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Canine cutaneous mast cell tumors (MCT) are among the most frequently observed tumors in small animals and are the most common skin tumors in dogs. Many attempts have been made to predict their biological behavior because this tumor entity occurs from relatively benign tumors with a good long-term prognosis to highly malignant tumors with short survival times. So far, the histological grade is the most independent predictive prognostic factor; however, underlying molecular mechanisms that contribute to the variable malignancy of these tumors are widely unknown so far. One important aspect is the identification of mutations in the proto-oncogene c-KIT which has been associated with higher histological tumor grade and also with a worse prognosis. However, only up to 17 % of canine MCT exhibit relevant c-KIT mutations and thus additional factors must contribute to MCT carcinogenesis.
In human mast cell diseases CD25, the α-subunit of the interleukin-2 receptor (IL-2R), has recently been defined as a minor diagnostic criterion for systemic mastocytosis (SM). The IL-2R is normally restricted to lymphoid immune cells but has also been described in several human tumors so far. Therefore the aim of the present study was to investigate the expression of the IL-2R and the ligand interleukin-2 (IL-2) in canine cutaneous MCT with regard to a potential influence on MCT development, MCT proliferation and the manifestation of a malignant phenotype. To this end the mRNA and protein expression of the three subunits of the IL-2R and the ligand IL-2 were analyzed in 90 canine cutaneous MCT and correlated with the histological grade and the c-KIT mutation status. Furthermore co-expression of CD25 and KIT was investigated in non-neoplastic resting and activated mast cells compared with canine MCT. Finally an immunohistochemistry based IL-2 linking assay was established to reveal a potential IL-2 binding capacity of IL-2R expressing neoplastic mast cells.
Canine neoplastic mast cells expressed both the IL-2R and IL-2 but the expression was negatively correlated with tumor grade and c-KIT mutation status. In contrast, non-neoplastic resting mast cells lacked CD25 expression while few activated mast cells exhibited the CD25 protein. Additionally, IL-2R expressing tumor cells were shown to be able to bind the ligand IL-2. In conclusion the IL-2R/IL-2 system seems to have an impact on canine cutaneous MCT since the complete receptor and the ligand are expressed by canine neoplastic mast cells. The decreased expression in dedifferentiated tumors, however, diminishes their potential as a malignancy marker but raises questions as to a potential influence in early MCT development, especially since CD25 was not present in non-neoplastic resting mast cells. The ability of neoplastic mast cells to bind the ligand IL-2 suggests a pro-proliferative IL-2R function, although the negative correlation between IL-2R expression and tumor grade questions a major role in MCT proliferation. In any case, the IL-2R expression of canine MCT cells should be taken into consideration when dealing with new forms of antitumor therapies. Especially the recently proposed intratumoral IL-2 application for canine MCT should be carefully applied and monitored, at least for lower grade tumors as shown by this study.