Close Association of Intraepithelial Accumulation of M2-Skewed Macrophages with Neoplastic Epithelia of the Esophagus.

Tumor-associated macrophages (TAMs) are the most abundant cancer stromal cells and are directed by the tumor microenvironment to acquire trophic functions facilitating angiogenesis, matrix breakdown and cancer cell motility. TAMs have anti-inflammatory or alternatively activated (M2) phenotypes expressing CD204 and/or CD163. We previously reported that infiltration of a large number of CD204-positive TAMs are associated with angiogenesis, progression and poor disease-free survival of human esophageal squamous cell carcinomas (ESCCs). In this study, we investigated the initraepithelial distribution of TAMs in the early human esophageal carcinogenesis. We found that the numbers of CD68-, CD163- or CD204-positive macrophages within the unit length of 38 lesions of carcinoma in situ (CIS) excised by endoscopic mucosal dissection were significantly higher than those in the corresponding non-neoplastic squamous epithelia. Mapping of the infiltrating number of CD204-positive macrophages per 5 mm unit length within the whole epithelial area of 5 resected cancer laden esophagi demonstrated that the areas with high CD204-positive macrophage infiltration were significantly associated with CIS or squamous intraepithelial neoplasia. These results may suggest that macrophages with the M2-skewed phenotype have some biological roles in the early squamous carcinogenesis of the esophagus.