Relations between different coping strategies for social stress, tumor development and neuroendocrine and immune activity in male mice.

This study analyzes the effects of acute social stress and different coping strategies employed in response to it on the development of B16F10 melanoma pulmonary metastases, the activation of the HPA axis and the NKG2D receptor expression. To this end, male OF1 mice were subjected to 24h of social stress using the sensorial contact model. This model includes three 5-min sessions of direct social interaction with resident cagemates selected for consistent levels of aggression. Subjects' behavior was videotaped and assessed. Six days after the first social interaction (1st social stress), the animals were inoculated with tumor cells or vehicle, and six days later, both tumor-bearing and non tumor-bearing mice were subjected to a second 24h sensorial contact social stress session (2nd social stress). One hour after the 2nd social interaction, corticosterone levels and NKG2D receptor expression were determined. Lung metastatic foci numbers were determined 21 days after inoculation (15 days post-stress). Social stress increased the number of pulmonary metastases and the serum corticosterone level. A combination of cluster and discriminant analyses established the existence of two types of coping strategies: (1) a passive-reactive strategy characterized by subjects dedicating a greater percentage of time to submission, flee and avoidance behaviors; and (2) an active-proactive strategy, characterized by subjects dedicating a greater percentage of time to attack and non social exploration behaviors. Subjects belonging to the passive-reactive group were found to have a higher number of tumor foci, a higher level of corticosterone and a lower NKG2D receptor expression than subjects in the active-proactive group. These data indicate the relationship between different coping strategies for social stress and tumor development.

Social stress, coping strategies and tumor development in male mice: behavioral, neuroendocrine and immunological implications.

The relationships between acute social stress, immunological alterations and the development of pulmonary metastases of B16F10 melanoma were analyzed. In particular, the effects of different behavioral coping strategies on the development of the metastases were studied. Tumor bearing and tumor non-bearing mice were subjected for 24h to a sensory contact social stress model. This included two 5 min sessions of direct social interaction with their resident cagemates (which had been selected for consistent levels of aggression). The subjects' behavior was videotaped and assessed. Corticosterone, IL-2, IL-12 and splenic cell proliferation responses to Con-A were determined 1h and 3 days post-stress. Lung metastatic foci numbers were determined 21 days after inoculation (15 days post-stress). Social stress increased the number of pulmonary metastases and the serum level of corticosterone but decreased the splenic proliferative capacity. No direct relationship could be established between the development of the metastases and the assayed interleukin response. A combination of cluster and discriminant analyses established that there were three types of coping strategies. Subjects engaging in a strategy characterized by an absence of attack, low non-social exploration levels and high levels of defense, subordination and avoidance, developed most pulmonary metastases. Social stress effects on tumor development appear to depend on the subject's coping strategy in such situations (although one cannot rule out the possibility that differences in the development of the disease per se are responsible for the different behavioral patterns observed).

Evaluation of Depressive and Anxious Behavior with the Use of Propranolol in Melanoma-Bearing Mice

HIGHLIGHTS: Tumor progression and anxiety and depression behaviors under evaluation during propranolol use in murine melanoma. Evaluation of anxiety and depression through forced swimming behavior tests, elevated plus maze, open field and marble-burying test.

Abstract Melanoma, a severe form of skin cancer, has rapid growth and has been prone to behavioral disorders that worsen the patient's prognosis and survival. Among these psychic disorders can occur anxiety and depression, in addition to cognitive deficit. In order to try to elucidate the neuropsychological disorders that occur in melanoma, the objective of this study was to evaluate propranolol in tumor progression and in anxious and depressive behaviors in an animal model with melanoma. B16F10 cells were injected into C57BL6/J mice subsequently treated with propranolol at doses of 1.43 mg/kg and 5.71 mg/kg and evaluated for tumor growth and in open field, forced swimming, elevated plus maze and marble-burying test at initial time and consolidated tumor. As a result, the group treated with propranolol at a dose of 5.71 mg/kg showed less tumor growth. In the initial behavioral tests, melanoma altered the animals' motility, but anxious behavior was not detected. Depressive behavior was detected in the forced swimming test in the two doses of the treatment used. When taking time with consolidated tumor, there was a reduction in the locomotor activity of the animals in the open field test, impairing the analysis of anxious and depressive behavior. The data suggest that there was a reduction in the progression of melanoma, there was no anxious behavior in the animals, only the depressive behavior and the use of propranolol did not improve the evaluated behavior.

Effect of restraint stress on immune system and experimental B16 melanoma metastasis in aged mice.

An overnight restraint stress was given to young and old mice and its effect was examined in terms of the number and function of T cells and natural killer (NK) cells in spleen and patterns of lung metastasis of B16 melanoma cells. A great decrease was observed in the number and proliferative activity of splenic T cells in old mice after the stress. The decrease in young mice was rather temporary with a quick recovery. The number of NK cells in spleen was not different between young and old mice before giving the stress, but a significant decrease was observed in the old after the stress. NK activity was always much lower in old than in young throughout the experiment. The pattern of metastasis of B16 melanoma cells was different between young and old mice. Metastatic colonies in lungs were larger in number and bigger in size in young mice than in old mice. After the stress, the number increased and the size unchanged in old mice, while the size increased and the number remained unchanged in young mice. It was shown that the same restraint stress resulted in a more serious influence on the immune cells in old than in young mice and gave rise to a differential effect on the pattern of tumor metastasis between young and old mice.

Stress-behavior interactions in hamster tumor growth.

The aim of this study was to investigate the effects of a mechanical stressor and individual behavior differences (separately and in combination) on tumor development in the female Syrian hamster. Studies by other investigators have documented the tumor-enhancing effects of such mechanical stressors as rotational stress. Previous studies by our group found that both size of tumor and time to tumor detection were significantly related to a dimension we call "activation." Eighty 100-day old female Syrian hamsters were placed in circular plexiglas environments in groups of 10. Nineteen days after introduction to the cages, a stress condition was imposed on half the animals (four cages). This consisted of shaking each cage of animals three times a week for three 10-minute intervals. Each group's behavior was videotaped in multiple samples to document pre- and poststress behaviors. Twelve days after the stress condition was initiated, each animal was injected subcutaneously midback with one melanoma tumor fraction. Animals were palpated every three days to determine time to detection of tumor. The videotaped behavior samples were coded for behaviors associated with "activation," inactivity, and interaction. Factor analysis resulted in basically the same first factor of activation found in our previous studies. Hamsters in the nonstressed groups had a significantly longer time to tumor development than those in the stressed groups (22.5 days vs. 12.6 days, p less than 0.005). While no prestress behaviors were associated significantly with time to tumor detection, the poststress activation factor was significantly correlated with longer time to tumor development in the stressed group (r = .61, p less than 0.0001). These results suggest that while the stress condition is more powerful than prestress individual behaviors in affecting the outcome variable, stress appears to interact with the individual behaviors related to "activation" to mitigate the negative effects of stress on tumor growth.

Repeated restraint stress impairs the antitumor T cell response through its suppressive effect on Th1-type CD4+ T cells.

Stressful events suppress a broad spectrum of immunological responses. However, the effects of stress on the antitumor T cell response against syngeneic tumors have not yet been closely studied. In the present study, we investigated the effects of repeated restraint stress on the antitumor T cell response against syngeneic B16 melanoma. The stress, before and after immunization with tumor cells, decreased the potential of the spleen cells to turn into antitumor cytotoxic T lymphocytes (CTLs) after in vitro restimulation. In a cytokine assay, the stress significantly suppressed the tumor-specific CD4+ T cell-dependent IFN-gamma production of immunized spleen cells. The stress also decreased their spontaneous IL-2 production, but it apparently had no effect on IL-4 production. The in vitro addition of IL-2, however, restored the stress-induced inability of the spleen cells to turn into antitumor CTLs after in vitro restimulation, thus suggesting that stress has no definite effect on tumor-specific CD8+ T cells. Stress had no effect on the natural killer (NK) activity of the spleen cells, but did decrease their responsiveness to poly (I:C), an NK activity augmentator. In addition, stress did not influence primary tumor growth but did decrease the degree of protective immunity at rechallenge. On the other hand, stress elevated the serum level of corticosterone and, in addition, the in vivo administration of dexamethasone, a synthetic glucocorticoid, decreased the capacity of the immunized spleen cells to turn into antitumor CTLs after in vitro restimulation and to produce both IFN-gamma and IL-2 in a manner similar to that of mice burdened by stress. Moreover, stress decreased the potential of spleen cells to produce both IFN-gamma and IL-2 in response to anti-CD3 mAb. Overall, these findings provide evidence that stress significantly impairs the antitumor T cell responses through its suppressive effect on Th1-type CD4+ T cells.

Effects of daily or weekly thermal (footpad) stress upon manifestation of melanoma tumours.

A total of 48 C57 male and female mice received thermal stimulation to their footpads either daily, weekly, or never. After either two or three weeks of this treatment the mice were injected to discern if the initiation of carcinogenic cell proliferation during a stressful period would influence the rate of development of the tumour. The latency in days for the onset of a discernable node over the injection site was measured. A statistically significant interaction between the temporal pattern of treatments and sex explained about 25% of the variance in the latency of the appearance of tumours. Post hoc analysis showed the source of interaction involved the group that had not received the thermal stress. The results may suggest that either weekly or daily thermal stress may have reduced the females' resistance to tumorigenesis. However, this pattern and type of stress did not influence the first appearance of these skin tumours in the males.