TY - JOUR
T1 - Impact of inflammation-metaplasia-adenocarcinoma sequence and inflammatory microenvironment in esophageal carcinogenesis using surgical rat models
AU - Miyashita, Tomoharu
AU - Tajima, Hidehiro
AU - Shah, Furhawn A.
AU - Oshima, Masanobu
AU - Makino, Isamu
AU - Nakagawara, Hisatoshi
AU - Kitagawa, Hirohisa
AU - Fujimura, Takashi
AU - Harmon, John W.
AU - Ohta, Tetsuo
N1 - Funding Information:
ACKNOWLEDGMENT This work was supported by the Japan Society for the Promotion of Sciences (JSPS) KAKENHI Grant number 25462016.
PY - 2014/6
Y1 - 2014/6
N2 - Background and Aims: 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. Animals and 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. Conclusion: 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.
AB - Background and Aims: 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. Animals and 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. Conclusion: 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.
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U2 - 10.1245/s10434-014-3537-5
DO - 10.1245/s10434-014-3537-5
M3 - Article
C2 - 24526548
AN - SCOPUS:84902131482
SN - 1068-9265
VL - 21
SP - 2012
EP - 2019
JO - Annals of surgical oncology
JF - Annals of surgical oncology
IS - 6
ER -