Multifunctional regulatory molecule, dipeptidyl peptidase IV plays an important role in tumorigenesis. Depending on the interaction with specific biomolecules, implicated in initiation, promotion and progression of cancer, and depending on the modulation of bioactive peptides according to the intensity of expression, DPPIV may exert tumor-suppressing activity, as well as completely opposite - tumor-promoting activity [2
In the initial steps of pathogenesis of melanoma the alterations in expression and activity of DPPIV might be significant: a) During malignant transformation of melanocytes into melanoma cells, down-regulation of DPPIV expression and later complete loss of expression occurs [13
]; b) DPPIV gene is localized in chromosome 2q24.2, interestingly this chromosome is altered in 35% of melanoma specimens, indicating that loss of DPPIV expression caused by deletion may be even related to progression of melanoma; c) Induction of normal levels of DPPIV expression in human melanoma cells transfected with gene coding for the DPPIV caused loss of characteristics of malignant cells and phenotype changes, suggesting the tumor – suppressing properties of DPPIV [17
]; d) Results from one study showed decline in an invasive potential of melanoma cell lines in which DPPIV was reexpressed at levels similar to those in non-transformed melanocytes [15
]; e) Additionally, DPPIV was identified as one of the potential markers for distinction between benign deep penetrating nevi and melanoma [16
Due to its role in regulation of immune, inflammatory and neuroendocrine processes, disturbances in serum DPPIV activity and/or expression are related to different pathophysiological conditions [2
]. For example, lower activity of DPPIV in serum is found in patients with diabetes mellitus, hypertension associated with angioedema induced by angiotensin-converting enzyme treatment, in disorders such as anxiety and depression, in patients with autoimmune diseases and different immune-mediated disorders, including rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease. On the other hand, increase in DPPIV serum activity is related to liver disorders, osteoporosis, infectious diseases and anorexia and bulimia. All mentioned details concerning the complexity of DPPIV should be taken into account for better understanding of its functions. Although it is suggested that activity of DPPIV in serum may decrease with age due to enhanced sialylation [2
], absence of significant age influence on serum DPPIV activity was documented as well [28
]. In the group of healthy control persons, no significant age-related differences in DPPIV serum activity were noticed; 3 out of 6 healthy controls who had decreased DPPIV activity were under the age of 30. It is important to note that significant differences between obtained reference values for serum DPPIV activity for healthy persons could be seen in the literature, depending on the experimental procedure and the number of examined subjects. Considering the cut-off values for DPPIV activity in serum, obtained by analyzing 40 healthy control people, our results are in agreement with some of the previously reported data, while at the same time are in contrast to higher or lower values presented in other research articles [2
] and references cited therein, [29
We report for the first time that there is a statistically significant decrease in the serum DPPIV activity, in the percentage of CD26+ overall white blood cells and in the lymphocyte percentage in patients with melanoma in comparison to healthy control people. Apparently, decrease in the mentioned parameters observed in the group of patients with melanoma is not dependent on the presence of metastatic disease, since differences in measured parameters were not statistically significant between the subgroup of melanoma patients without metastatic disease and the subgroup of patients with metastatic disease. Significant decline in serum DPPIV activity found in melanoma patients compared to healthy controls might indicate its possible role in development and progression of melanoma, but further research needs to be done in order to fully elucidate the cause and the importance of observed changes in DPPIV activity. However, alterations in DPPIV serum activity observed in the group of melanoma patients might be, at least to some extent, attributed to other individually specific physiological and pathophysiological processes.
Decreased percentage of lymphocytes found in 29 out of 64 examined patients with melanoma points to impaired immune functions, which may affect the course of this malignant disease. In this regard, one of the approaches in the treatment of different forms of cancer is immunotherapy, based on the use of immunomodulatory factors in order to enhance the antitumor immune response, and those agents may elevate level of DPPIV as well.
Changes in the DPPIV serum activity in patients with melanoma associated with decrease in the percentage of CD26+ white blood cells could be explained by significant decrease in the lymphocyte percentage, caused by tumor-specific immunosuppression or by alterations in lymphocytes homing induced by changes in chemokine gradients. Since cell surface CD26 associates with extracellular ADA, changes in CD26 expression on lymphocytes might, at least in some part, influence their overall number as a result of fact that ecto-ADA free lymphocytes are not capable to catalyze and inactivate potentially toxic adenosine to non-toxic inosine [1
]. However, one explanation to be investigated could be related to changes in the lymphocyte subsets, some richer than another in CD26 expression.