CD26/Dipeptidyl Peptidase IV in Context: the Different Roles of a Multifunctional Ectoenzyme in Malignant Transformation

C D26, the T cell activation molecule, is a 110-kD gly-coprotein that is also present on epithelial cells of various tissues, including the liver, kidney, and intestine. CD26 possesses a known dipeptidyl peptidase (DPP)IV activity in its extracellular domain (1). A paper by Wesley et al. in this issue indicates a possible role for CD26/DPPIV in suppressing malignant transformation of melanocytes to melanoma (2). The series of work by Houghton and colleagues , focusing on melanoma and melanocytes, has shown that loss of expression and its enzymatic activity of CD26/DPPIV occurs during malignant transformation of melanocytes into melanoma (3). The exact pathological role of its disappearance however, has been unclear. Wes-ley et al. now elegantly demonstrate that the inducible gene transduction of CD26 into melanoma cells reverses the malignant phenotype of the cells toward " benign " melano-cyte-like phenotype, characterized by loss of tumorigenicity, reappearance of anchorage-dependent growth, restoration of a block in differentiation, and serum dependence. They further show that mutant DPPIV lacking serine protease activity is also able to restore the serum dependence in mel-anoma cells. Finally, the recruitment of another serine pro-tease, fibroblast activation protein-␣ , may partly account for this reversal by mutant DPPIV. What is the mechanism of such biological behavior of CD26/DPPIV in melanocytes and melanoma? The authors suggest the possibility that CD26/DPPIV might degrade autocrine growth factors, which are yet unidentified and hence regulate (suppress) the growth of benign melano-cytes. These findings are quite impressive, as they present direct evidence that the loss of surface expression of CD26/ DPPIV plays a pivotal role in malignant transformation of melanocytes toward melanoma. Besides CD26/DPPIV, this serine protease family also consists of a group of membrane-associated enzymes (ec-topeptidases) including CD10/NEP, CD13/APN, and BP-1/6C3/APA, which are zinc metallopeptidases (4). The expression of these ectopeptidases, including CD26/DPPIV, and their roles in various malignancies are under intense investigation. Analogous to the loss of CD26/DPPIV in melanoma, the cell surface expression of CD10/NEP is lost during the development of androgen-independent prostate cancer from its androgen-dependent phenotype (5). Indeed, Shipp et al. (6) demonstrated that CD10/NEP inhibits the growth of small cell carcinoma (SCC) of the lung through the cleavage of bombesin-like peptides, which are autocrine growth factors for those cells. They further showed that expression levels of CD10/NEP in the SCC cells were reduced and that the growth of SCC was inhibited by CD10/NEP and potentiated by CD10/NEP inhibition. In …