Cellular localization of thrombomodulin in human epithelium and squamous malignancies

Thrombomodulin is a cell surface glycoprotein that functions as an anticoagulant. Although initially identified on endothelial cells, thrombomodulin is also expressed by other vascular cells, by mesothelial cells, and by epidermal keratinocytes. To determine whether thrombomodulin is expressed by epithelial cells in locations other than skin, we conducted a survey of thrombomodulin protein and mRNA in human epithelium. Thrombomodulin protein was detected by immunohistochemistry in all samples containing stratified squamous epithelium, including oral mucosa, larynx, esophagus, uterine ectocervix, and vagina. In these tissues, thrombomodulin staining localized to the suprabasal layer, with minimal staining observed in the basal or superficial layers of epithelium. Thrombomodulin was not detected in cuboidal, simple columnar, or pseudostratified columnar epithelium and was detected variably in transitional epithelium. Thrombomodulin staining was also observed in 21 of 26 cases of invasive squamous cell carcinoma and in several examples of squamous carcinoma-in-situ and squamous metaplasia. Expression of thrombomodulin mRNA was confirmed by in situ hybridization in both normal and malignant squamous epithelium. Full-length, functionally active thrombomodulin was demonstrated in cultured squamous epithelial cells. These data demonstrate that thrombomodulin expression correlates with the squamous phenotype and suggest that hemostasis is regulated by compartmentalization of procoagulant and anti-coagulant epithelial proteins.