Catecholamine, Indoleamine and Corticosteroid Responses in Mice Bearing Tumors

Abstract

The neurochemical and endocrine responses to inoculation of mice with the murine lymphoma cell line AW5E was studied. This cell line was chosen because it is NK cell lysis resistant and thus does not induce a normal immune response. Immune activation has long been known to be a potent stimulator of the hypothalamo-pituitary-adrenocortical (HPA) axis as well as brain catecholamine and indoleamine metabolism, involving increases in the brain concentrations of catabolites of norepinephrine (NE) and serotonin (5-HT), as well as free tryptophan. Mice injected intravenously with AW5E tumor cells exhibited small increases in plasma corticosterone and hypothalamic NE and 5-HT catabolites one day after injection. There were no significant changes after 6 or 8 days, but a sustained increase in hypothalamic NE and 5-HT metabolism appeared 10 days after injection. There were similar, but more limited changes in the brain stem and prefrontal cortex. On the last day tested (day 14), plasma corticosterone was slightly elevated, as were hypothalamic dopamine, NE and 5-HT catabolites and tryptophan. These results indicate that inoculation with AW5E tumor cells increases brain catecholamine and serotonin metabolism, the hypothalamus being the most sensitive region. The most marked increases occurred in the few days preceding death, and thus may be associated with the pathology of the tumor growth.

Effects of Social Stress on Immunomodulation and Tumor Development

“…Furthermore, a significant increase was found in the turnover of both 5HT and DA in inoculated animals, both control subjects and those exposed to social stress. These results coincide with the increase in the 5HT and DA activity found in the hypothalamus of mice after various days of inoculation with lymphoma tumor cells (Chuluyan et al, 2000). Although it has been found that an acute defeat experience may produce an increase in the serotonergic activity in different areas of the brain, including the hypothalamus (Blanchard et al, 1993), in our study, social stress only produced a significant increase in the DA content, with the turnover of this catecholamine remaining unchanged.…”

“…Some studies have observed changes in the brain neurotransmitters produced in mice bearing tumors, that have been associated with hyperammonemia and reduced food intake (Chance et al, 2003). Chuluyan et al (Chuluyan et al, 2000) found changes in the monoaminergic activity in different areas of the brain in mice inoculated with murine lymphoma cells, neoplasic line cells that do not induce an immune response. Few studies have focused on the behavioral and neurochemical effects produced by the activation of the immune system in situations of social stress.…”

Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

“…However, this detection appears to be dependent upon the type of tumor and the timing of the blood sampling relative to tumor growth, as elevations in circulating cytokines do not necessarily accompany elevations in tumor cytokines, brain cytokines, or behavioral changes in these models (Catalano et al, 2003; Pyter et al, 2009). Given the known interactions between the HPA axis and inflammatory responses, it is important to note that solid tumors either increase or have no effect on basal circulating corticosterone concentrations (Azpiroz et al, 2008; Bojková et al, 2011; Chuluyan et al, 2000; Pyter et al, 2009; Yang et al, 2014), decrease stressor-triggered corticosterone responses (Pyter et al, 2009), and increase glucocorticoid receptor expression in brain regions involved in the HPA axis negative feedback loop (Pyter et al, 2009) in some rodent models.…”

Distal Tumors Elicit Distinctive Gene Expression Changes in Mouse Brain, Different from Those Induced by Arthritis

“…We observed down-regulation of Gabarapl2, a protein involved in vesicle transport and axonal elongation in mammalian neurons [26] and ataxin-2, a protein associated with spinocerebellar ataxia type 2; it is of note that a subset of patients with parkinsonian phenotype responded to dopamine treatment suggesting a link between ataxin-2 and dopamine [39]. On the other hand, previous studies have shown both decreased dopaminergic activity and increase in DOPAC:DA ratio in the hypothalamus of mice injected with mammary tumor cells and lymphoma cells, respectively [11,40]. Moreover, administration of L-deprenyl that prevents breakdown of dopamine, inhibited mammary tumor growth suggesting that tumor development might be associated with decreased dopamine signaling [40].…”

“…For instance, injection of tumorigenic cells has been shown to activate neuroendocrinal axes [4], and mice bearing tumors showed enhanced norepinephrine and serotonin catabolism and increased tryptophan levels in the brain [11]. These few studies suggesting a potential link between tumor development and the CNS led us to hypothesize that the presence of "foreign" tumorigenic cells at a distal site could be a stimulus strong enough to be molecularly "sensed" by the brain, long before growing tumors become noticeable by conventional methods.…”