A role for NK cells in greater susceptibility of young rats to metastatic formation

Cancer is the second leading cause of death in children (after accidents) and is more prevalent in the first 5 years of life than in the subsequent 10 years. Very young animals have been shown to be more susceptible to malignant growth and whether such increased susceptibility is attributable to reduced resistance of the host to tumor development or to increased incidence of cancerous cells is, as yet, unclear. In the current study, we used 36 day old male and female rats and adult rats to specifically study the role of natural killer (NK) cell activity, as well as hormones known to regulate their activity, in mediating reduced resistance to tumor metastasis at prepubescence. A mammary adenocarcinoma cell line (MADB106) syngeneic to the Fischer 344 rat was used. Following i.v. injection, MADBI06 tumor cells seed and colonize only in the lungs, a process shown in adult rats to be controlled by NK cells during the first 24 hours after tumor inoculation. As was found in our previous studies, young rats demonstrated a 10-fold higher percentage of lung tumor cell retention compared to adult rats. Importantly, this higher percentage of tumor cell retention was evident using the same number of tumor cells per kg of body weight in young and adult rats, and maintained even when young rats were challenged with 10- and 100- fold fewer MADBI06 cells per kg than adults. Selective depletion of NK cells markedly increased tumor cell retention in all rats, indicating that NK cells play a crucial role in resistance against MADBI06 retention in both young and adult rats. Employing in vitro assessment of whole blood NK cytotoxicity, young animals exhibited markedly less specific killing compared to the mature animals. Taken together, these findings indicate a reduced resistance of the young rats against MADB 106 retention that is mediated by diminished NK activity in these rats. Factors other than NK cells appear to play a minor role determining age differences in this model. Ageand sex-related differences in plasma β-endorphin and corticosterone levels were also found, suggesting different activation levels of the HPA axis. These differences, however, seem unlikely to underlie the reduced NK activity in young rats.