On the origin of serum CD26 and its altered concentration in cancer patients

Abstract

Dipeptidyl peptidase IV (DPP-IV), assigned to the CD26 cluster, is expressed on epithelial cells and lymphocytes and is a multifunctional or pleiotropic protein. Its peptidase activity causes degradation of many biologically active peptides, e.g. some incretins secreted by the enteroendocrine system. DPP-IV has, therefore, become a novel therapeutic target for inhibitors that extend endogenously produced insulin half-life in diabetics, and several reviews have appeared in recent months concerning the clinical significance of CD26/DPP-IV. Biological fluids contain relatively high levels of soluble CD26 (sCD26). The physiological role of sCD26 and its relation, if any, to CD26 functions, remain poorly understood because whether the process for CD26 secretion and/or shedding from cell membranes is regulated or not is not known. Liver epithelium and lymphocytes are often cited as the most likely source of sCD26. It is important to establish which tissue or organ is the protein source as well as the circumstances that can provoke an abnormal presence/absence or altered levels in many diseases including cancer, so that sCD26 can be validated as a clinical marker or a therapeutic target. For example, we have previously reported low levels of sCD26 in the blood of colorectal cancer patients, which indicated the potential usefulness of the protein as a biomarker for this cancer in early diagnosis, monitoring and prognosis. Through this review, we envisage a role for sCD26 and the alteration of normal peptidase capacity (in clipping enteroendocrine or other peptides) in the complex crosstalk between the lymphoid lineage and, at least, some malignant tumours.

Fig. 1

Scheme of the cancer immunoediting model in which a hypothesis explaining the lower levels of sCD26 found in serum cancer patients is included. a The tumour microenvironment (or stroma, composed of epithelial and inflammatory cells, activated fibroblasts, ECM and blood vessels) plays a critical role in tumourigenesis. DPP-IV/CD26 and other DASH proteins play a not wholly known role in the process of tumour progression to malignancy in enzyme activity-dependent and -independent fashions, as reviewed in [2, 11, 14]. b According to the cancer immunoediting hypothesis, the escape of tumour variants, which will grow into clinical apparent tumours, develops from cellular and molecular mechanisms leading to immune tolerance. Tumour cells employ a plethora of mechanisms that may act in concert to directly evade effector T cells responses, such as negative costimulatory signals, apoptosis and impairment of the antigen presentation machinery. However, the dominant mechanism which renders T cells tolerant during tumour growth is to change the tumour microenvironment through secretion of many immunosuppressive mediators and absence of some inflammatory mediators. This network leads to: problems in tumour antigen processing by APCs, particularly DCs, and later presentation to T cells in secondary lymphoid organs; the inhibition of DC maturation and differentiation; and the recruitment of different regulatory populations (NKT cells, Tregs, subsets of myeloid and plasmacytoid DCs, and others) [174, 338]. c As consequence, effector T cells become anergic after tumour-specific Ag presentation. A huge amount of information supports T cells as a major source of circulating sCD26. Serum concentration of sCD26 is significantly lower in patients of some cancers (see text). Taking into account these facts, we propose that tumour-specific tolerant cells or a subset of regulatory cells may be responsible of sCD26 lower concentrations in cancer patients. This drop in sCD26 may have further consequences