Modulation of $\text{in situ}$ murine neuroblastoma tumor growth by the adrenergic nervous system: Differential response of clonal cell lines to chemical sympathectomy

Abstract

The $\text{in situ}$ growth characteristics of C-1300, NIE-115 and NS20Y murine neuroblastoma (MNB) tumor cell lines were compared in normal and sympathectomized A/J mice. Adrenergic nerve ablation was produced in neonatal mice by administration of 6-hydroxydopamine (6-OHDA) at a dose of 100 μg/gm body weight on post-natal days 4, 6, 8 and 10; controls received equivalent volumes of the vehicle solution (0.9% NaCl/0.1% Ascorbic Acid). All mice were inoculated subcutaneously with 10⁶ viable MNB cells four to six weeks after treatment with 6-OHDA or vehicle. The growth rates of tumors produced by the adrenergic MNB cell lines, C-1300 and N1E-115, were significantly lower in sympathectomized mice when compared to control animals. In contrast, tumors induced by the cholinergic MNB cell line, NS20Y, grew at similar rates in both sympathectomized and control mice. All tumors obtained from control and sympathectomized mice regardless of whether they derived from cell lines characterized as cholinergic (NS20Y) or adrenergic (C-1300, N1E-115), contained both norepinephrine and dopamine. Depletion of adrenergic neurotransmitter in A/J mice was induced by administration of reserpine (5–10 μg/kg/day) beginning 30 days prior to implantation of the C-1300 MNB cell line and continuing until sacrifice of the animal. The effect of this treatment on organ and tumor catecholamine concentrations was confirmed by high-pressure liquid chromatography. Splenic catecholamine levels in reserpine-treated animals were reduced to 20% of controls as compared to 9% in the neonatally-sympathectomized group. However, there was no discernible effect on C-1300 MNB tumor growth in the reserpine-treated animals. C-1300 MNB tumor concentrations of nor-epinephrine and dopamine were significantly lower in the reserpine-treated animals than in controls. The suppression of tumor growth by adrenergic nerve ablation is selective for specific MNB tumor cell lines. An anatomically intact sympathetic nervous system appears to exert a greater influence than competency of adrenergic neuro-humoral transmission on MNB tumor growth. These data support the hypothesis that modulation of MNB tumor growth by the adrenergic nervous system is not mediated via catecholamines but may be modulated by endogenous growth factor(s).