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      Tumor-Associated Macrophages (TAMs) Form an Interconnected Cellular Supportive Network in Anaplastic Thyroid Carcinoma

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          Abstract

          Background

          A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC.

          Methodology/Principal Findings

          Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a “microglia-like” appearance on these cells which we termed “Ramified TAMs” (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells.

          Conclusion

          ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined.

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          Exploring the full spectrum of macrophage activation.

          David Mosser, Justin Edwards (2008)
          Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.
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            Free radicals and antioxidants in normal physiological functions and human disease.

            Marian Valko, Dieter Leibfritz, Jan Moncol … (2007)
            Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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              The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

              Karen Bedard, Karl-Heinz Krause (2007)
              For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX activity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.
              Article 0 comments Cited 828 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 21 July 2011
                Volume: 6
                Issue: 7
                Electronic Location Identifier: e22567
                Affiliations
                [1 ]Department of Biopathology, Institut Gustave Roussy, Villejuif, France
                [2 ]F.R.E. 2939, C.N.R.S., Villejuif, France
                [3 ]U.M.R. 8126, C.N.R.S., Villejuif, France
                [4 ]Unité 753, I.N.S.E.R.M., Villejuif, France
                [5 ]Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Villejuif, France
                Florida International University, United States of America
                Author notes

                Conceived and designed the experiments: BC CD. Performed the experiments: MT UW CPD. Analyzed the data: BC AAG SC MS CD. Contributed reagents/materials/analysis tools: BC MT JMB MS CD. Wrote the paper: BC MS CD.

                Article
                Publisher ID: PONE-D-10-05881
                DOI: 10.1371/journal.pone.0022567
                PMC ID: 3141071
                PubMed ID: 21811634
                SO-VID: b243b269-0aaf-4a22-86e9-604dd38f0dcb
                Copyright © Caillou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 2 December 2010
                Date accepted : 29 June 2011
                Page count
                Pages: 13
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Biochemistry
                Subject: Cytochemistry
                Subject: Immunocytochemistry
                Subject: Immunology
                Subject: Immunopathology
                Subject: Medicine
                Subject: Clinical Immunology
                Subject: Immune Cells
                Subject: Monocytes
                Subject: Immunologic Subspecialties
                Subject: Tumor Immunology
                Subject: Immunopathology
                Subject: Diagnostic Medicine
                Subject: Pathology
                Subject: Anatomical Pathology
                Subject: Cytopathology
                Subject: General Pathology
                Subject: Molecular Pathology
                Subject: Endocrinology
                Subject: Thyroid
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Tumor Physiology
                Subject: Cancer Detection and Diagnosis
                Subject: Cancer Risk Factors
                Subject: Cancer Treatment
                Subject: Cancers and Neoplasms

                ScienceOpen disciplines: Uncategorized
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