title: Impact of inflammation-metaplasia-adenocarcinoma sequence and inflammatory microenvironment in esophageal carcinogenesis using surgical rat models.
abstract: OBJECTIVE
  Chronic inflammation has been demonstrated to correlate with tumor onset and progression. Tumor-associated macrophages (TAMs) play an important role in inflammatory tumor microenvironment. We hypothesized that an inflammatory microenvironment around TAMs may promote the development of esophageal carcinomas when induced by duodenal content reflux without carcinogens.
  
  
  METHODS
  A total gastrectomy followed by esophagojejunostomy was performed on rats in order to induce chronic duodenal content reflux esophagitis. The animals were sacrificed sequentially, at the 20th, 30th, 40th and 50th week after surgery, and their esophagi were examined. The primary antibodies against CD68, CD163, pStat3 and Foxp3 were used. Expression and localization of infiltrated cells was assessed by immunohistochemical analysis.
  
  
  RESULTS
  At 20-weeks' post-surgery, squamous proliferative hyperplasia (PHP) and Barrett's metaplasia (BM) were observed. Adenocarcinoma (ADC) associated with BM, and squamous cell carcinoma (SCC) were observed 30-50 weeks' post-surgery. Numerous CD68 and pStat3-positive cells were identified surrounding PHP and BM after 20 weeks, and around ADC and SCC after 30 weeks. Moderate infiltration of CD163-positive macrophages was seen with BM, ADC, and SCC after 30 weeks. However, very few Foxp3-positive cells were observed around ADC and SCC.
  
  
  CONCLUSIONS
  Macrophages infiltrate the esophagus and activate the pStat3 pathway in stromal cells and epithelium. M2 phenotype macrophages infiltrate following infiltration of M1 macrophage and contribute to tumor development through regulatory T cells (Tregs). The involvement of immune cells such as TAMs and Tregs in the inflammatory microenvironment promotes esophageal carcinogenesis.
authors: Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan, tomoharumiya@gmail.com.
authors: Tomoharu
authors: T
authors: Miyashita
authors: Hidehiro
authors: H
authors: Tajima
authors: Furhawn A
authors: FA
authors: Shah
authors: Masanobu
authors: M
authors: Oshima
authors: Isamu
authors: I
authors: Makino
authors: Hisatoshi
authors: H
authors: Nakagawara
authors: Hirohisa
authors: H
authors: Kitagawa
authors: Takashi
authors: T
authors: Fujimura
authors: John W
authors: JW
authors: Harmon
authors: Tetsuo
authors: T
authors: Ohta
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000473:pathology*; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001471:Barrett Esophagus / Q000473:pathology; D063646:Carcinogenesis / Q000737:chemistry / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000473:pathology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000737:chemistry; D004938:Esophageal Neoplasms / Q000737:chemistry / Q000473:pathology*; D004942:Esophagitis, Peptic / Q000473:pathology*; D004947:Esophagus / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D005743:Gastrectomy; D007249:Inflammation / Q000473:pathology*; D008264:Macrophages / Q000737:chemistry; D008297:Male; D008679:Metaplasia; D010766:Phosphorylation; D051381:Rats; D011956:Receptors, Cell Surface / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000737:chemistry; D050378:T-Lymphocytes, Regulatory; D059016:Tumor Microenvironment; D000098902:CD163 Antigen; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051858:Forkhead Transcription Factors; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor; D000098902:CD163 Antigen; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C500522:Foxp3 protein, rat; C494088:Stat3 protein, rat