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      Genetic and Pharmacological Targeting of CSF-1/CSF-1R Inhibits Tumor-Associated Macrophages and Impairs BRAF-Induced Thyroid Cancer Progression

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          Abstract

          Advanced human thyroid cancers are densely infiltrated with tumor-associated macrophages (TAMs) and this correlates with a poor prognosis. We used BRAF-induced papillary thyroid cancer (PTC) mouse models to examine the role of TAMs in PTC progression. Following conditional activation of BRAF V600E in murine thyroids there is an increased expression of the TAM chemoattractants Csf-1 and Ccl-2. This is followed by the development of PTCs that are densely infiltrated with TAMs that express Csf-1r and Ccr2. Targeting CCR2-expressing cells during BRAF-induction reduced TAM density and impaired PTC development. This strategy also induced smaller tumors, decreased proliferation and restored a thyroid follicular architecture in established PTCs. In PTCs from mice that lacked CSF-1 or that received a c-FMS/CSF-1R kinase inhibitor, TAM recruitment and PTC progression was impaired, recapitulating the effects of targeting CCR2-expressing cells. Our data demonstrate that TAMs are pro-tumorigenic in advanced PTCs and that they can be targeted pharmacologically, which may be potentially useful for patients with advanced thyroid cancers.

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          Most cited references 47

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          Mutations of the BRAF gene in human cancer.

          Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
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            Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.

            Mononuclear phagocytes are versatile cells that can express different functional programs in response to microenvironmental signals. Fully polarized M1 and M2 (or alternatively activated) macrophages are the extremes of a continuum of functional states. Macrophages that infiltrate tumor tissues are driven by tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
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              Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.

              Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                23 January 2013
                : 8
                : 1
                Affiliations
                [1 ]Human Oncology and Pathogenesis Program, Memorial-Sloan-Kettering Cancer Center, New York, New York, United States of America
                [2 ]Department of Medicine, Memorial-Sloan-Kettering Cancer Center, New York, New York, United States of America
                [3 ]Department of Infectious Diseases Service & Immunology Program, Memorial-Sloan-Kettering Cancer Center, New York, New York, United States of America
                [4 ]Department of Pathology, Memorial-Sloan-Kettering Cancer Center, New York, New York, United States of America
                [5 ]Department of Cancer Biology & Genetics, Memorial-Sloan-Kettering Cancer Center, New York, New York, United States of America
                Cardiff University, United Kingdom
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MR JAF. Performed the experiments: MR MG. Analyzed the data: MR MG RG JAK JAF. Contributed reagents/materials/analysis tools: TMH EP JAJ. Wrote the paper: MR JAF.

                Article
                PONE-D-12-29549
                10.1371/journal.pone.0054302
                3553126
                23372702

                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.

                Page count
                Pages: 10
                Funding
                This project has been funded, in part, by K08 CA133183 and American Thyroid Association THANC award (MR), K08 AI071998 (TMH), RO1 CA50706 and R01 CA72597 (JAF), the Lefkovsky Family Foundation and the Byrne fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Genetic Mutation
                Mutation Types
                Model Organisms
                Animal Models
                Mouse
                Medicine
                Endocrinology
                Thyroid
                Oncology
                Cancers and Neoplasms
                Endocrine Tumors
                Thyroid, Papillary Carcinoma
                Head and Neck Tumors
                Basic Cancer Research

                Uncategorized

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