title: Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biopathology, Institut Gustave Roussy, Villejuif, France. bercaillou@gmail.com
authors.forename: Bernard
authors.initials: B
authors.lastname: Caillou
authors.forename: Monique
authors.initials: M
authors.lastname: Talbot
authors.forename: Urbain
authors.initials: U
authors.lastname: Weyemi
authors.forename: Catherine
authors.initials: C
authors.lastname: Pioche-Durieu
authors.forename: Abir
authors.initials: A
authors.lastname: Al Ghuzlan
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Bidart
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.forename: Corinne
authors.initials: C
authors.lastname: Dupuy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape; D018031:Connexin 43 / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism / Q000648:ultrastructure; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D049268:Positron-Emission Tomography; D013194:Staining and Labeling; D013347:Subcellular Fractions / Q000378:metabolism; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology* / Q000648:ultrastructure; D014057:Tomography, X-Ray Computed
chemical_list: D017252:CD3 Complex; D018031:Connexin 43; D051272:Glucose Transporter Type 1; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; C495677:SLC2A1 protein, human; D019255:NADPH Oxidases; C086986:CYBA protein, human