Sympathetic nervous system modulation of tumor metastases and host defense mechanisms

The sympathetic nervous system can signal cells of the immune system through release of norepinephrine (NE), and may thus modulate several aspects of immune reactivity. We have examined the consequences of chemical denervation using 6-hydroxydopamine (6-OHDA) on the response of BALB/c mice to tumor cell challenge. In this study, chemical axotomy prior to the intravenous (i.v.) injection of the alveolar carcinoma line 1 significantly increased the number of pulmonary metastases. In contrast, axotomy performed after i.v. injection of tumor cells had no effect on the number of lung metastases. Line 1 tumor cells have been reported to be susceptible to lysis by natural killer (NK) cells. To examine possible mechanisms through which prior axotomy leads to increased lung metastases, we tested the effects of axotomy on in vitro and in vivo NK cell activity. No differences in NK cell activity were found between 6-OHDA- and vehicle-treated mice. Line 1 tumor cell growth in vitro was unaffected by both 6-OHDA and NE, and the tumor cells do not express beta-adrenergic receptors. Priming mice with lethally irradiated line 1 cells significantly reduced the number of lung metastases following challenge with live tumor cells; axotomy did not alter this decrease in metastases associated with priming. In summary, chemical axotomy of mice prior to injection of alveolar carcinoma cells resulted in an increased number of pulmonary metastases that was not correlated with alterations in either NK cell cytotoxicity or the putative immunological consequences of in vivo priming.