Significantly enhanced lung metastasis and reduced organ NK cell functions in dietinduced obese rats

Background: Obesity was identified as a major risk factor for malignant diseases, but underlying mechanisms remain unclear. Natural killer (NK) cells, a pivotal aspect of innate immunity, are capable of identifying and killing virally infected and tumor cells. Previous studies have shown altered NK cell functions in obesity, and the current study aimed to investigate the relationship between altered NK cell functions and increased cancer risk in obesity. Methods: To induce obesity male F344-rats received a high-fat diet (34% fat) or a control diet (4% fat). Thereafter, syngeneic mammary adenocarcinoma cells (MADB106) or a vehicle were intravenously (i.v.) injected. 15 min after injection, half of each group of rats were killed, lungs removed and immunohistochemically stained. Numbers of NK cells, MADB106 cells and NK cell-tumor cell interactions were quantified. Twenty-one days after tumor-cell injection the other half group of rats was killed and lung metastases were counted and relative mRNA concentrations of different NK cell receptors were determined. Results: After short-term MADB106-challenge, DIO fed animals showed significantly decreased NK cell numbers in the blood and NK cell-tumor cell interactions in the lung as compared to their control littermates. Twenty-one days after MADB106 injection, the lungs of the DIO fed rats showed significantly more lung metastases compared to control animals, accompanied by reduced relative mRNA concentrations of the activating NK cell receptor NKG2D. Conclusions: We conclude that induction of obesity in F344-rats leads to reduced lung NK cell function against tumor cells and results in significantly enhanced lung metastasis as compared to lean animals. It can be hypothesized that obesity-induced altered NK cell functions play an important role in cancer growth and metastasis.