title: Follicular thyroid carcinoma but not adenoma recruits tumor-associated macrophages by releasing CCL15.
abstract: BACKGROUND
  The differential diagnosis of follicular thyroid carcinoma (FTC) and follicular adenoma (FA) before surgery is a clinical challenge. Many efforts have been made but most focusing on tumor cells, while the roles of tumor associated macrophages (TAMs) remained unclear in FTC. Here we analyzed the differences between TAMs in FTC and those in FA.
  
  
  METHODS
  We first analyzed the density of TAMs by CD68 immunostaining in 59 histologically confirmed FTCs and 47 FAs. Cytokines produced by FTC and FA were profiled using antibody array, and validated by quantitative PCR. Chemotaxis of monocyte THP-1 was induced by condition medium of FTC cell lines (FTC133 and WRO82-1) with and without anti-CCL15 neutralizing antibody. Finally, we analyzed CCL15 protein level in FTC and FA by immunohistochemistry.
  
  
  RESULTS
  The average density of CD68(+) cells was 9.5 ± 5.4/field in FTC, significantly higher than that in FA (4.9 ± 3.4/field, p < 0.001). Subsequently profiling showed that CCL15 was the most abundant chemokine in FTC compared with FA. CCL15 mRNA in FTC was 51.4-folds of that in FA. CM of FTC cell lines induced THP-1 cell chemotaxis by 33 ~ 77%, and anti-CCL15 neutralizing antibody reduced THP-1 cell migration in a dose-dependent manner. Moreover, we observed positive CCL15 immunostaining in 67.8% of FTCs compared with 23.4% of FAs.
  
  
  CONCLUSIONS
  Our study suggested FTC might induce TAMs infiltration by producing CCL15. Measurement of TAMs and CCL15 in follicular thyroid lesions may be applied clinically to differentiate FTC from FA pre-operation.
authors.affiliation: Shanghai Key Laboratoryfor Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin 2nd Road, Shanghai, 200025, P.R. China. huanggua724@126.com.
authors.forename: Feng-Jiao
authors.initials: FJ
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratoryfor Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin 2nd Road, Shanghai, 200025, P.R. China. zhouxy@sibs.ac.cn.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratoryfor Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin 2nd Road, Shanghai, 200025, P.R. China. lei.yelei@gmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P.R. China. xcf0222@163.com.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Fei
authors.affiliation: Shanghai Key Laboratoryfor Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin 2nd Road, Shanghai, 200025, P.R. China. shuwang999@hotmail.com.|Laboratory for Endocrine & Metabolic Diseases of Institute of Health Science, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 227 South Chongqing Road, Shanghai, 200025, P.R. China. shuwang999@hotmail.com.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratoryfor Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin 2nd Road, Shanghai, 200025, P.R. China. wqingw@hotmail.com.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratoryfor Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin 2nd Road, Shanghai, 200025, P.R. China. gning@sibs.ac.cn.|Laboratory for Endocrine & Metabolic Diseases of Institute of Health Science, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 227 South Chongqing Road, Shanghai, 200025, P.R. China. gning@sibs.ac.cn.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D044963:Biopsy, Fine-Needle; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D008297:Male; D057234:Preoperative Period; D012333:RNA, Messenger / Q000096:biosynthesis; D046888:Tissue Array Analysis
chemical_list: C108814:CCL15 protein, human; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger