CD26 expression determines lung metastasis in mutant F344 rats: involvement of NK cell function and soluble CD26

The association between CD26 expression, tumor cell adhesion, metastasis, and natural killer (NK) cell function was investigated in a CD26 mutant Fischer 344 (F344/DuCrj) substrain from Japanese breeders (F344JAP) in comparison with wild-type F344 substrains from US (F344/Crl) and Hannover (HAN; F344/Ztm) breeders. F344JAP rats lack the dipeptidyl peptidase IV activity of CD26 and show a reduced cell surface expression of the mutated CD26 glycoprotein. In vivo adhesion of vital dye-labeled MADB106 tumor cells, tumor colonization, CD26 enzymatic activity, and CD26 immunoreactivity in lungs and soluble CD26-like protein expression in serum were markedly reduced in F344JAP rats. These findings demonstrate that CD26 protein expression exerts a key role in lung metastasis. In addition, NK cell cytotoxicity against MADB106 cells was diminished in the mutant F344 substrain, suggesting that CD26 enzymatic activity sustains NK cytotoxicity. Interestingly, tumor cells lacked CD26 immunoreactivity in vitro, but displayed CD26 immunoreactivity in situ after in vivo inoculation as well as after incubation with rat serum, indicating that soluble CD26-like protein assembles in tumor cells during in vivo passage, which may interact with the process of tumor adhesion and metastasis. Overall, these findings indicate that altered expression and function of a single enzyme—the CD26 protein—can drastically change the outcome of metastatic disease.