, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, Hainan 572000, P.R. China
| | - Jixing Lin
- Department of Thoracic Surgery, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, Hainan 572000, P.R. China
| | - Tianhui Xue
- Department of Oncology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, Hainan 572000, P.R. China
| | - Qianwen Ye
- Department of Oncology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, Hainan 572000, P.R. China
| | - Bing Yan
- Department of Oncology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, Hainan 572000, P.R. China
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Chen Y, Gao Y, Ma X, Wang Y, Liu J, Yang C, Wang Y, Bao C, Song X, Feng Y, Sun Y, Qiao S. A study on the correlation between M2 macrophages and regulatory T cells in the progression of colorectal cancer. Int J Biol Markers 2022; 37:412-420. [DOI: 10.1177/03936155221132572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background M2 macrophages and regulatory T cells (Tregs) can promote tumors and development by inhibiting the anti-tumor immune response. This study investigated the effect of CD163-positive M2 macrophages and Foxp3-positive Tregs in the progression of colorectal cancer and lymph node metastasis. It also investigated the correlation between M2 macrophages and Tregs. Methods Postoperative tissue specimens and clinical data were collected from 197 patients with colorectal cancer who underwent initial surgical treatment in The Second Ward of Colorectal Surgery of the First Affiliated Hospital of Jinzhou Medical University from March 2020 to December 2020. Immunohistochemical methods were used to detect the expression levels of CD163 protein-labeled M2 macrophages and Foxp3 protein-labeled Tregs in colorectal cancer tissues, matched paracancer tissues, and lymph node tissues. The correlation between CD163 and Foxp3 in cancer tissues and lymph node tissues were analyzed, as well as the relationship between clinicopathological characteristics and preoperative tumor markers. Results M2 macrophages and Tregs were importantly positively correlated in cancer and lymph node tissues, which significantly increased in cancer and metastatic lymph node tissues. Interestingly, M2 macrophages in non-metastatic lymph nodes also increased significantly in patients with metastatic lymph nodes. In addition, both CD163 and Foxp3 were upregulated with increasing tumor node metastasis stage, depth of infiltration, and lymphatic metastasis; and both were positively correlated with carcinoembryonic antigen. Conclusion CD163 may be a good predictor of pre-metastatic status of colorectal cancer lymph nodes. carcinoembryonic antigen affects the distribution of M2 macrophages and Tregs in colorectal cancer. There is a certain correlation between the two types of cells. It is possible that M2 macrophages, together with suppressor Tregs cells, promote an immunosuppressive environment.
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Affiliation(s)
- Yanlei Chen
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Yu Gao
- Computer Teaching and Research Section, Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Xueqian Ma
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Yanping Wang
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Jinhao Liu
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Chunyu Yang
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Yue Wang
- Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Cuifen Bao
- Basic Medical Experimental Teaching Center, Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Xiaoyu Song
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Yang Feng
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Yan Sun
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Shifeng Qiao
- The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
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Oruc A, Simsek G. A Pathophysiological Approach To Current Biomarkers. Biomark Med 2022. [DOI: 10.2174/9789815040463122010012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Biomarkers are necessary for screening and diagnosing numerous diseases,
predicting the prognosis of patients, and following-up treatment and the course of the
patient. Everyday new biomarkers are being used in clinics for these purposes. This
section will discuss the physiological roles of the various current biomarkers in a
healthy person and the pathophysiological mechanisms underlying the release of these
biomarkers. This chapter aims to gain a new perspective for evaluating and interpreting
the most current biomarkers.
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Affiliation(s)
- Aykut Oruc
- Department of Physiology,Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpaşa,
Istanbul, Turkey
| | - Gonul Simsek
- Department of Physiology,Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpaşa,
Istanbul, Turkey
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Dobrodeeva LK, Shtaborov VA, Geshavets NP. Immune background state among the residents of the north, depending on nutrition type. FOOD AGR IMMUNOL 2022. [DOI: 10.1080/09540105.2022.2070605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Lilia Konstantinovna Dobrodeeva
- N. Laverov Federal Center for Integrated Arctic Research of the Ural Branch of the Russian Academy of Sciences, Arkhangelsk, Russian Federation
| | - Vyacheslav Anatolyevich Shtaborov
- N. Laverov Federal Center for Integrated Arctic Research of the Ural Branch of the Russian Academy of Sciences, Arkhangelsk, Russian Federation
| | - Natalia Pavlovna Geshavets
- N. Laverov Federal Center for Integrated Arctic Research of the Ural Branch of the Russian Academy of Sciences, Arkhangelsk, Russian Federation
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Yu YL, Tseng WK, Fan CW, Chang PH, Kuo HC, Pan YP, Yeh KY. Pretreatment Nutrition-Inflammation Biomarkers Correlated with Differential Cytokine Profiles in Taiwanese Patients with Colorectal Cancer. Nutr Cancer 2021; 74:1614-1624. [PMID: 34323132 DOI: 10.1080/01635581.2021.1957130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Systemic inflammation plays a pivotal role in colorectal cancer (CRC) development. Two hallmarks reflect the severity of inflammation-circulating cytokines and nutrition-inflammation biomarkers (NIBs); however, their interplay has not been fully investigated. In total, 128 CRC patients were included. Ten circulating cytokines (TNF-α, TGF-β, IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-12, IL-13, and IL-23) and NIBs were analyzed. The relationship between cytokines, NIBs, clinicopathological variables, and overall survival (OS) was assessed using univariate and multivariate analyses. Three NIBs (CRP-to-albumin ratio [CAR]), neutrophil-to-lymphocyte ratio [NLR]), and prognostic nutritional index [PNI]) were associated with OS in univariate analysis; however, CAR was better for OS prediction in multivariate analysis (P = 0.015). None of the serum cytokines analyzed showed a significant association with OS. High CAR (≥0.25) and high IL-10 (≥76.6 pg/mL), high NLR (≥8.2) and high IL-23 (≥51.2 pg/mL), and high PNI (≥42.4) and high IL-1β (≥14.3 pg/mL) values were correlated. CAR, NLR, and PNI were not correlated with each other, whereas circulating cytokines were closely interrelated. High CAR was an independent predictor of poor OS in patients with CRC. Different NIBs have unique cytokine profiles, but show no correlation with each other. There is a close association among the circulating cytokines.
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Affiliation(s)
- Yen-Lin Yu
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Wen-Ko Tseng
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chung-Wei Fan
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Pei-Hung Chang
- Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Hsuan-Chih Kuo
- Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Yi-Ping Pan
- Department of Nutrition, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Kun-Yun Yeh
- Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
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Yu YL, Fan CW, Tseng WK, Chang PH, Kuo HC, Pan YP, Yeh KY. Correlation Between the Glasgow Prognostic Score and the Serum Cytokine Profile in Taiwanese Patients with Colorectal Cancer. Int J Biol Markers 2021; 36:40-49. [PMID: 34096371 DOI: 10.1177/17246008211022769] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND The Glasgow Prognostic Score and circulating cytokine levels are related to the prognosis of colorectal cancer and the severity of chronic inflammation. The association between the Glasgow Prognostic Score and circulating cytokines in colorectal cancer remains unclear. METHODS The levels of 10 circulating cytokines (TNF-α, TGF-β, IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-12, IL-13, and IL-23) were measured in 128 patients with colorectal cancer. The relationship between the Glasgow Prognostic Score, clinicopathologic variables, and cytokine levels was assessed by univariate and multivariate logistic regression analyses. The correlation among cytokines was also examined. RESULTS Patients with advanced stage colorectal cancer had lower levels of albumin (P = 0.003), higher levels of C-reactive protein (CRP; P < 0.001), carcinoembryonic antigen (CEA; P < 0.001), interferon (IFN)-γ (P < 0.001), and interleukin (IL)-10 (P = 0.006), and shorter survival outcomes (P < 0.001). Patients with a high Glasgow Prognostic Score (1 or 2) had lower 5-year progression-free survival and poor overall survival (log-rank P < 0.001). A high Glasgow Prognostic Score was significantly correlated with abnormal CEA levels (CEA > 5 ng/mL, P = 0.033), and higher levels of tumor necrosis factor (TNF)-α (TNF-α ⩾ 53.9 pg/mL, P = 0.035) and IL-10 (IL-10 ⩾ 75.95 pg/mL, P = 0.008). TNF-α, IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-13, and IL-23 were significantly correlated with each other (all P < 0.05). Only IL-10 was correlated with abnormal CEA levels (P < 0.001). CONCLUSION The Glasgow Prognostic Score and level of circulating cytokines have an intergroup correlation, and there is a close association among cytokines in colorectal cancer.
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Affiliation(s)
- Yen-Lin Yu
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung
| | - Chung-Wei Fan
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung
| | - Wen-Ko Tseng
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung
| | - Pei-Hung Chang
- Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung
| | - Hsuan-Chih Kuo
- Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung
| | - Yi-Ping Pan
- Department of Nutrition, Chang Gung Memorial Hospital, Keelung
| | - Kun-Yun Yeh
- Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung
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Bogen JP, Hinz SC, Grzeschik J, Ebenig A, Krah S, Zielonka S, Kolmar H. Dual Function pH Responsive Bispecific Antibodies for Tumor Targeting and Antigen Depletion in Plasma. Front Immunol 2019; 10:1892. [PMID: 31447859 PMCID: PMC6697062 DOI: 10.3389/fimmu.2019.01892] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 07/26/2019] [Indexed: 01/08/2023] Open
Abstract
Shedding of membrane-bound cell surface proteins, where the extracellular domain is released and found in the circulation is a common phenomenon. A prominent example is CEACAM5 (CEA, CD66e), where the shed domain plays a pivotal role in tumor progression and metastasis. For treatment of solid tumors, the presence of the tumor-specific antigen in the plasma can be problematic since tumor-specific antibodies might be intercepted by the soluble antigen before invading their desired tumor target area. To overcome this problem, we developed a generic procedure to generate bispecific antibodies, where one arm binds the antigen in a pH-dependent manner thereby enhancing antigen clearance upon endosomal uptake, while the other arm is able to target tumor cells pH-independently. This was achieved by incorporating pH-sensitive binding modalities in the common light chain IGKV3-15*01 of a CEACAM5 binding heavy chain only antibody. Screening of a histidine-doped light chain library using yeast surface display enabled the isolation of pH-dependent binders. When such a light chain was utilized as a common light chain in a bispecific antibody format, only the respective heavy/light chain combination, identified during selections, displayed pH-responsive binding. In addition, we found that the altered common light chain does not negatively impact the affinity of other heavy chain only binders toward their respective antigen. Our strategy may open new avenues for the generation of bispecifics, where one arm efficiently removes a shed antigen from the circulation while the other arm targets a tumor marker in a pH-independent manner.
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Affiliation(s)
- Jan P Bogen
- Department of Applied Biochemistry, Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Darmstadt, Germany
| | - Steffen C Hinz
- Department of Applied Biochemistry, Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Darmstadt, Germany
| | - Julius Grzeschik
- Department of Applied Biochemistry, Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Darmstadt, Germany
| | - Aileen Ebenig
- Department of Applied Biochemistry, Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Darmstadt, Germany
| | - Simon Krah
- Protein Engineering and Antibody Technologies, Merck KGaA, Darmstadt, Germany
| | - Stefan Zielonka
- Protein Engineering and Antibody Technologies, Merck KGaA, Darmstadt, Germany
| | - Harald Kolmar
- Department of Applied Biochemistry, Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Darmstadt, Germany
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Keirsse J, Van Damme H, Geeraerts X, Beschin A, Raes G, Van Ginderachter JA. The role of hepatic macrophages in liver metastasis. Cell Immunol 2018; 330:202-215. [PMID: 29661474 DOI: 10.1016/j.cellimm.2018.03.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Revised: 03/12/2018] [Accepted: 03/29/2018] [Indexed: 12/21/2022]
Abstract
The liver is a major target organ for metastasis of both gastrointestinal and extra-gastrointestinal cancers. Due to its frequently inoperable nature, liver metastasis represents a leading cause of cancer-associated death worldwide. In the past years, the pivotal role of the immune system in this process is being increasingly recognised. In particular, the role of the hepatic macrophages, both recruited monocyte-derived macrophages (Mo-Mfs) and tissue-resident Kupffer cells (KCs), has been shown to be more versatile than initially imagined. However, the lack of tools to easily distinguish between these two macrophage populations has hampered the assignment of particular functionalities to specific hepatic macrophage subsets. In this Review, we highlight the most remarkable findings regarding the origin and functions of hepatic macrophage populations, and we provide a detailed description of their distinct roles in the different phases of the liver metastatic process.
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Affiliation(s)
- Jiri Keirsse
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Helena Van Damme
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Xenia Geeraerts
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Alain Beschin
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Geert Raes
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jo A Van Ginderachter
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
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The Roles of Carcinoembryonic Antigen in Liver Metastasis and Therapeutic Approaches. Gastroenterol Res Pract 2017; 2017:7521987. [PMID: 28588612 PMCID: PMC5447280 DOI: 10.1155/2017/7521987] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 04/16/2017] [Indexed: 12/22/2022] Open
Abstract
Metastasis is a highly complicated and sequential process in which primary cancer spreads to secondary organic sites. Liver is a well-known metastatic organ from colorectal cancer. Carcinoembryonic antigen (CEA) is expressed in most gastrointestinal, breast, and lung cancer cells. Overexpression of CEA is closely associated with liver metastasis, which is the main cause of death from colorectal cancer. CEA is widely used as a diagnostic and prognostic tumor marker in cancer patients. It affects many steps of liver metastasis from colorectal cancer cells. CEA inhibits circulating cancer cell death. CEA also binds to heterogeneous nuclear RNA binding protein M4 (hnRNP M4), a Kupffer cell receptor protein, and activates Kupffer cells to secrete various cytokines that change the microenvironments for the survival of colorectal cancer cells in the liver. CEA also activates cell adhesion-related molecules. The close correlation between CEA and cancer has spurred the exploration of many CEA-targeted approaches as anticancer therapeutics. Understanding the detailed functions and mechanisms of CEA in liver metastasis will provide great opportunities for the improvement of anticancer approaches against colorectal cancers. In this report, the roles of CEA in liver metastasis and CEA-targeting anticancer modalities are reviewed.
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Tobi M, Thomas P, Ezekwudo D. Avoiding hepatic metastasis naturally: Lessons from the cotton top tamarin (Saguinus oedipus). World J Gastroenterol 2016; 22:5479-94. [PMID: 27350726 PMCID: PMC4917608 DOI: 10.3748/wjg.v22.i24.5479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 04/26/2016] [Accepted: 05/21/2016] [Indexed: 02/06/2023] Open
Abstract
Much has been written about hepatic metastasis and animal models abound. In terms of the human experience, progress in treating this final common pathway, a terminal event of many human malignancies has been relatively slow. The current thinking is that primary prevention is best served by early detection of cancer and eradication of early stage cancers by screening. Some cancers spread early in their course and the role of screening may be limited. Until relatively recently there has not been a pathfinder model that makes the evasion of this unfortunate event a reality. This review discusses such an animal model and attempts to relate it to human disease in terms of intervention. Concrete proposals are also offered on how scientists may be able to intervene to prevent this deadly progression of the cancer process.
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A novel mixed integer programming for multi-biomarker panel identification by distinguishing malignant from benign colorectal tumors. Methods 2015; 83:3-17. [PMID: 25980368 DOI: 10.1016/j.ymeth.2015.05.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 05/07/2015] [Accepted: 05/08/2015] [Indexed: 01/20/2023] Open
Abstract
Multi-biomarker panels can capture the nonlinear synergy among biomarkers and they are important to aid in the early diagnosis and ultimately battle complex diseases. However, identification of these multi-biomarker panels from case and control data is challenging. For example, the exhaustive search method is computationally infeasible when the data dimension is high. Here, we propose a novel method, MILP_k, to identify serum-based multi-biomarker panel to distinguish colorectal cancers (CRC) from benign colorectal tumors. Specifically, the multi-biomarker panel detection problem is modeled by a mixed integer programming to maximize the classification accuracy. Then we measured the serum profiling data for 101 CRC patients and 95 benign patients. The 61 biomarkers were analyzed individually and further their combinations by our method. We discovered 4 biomarkers as the optimal small multi-biomarker panel, including known CRC biomarkers CEA and IL-10 as well as novel biomarkers IMA and NSE. This multi-biomarker panel obtains leave-one-out cross-validation (LOOCV) accuracy to 0.7857 by nearest centroid classifier. An independent test of this panel by support vector machine (SVM) with threefold cross validation gets an AUC 0.8438. This greatly improves the predictive accuracy by 20% over the single best biomarker. Further extension of this 4-biomarker panel to a larger 13-biomarker panel improves the LOOCV to 0.8673 with independent AUC 0.8437. Comparison with the exhaustive search method shows that our method dramatically reduces the searching time by 1000-fold. Experiments on the early cancer stage samples reveal two panel of biomarkers and show promising accuracy. The proposed method allows us to select the subset of biomarkers with best accuracy to distinguish case and control samples given the number of selected biomarkers. Both receiver operating characteristic curve and precision-recall curve show our method's consistent performance gain in accuracy. Our method also shows its advantage in capturing synergy among selected biomarkers. The multi-biomarker panel far outperforms the simple combination of best single features. Close investigation of the multi-biomarker panel illustrates that our method possesses the ability to remove redundancy and reveals complementary biomarker combinations. In addition, our method is efficient and can select multi-biomarker panel with more than 5 biomarkers, for which the exhaustive methods fail. In conclusion, we propose a promising model to improve the clinical data interpretability and to serve as a useful tool for other complex disease studies. Our small multi-biomarker panel, CEA, IL-10, IMA, and NSE, may provide insights on the disease status of colorectal diseases. The implementation of our method in MATLAB is available via the website: http://doc.aporc.org/wiki/MILP_k.
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Beauchemin N, Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 2013; 32:643-71. [DOI: 10.1007/s10555-013-9444-6] [Citation(s) in RCA: 288] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Orava EW, Abdul-Wahid A, Huang EHB, Mallick AI, Gariépy J. Blocking the attachment of cancer cells in vivo with DNA aptamers displaying anti-adhesive properties against the carcinoembryonic antigen. Mol Oncol 2013; 7:799-811. [PMID: 23656757 DOI: 10.1016/j.molonc.2013.03.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 03/27/2013] [Accepted: 03/31/2013] [Indexed: 01/28/2023] Open
Abstract
The formation of metastatic foci occurs through a series of cellular events, initiated by the attachment and aggregation of cancer cells leading to the establishment of micrometastases. We report the derivation of synthetic DNA aptamers bearing anti-adhesive properties directed at cancer cells expressing the carcinoembryonic antigen (CEA). Two DNA aptamers targeting the homotypic and heterotypic IgV-like binding domain of CEA were shown to block the cell adhesion properties of CEA, while not recognizing other IgV-like domains of CEACAM family members that share strong sequence and structural homologies. More importantly, the pre-treatment of CEA-expressing tumour cells with these aptamers prior to their intraperitoneal implantation resulted in the prevention of peritoneal tumour foci formation. Taken together, these results highlight the effectiveness of targeting the cell adhesion properties of cancer cells with aptamers in preventing tumour implantation.
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Affiliation(s)
- Erik W Orava
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
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15
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Dallas MR, Liu G, Chen WC, Thomas SN, Wirtz D, Huso DL, Konstantopoulos K. Divergent roles of CD44 and carcinoembryonic antigen in colon cancer metastasis. FASEB J 2012; 26:2648-56. [PMID: 22415308 DOI: 10.1096/fj.12-203786] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
After separating from a primary tumor, metastasizing cells enter the circulatory system and interact with host cells before lodging in secondary organs. Previous studies have implicated the surface glycoproteins CD44 and carcinoembryonic antigen (CEA) in adhesion, migration, and invasion, suggesting that they may influence metastatic progression. To elucidate the role of these multifunctional molecules while avoiding the potential drawbacks of ectopic expression or monoclonal antibody treatments, we silenced the expression of CD44 and/or CEA in LS174T colon carcinoma cells and analyzed their ability to metastasize in 2 independent mouse models. Quantitative PCR revealed that CD44 knockdown increased lung and liver metastasis >10-fold, while metastasis was decreased by >50% following CEA knockdown. These findings were corroborated by in vitro experiments assessing the metastatic potential of LS174T cells. Cell migration was decreased as a result of silencing CEA but was enhanced in CD44-knockdown cells. In addition, CD44 silencing promoted homotypic aggregation of LS147T cells, a phenotype that was reversed by additional CEA knockdown. Finally, CD44-knockdown cells exhibited greater mechanical compliance than control cells, a property that correlates with increased metastatic potential. Collectively, these data indicate that CEA, but not CD44, is a viable target for therapeutics aimed at curbing colon carcinoma metastasis.
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Affiliation(s)
- Matthew R Dallas
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
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Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver. Clin Exp Metastasis 2011; 28:923-32. [PMID: 21901530 DOI: 10.1007/s10585-011-9419-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 08/15/2011] [Indexed: 12/14/2022]
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17
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The liver prometastatic reaction of cancer patients: implications for microenvironment-dependent colon cancer gene regulation. CANCER MICROENVIRONMENT 2011; 4:163-80. [PMID: 21870094 DOI: 10.1007/s12307-011-0084-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 08/08/2011] [Indexed: 02/07/2023]
Abstract
Colon cancer frequently metastasizes to the liver but the genetic and phenotypic properties of specific cancer cells able to implant and grow in this organ have not yet been established. The contribution of the patient's genetic, physiologic and pathologic backgrounds to the incidence and development of hepatic colon cancer metastases is also presently misunderstood. At a transcriptional level, hepatic metastasis development is in part associated with marked changes in gene expression of colon cancer cells that may originate in the primary tumor. Other changes occur in the liver and are regulated by hepatic cells, which represent the new microenvironment for metastatic colon cancer cells. However, hepatic parenchymal and non-parenchymal cell functions are also affected by both tumor-derived factors and systemic host factors, which suggests that the hepatic metastasis microenvironment is a functional linkage between the hepatic pathophysiology of the colon cancer patient and the biology of its cancer cells. Therefore, together with metastasis-related gene profiles suggesting the existence of liver metastasis potential in primary tumors, new biomarkers of the prometastatic microenvironment supported by the liver reaction to colon cancer factors may be helpful for the individual assessment of hepatic metastasis risk in colon cancer patients. In addition, knowledge on hepatic metastasis gene regulation by the hepatic microenvironment may open multiple opportunities for therapeutic intervention during colon cancer metastasis at both subclinical and advanced stages.
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The Tumor Microenvironment at Different Stages of Hepatic Metastasis. LIVER METASTASIS: BIOLOGY AND CLINICAL MANAGEMENT 2011. [DOI: 10.1007/978-94-007-0292-9_3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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The prometastatic microenvironment of the liver. CANCER MICROENVIRONMENT 2008; 1:113-29. [PMID: 19308690 PMCID: PMC2654354 DOI: 10.1007/s12307-008-0011-6] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2008] [Accepted: 03/13/2008] [Indexed: 02/07/2023]
Abstract
The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients.
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Miles FL, Pruitt FL, van Golen KL, Cooper CR. Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis 2007; 25:305-24. [PMID: 17906932 DOI: 10.1007/s10585-007-9098-2] [Citation(s) in RCA: 176] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2007] [Accepted: 09/05/2007] [Indexed: 12/21/2022]
Abstract
In order for cancer cells to successfully colonize a metastatic site, they must detach from the primary tumor using extracellular matrix-degrading proteases, intravasate and survive in the circulation, evade the immune response, and extravasate the vasculature to invade the target tissue parenchyma, where metastatic foci are established. Though many of the steps of metastasis are widely studied, the precise cellular interactions and molecular alterations associated with extravasation are unknown, and further study is needed to elucidate the mechanisms inherent to this process. Studies of leukocytes localized to inflamed tissue during the immune response may be used to elucidate the process of cancer extravasation, since leukocyte diapedesis through the vasculature involves critical adhesive interactions with endothelial cells, and both leukocytes and cancer cells express similar surface receptors capable of binding endothelial adhesion molecules. Thus, leukocyte extravasation during the inflammatory response has provided a model for transendothelial migration (TEM) of cancer cells. Leukocyte extravasation is characterized by a process whereby rolling mediated by cytokine-activated endothelial selectins is followed by firmer adhesions with beta1 and beta2 integrin subunits to an activated endothelium and subsequent diapedesis, which most likely involves activation of Rho GTPases, regulators of cytoskeletal rearrangements and motility. It is controversial whether such selectin-mediated rolling is necessary for TEM of cancer cells. However, it has been established that similar stable adhesions between tumor and endothelial cells precede cancer cell transmigration through the endothelium. Additionally, there is support for the preferential attachment of tumor cells to the endothelium and, accordingly, site-specific metastasis of cancer cells. Rho GTPases are critical to TEM of cancer cells as well, and some progress has been made in understanding the specific roles of the Rho GTPase family, though much is still unknown. As the mechanisms of cancer TEM are elucidated, new approaches to study and target metastasis may be utilized and developed.
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Affiliation(s)
- Fayth L Miles
- Department of Biological Sciences, Center for Translational Cancer Research, University of Delaware, Newark, DE 19716, USA
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Aarons CB, Bajenova O, Andrews C, Heydrick S, Bushell KN, Reed KL, Thomas P, Becker JM, Stucchi AF. Carcinoembryonic antigen-stimulated THP-1 macrophages activate endothelial cells and increase cell–cell adhesion of colorectal cancer cells. Clin Exp Metastasis 2007; 24:201-9. [PMID: 17487559 DOI: 10.1007/s10585-007-9069-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2006] [Accepted: 03/12/2007] [Indexed: 12/11/2022]
Abstract
The liver is the most common site for metastasis by colorectal cancer, and numerous studies have shown a relationship between serum carcinoembryonic antigen (CEA) levels and metastasis to this site. CEA activates hepatic macrophages or Kupffer cells via binding to the CEA receptor (CEA-R), which results in the production of cytokines and the up-regulation of endothelial adhesion molecules, both of which are implicated in hepatic metastasis. Since tissue macrophages implicated in the metastatic process can often be difficult to isolate, the aim of this study was to develop an in vitro model system to study the complex mechanisms of CEA-induced macrophage activation and metastasis. Undifferentiated, human monocytic THP-1 (U-THP) cells were differentiated (D-THP) to macrophages by exposure to 200 ng/ml phorbol myristate acetate (PMA) for 18 h. Immunohistochemistry showed two CEA-R isoforms present in both U- and D-THP cells. The receptors were localized primarily to the nucleus in U-THP cells, while a significant cell-surface presence was observed following PMA-differentiation. Incubation of D-THP-1 cells with CEA resulted in a significant increase in tumor necrosis factor-alpha (TNF-alpha) release over 24 h compared to untreated D-THP-1 or U-THP controls confirming the functionality of these cell surface receptors. U-THP cells were unresponsive to CEA. Attachment of HT-29 cells to human umbilical vein endothelial cells significantly increased at 1 h after incubation with both recombinant TNF-alpha and conditioned media from CEA stimulated D-THP cells by six and eightfold, respectively. This study establishes an in vitro system utilizing a human macrophage cell line expressing functional CEA-Rs to study activation and signaling mechanisms of CEA that facilitate tumor cell attachment to activated endothelial cells. Utilization of this in vitro system may lead to a more complete understanding of the expression and function of CEA-R and facilitate the design of anti-CEA-R therapeutic modalities that may significantly diminish the metastatic potential of CEA overexpressing colorectal tumors.
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Affiliation(s)
- Cary B Aarons
- Department of Surgery, Boston University School of Medicine, Boston, MA 02118, USA.
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Matzaraki V, Alexandraki KI, Venetsanou K, Piperi C, Myrianthefs P, Malamos N, Giannakakis T, Karatzas S, Diamanti-Kandarakis E, Baltopoulos G. Evaluation of serum procalcitonin and interleukin-6 levels as markers of liver metastasis. Clin Biochem 2007; 40:336-42. [PMID: 17306245 DOI: 10.1016/j.clinbiochem.2006.10.027] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2006] [Revised: 09/15/2006] [Accepted: 10/12/2006] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Procalcitonin (PCT) and interleukin-6 (IL-6) are established markers of tissue inflammation and injury. The aim of the present study was to investigate the possible correlation of PCT and IL-6 with liver metastasis. DESIGN AND METHODS The study consisted of fifteen healthy controls (group A), twenty-one patients with solid tumors without metastases (group B), eleven patients with liver metastasis only (group C) and eleven patients with generalized metastatic disease (group D). RESULTS Serum PCT levels were significantly increased in group D compared to groups A (p<0.001) and B (p=0.004), but no difference was observed in PCT levels between groups C and B or C and D. IL-6 serum levels were markedly elevated in group C compared to group A (p<0.001) or to groups B (p<0.001) and D (p=0.02). A positive correlation was observed between PCT and IL-6 serum levels (r=0.357, p=0.019). CONCLUSIONS PCT levels are related to disease stage in cancer patients, whereas IL-6 concentration seems to be a more specific marker of liver metastasis.
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Affiliation(s)
- Vassiliki Matzaraki
- Athens University, School of Nursing ICU at KAT Hospital, 20 Velouhiou Str, Aharnes 136 71, Athens, Greece.
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Wang HH, Qiu H, Qi K, Orr FW. Current views concerning the influences of murine hepatic endothelial adhesive and cytotoxic properties on interactions between metastatic tumor cells and the liver. COMPARATIVE HEPATOLOGY 2005; 4:8. [PMID: 16336680 PMCID: PMC1334213 DOI: 10.1186/1476-5926-4-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2005] [Accepted: 12/09/2005] [Indexed: 02/07/2023]
Abstract
Substantial recent experimental evidence has demonstrated the existence of reciprocal interactions between the microvascular bed of a specific organ and intravascular metastatic tumor cells through expression of adhesion molecules and nitric oxide release, resulting in a significant impact upon metastatic outcomes. This review summarizes the current findings of adhesive and cytotoxic endothelial-tumor cell interactions in the liver, the inducibility, zonal distribution and sinusoidal structural influences on the hepatic endothelial regulatory functions, and the effects of these functions on the formation of liver cancer metastases. New insights into the traditional cancer metastatic cascade are also discussed.
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Affiliation(s)
- Hui Helen Wang
- Department of Health Sciences, Red River College and Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Hongming Qiu
- Department of Pathology, Health Sciences Center, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ke Qi
- Department of General Surgery, Nanshan Hospital, Shenzhen, Guangdong, China
| | - F William Orr
- Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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Jessup JM, Samara R, Battle P, Laguinge LM. Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway. Clin Exp Metastasis 2005; 21:709-17. [PMID: 16035616 DOI: 10.1007/s10585-004-7705-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Most circulating tumor cells die within 24 h of entering the hepatic microvasculature because their arrest initiates an ischemia-reperfusion (I/R) injury that is cytotoxic. Human colorectal carcinomas (CRC) produce the glycoprotein Carcinoembryonic Antigen (CEA) that increases experimental liver metastasis in nude mice. Since CEA induces release of IL-6 and IL-10, we hypothesized that CEA inhibits the I/R injury through a Kupffer cell-mediated cytokine-dependent pathway. We assessed cytokine effects in CRC co-cultured with liver and in vivo. Human CRC prelabeled with fluorescent dyes were incubated with a reoxygenated suspension of ischemic nude mouse liver fragments in a bioreactor. CEA, rhIL-6 or rhIL-10 were either administered to the donor mice prior to hepatic ischemia or during co-culture. Liver donors were athymic nude or iNOS, IL-6 or IL-10 knock out mice. Ischemic-reoxygenated liver kills Clone A CRC through production of nitric oxide (NO) and superoxide anion. Treatment of liver donors with CEA prior to hepatic ischemia inhibited this in vitro cytotoxicity through an IL-10 and Kupffer cell dependent pathway that inhibited NF-kappaB activation, NO production and iNOS upregulation. IL-10 but not IL-6 enhanced CRC survival in nude mouse liver in vivo. Thus, CEA enhanced metastasis by inducing IL-10 to inhibit iNOS upregulation in host liver.
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Affiliation(s)
- J Milburn Jessup
- Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
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