Natural Killer Cell Activity and Resistance to Tumor Metastasis in Prepubescent Rats: Deficient Baselines, but Invulnerability to Stress and β-Adrenergic Stimulation

Abstract

Although young children and animals exhibit high rates of tumor development, little is known about natural killer (NK) cell activity in the very young. We recently provided direct evidence that reduced levels of NK activity in prepubescent rats underlie higher levels of susceptibility to metastasis. The aim of the current study was to further characterize NK activity and tumor resistance in prepubescent rats, specifically with respect to the effects of stress and sex, as these factors have been shown to modulate tumor development in adult populations. Two NK outcomes were assessed: levels of whole blood NK cytotoxicity and lung tumor retention of NK-sensitive MADB106 tumor cells which metastasize only to the lungs. The corticosterone (CS) response to surgery was also assessed. In the first set of experiments, prepubescent males and females (36 days of age) and mature males (98 days) were subjected to abdominal surgery and 5 h later were either tested for plasma CS levels or challenged with MADB106 tumor cells. The findings indicated that whereas surgery increased CS levels in the young rats to similar levels observed in mature animals, surgical stress did not increase lung tumor retention in the young animals, despite exerting marked and significant effects in the mature rats. These findings persisted when lower tumor loads were used in the young rats to compensate for the markedly reduced resistance to metastasis in this population. Because surgery involves activation of the sympathetic nervous system (SNS) which is known to regulate NK activity, we assessed the impact of the β-adrenergic agonist, metaproterenol, on NK activity and on lung tumor retention. Metaproterenol (0.8 mg/kg, 1 h before testing) resulted in a large suppression of NK activity and resistance against MADB106 metastasis in mature males and females, but not in prepubescent animals. In mature, but not in young animals, males exhibited higher baseline levels of NK activity. Taken together, these findings indicate that NK cells of prepubescent rats are resistant to β-adrenergic stimulation, and suggest that prepubescent rats are markedly less responsive to SNS-induced suppression of NK activity, which may underlie their invulnerability to the effects of surgery on MADB106 metastasis.