The low affinity neurotrophin receptor p75 positive stem cells are the initial target cell population for esophageal squamous cell carcinogenesis

Proc Amer Assoc Cancer Res, Volume 45, 2004 2783 Introduction: The multistage progressive process of carcinogenesis is associated with the accumulation of specific genetic alterations in the target cell population. Thus identification of the initial target cells and precise investigations about relationship between genetic events and altered behavior is necessary to develop novel therapies for early lesions. We have previously defined the human esophageal keratinocyte differentiation lineage using differentially expressed cell surface molecules and demonstrated that human esophageal keratinocyte stem cells are characterized by the expression of the low affinity neurotrophin receptor p75NTR in vitro (Oncogene 2003). In this study, we elucidated from which cell subset the squamous cell carcinoma arise in human esophageal epithelium. Methods: From 38 patients with primary esophageal squamous cell carcinoma who underwent esophageal resection in our department, 38 normal epithelia, 20 low-grade intraepithelial neoplasia (LGN), 27 high-grade intraepithelial neoplasia(HGN) and 9 squamous cell carcinoma (SCC) lesions in which neoplastic epithelium was observed to just invade into the muscularis mucosae were selected. Serial sections were cut from each lesion and immunohistochemistry were performed to detect expression of differentiation marker molecules such as p75NTR, beta 4 integrin and beta 1 integrin. In addition, ki67 immuno-reactivity, expression of wild type and mutant type p53 protein were immunohistochemcally detected. Results: We firstly demonstrated the esophageal epithelial differentiation lineage in normal epithelium. Stem cells were defined as p75NTR positive, beta 4 integrin positive, beta 1 integrin negative cells in the interpapillary basal layer (IBL). The most upstream TA cells were defined as p75NTR diminishing, beta4 integrin positive, beta1 integrin positive cells in the papillary basal layer (PBL), followed by the next stage TA cells they were defined as p75NTR negative, beta 4 integrin positive, beta1 integrin negative cells in the suprabasal layer. Then we showed that the p75NTR positive cells remained in the IBL during the multistage process of carcinogenesis while other marker expressions became varied. And the initial genetic alterations such as p53 gene mutation and p53 protein accumulation occurred from the p75NTR positive cell population at LGN phase. Then we detected their mitotic alteration from resting state to actively dividing state along with their achievement of cellular atypia at progression of LGN to HGN. Conclusion: These data clearly demonstrated the important role of p75NTR positive IBL stem cells as the initial target cell population for esophageal squamous cell carcinogenesis, providing us with the target cells for precisely investigate novel molecular mechanisms involved in early stage of cancer development.