The influence of natural killer cell dysfunction on the increased colon cancer incidence in obesity
04 June 2018 (online)
Natural killer (NK) cells are a major component of the antitumor immune response and are involved in controlling tumor progression and metastases. Previous studies showed altered NK cell functions in obese individuals. Obesity is associated with an increased risk for several types of cancer, like colon, kidney and breast cancer, but underlying mechanisms remained unclear. Therefore, our aim was to characterize the impact of an altered NK cell functionality on the increased colon cancer risk in obesity.
Cytotoxicity, expression of activating NK cell receptors and cytokine secretion of human NK cells co-incubated with human colon tumor cells was determined with or without the influence of the adipocytokine leptin in vitro. Moreover, in vivo experiments in normal weight and obese rats were performed. Colon cancer growth was induced in half of the animals by injection of azoxymethane (AOM). NK cell parameters in peripheral blood, spleen and liver as well as in colon tumor tissue were analyzed by real-time RT-PCR, FACS analyses and immunohistochemnistry. In addition, FACS analyses investigating functional NK cell parameters and different NK cell subset phenotypes in blood samples of normal weight and obese humans were performed.
In vitro investigations demonstrated a decreased cytokine secretion and cytotoxicity of human NK cells against colon tumor cells after NK cell preincubation with leptin. In addition, leptin incubation decreased the expression of activating NK cell receptors. In obese animals, the number of NK cells as well as the expression of activating NK cell receptors in spleen and liver was lower compared to the normal weight animals. This correlated with an increased quantity, size and weight of colon tumors after AOM-treatment in obese rats. Results of human studies revealed evidence for an altered NK cell phenotype and a shift in NK cell subpopulations in obese individuals.
The results showed that the impaired NK cell functionality may be one reason for the higher colon cancer risk in obesity.