Depression promotes lung carcinoma progression by regulating the tumor microenvironment in tumor-bearing models of C57BL/6J mice.

Psychological stress is a common etiology among patients with lung cancer and serves as a potential indication of poor prognosis and advanced cancer clinical stage. Evidence indicates that depression is positively correlated with the evolvement of lung carcinoma. Nevertheless, the mechanisms underlying the effects of mental disorder on lung cancer have not been considerably and systemically explored. We hypothesized that mental disorder may affect the adjustment of the tumor microenvironment and immune cells. We used the chronic unpredictable mild stress (CUMS) procedure to induce depressed mice models and established tumor-bearing models of C57BL/6 J mice. Results revealed that the worsening of lung cancer was notably hastened in the CUMS + tumor group. Notably, the expression of PD-L1 in tumor issues increased in the tumor microenvironment, accompanied with a decline in the levels of CD8. On the basis of the date of tumor migration, our results indicated that MMPs and VEGF significantly increased after CUMS + tumor treatment. Thus, we demonstrated that modulation of the tumor microenvironment is pivotal for depression-promoted lung cancer migration.

1,25(OH)2D3 mitigate cancer-related fatigue in tumor-bearing mice: Integrating network pharmacological analysis.

Cancer-related fatigue (CRF) is one of the most common and serious complications in cancer patients, which greatly reduces the quality of life. The mechanism induced fatigue may be diverse. In this study, we tried to investigate the effect of 1,25(OH)2D3, the active metabolite of vitamin D on CRF in Lewis lung cancer-bearing mice. Network pharmacological analysis, behavioral testing, western blotting, ELISA and flow cytometry were used. We found that there was an interaction between proteins related to the role of 1,25(OH)2D3 and CRF-related proteins. The results of animal model experiments showed that 1,25(OH)2D3 could mitigate the CRF behavior of tumor-bearing mice, and the treatment of 1,25(OH)2D3 reduced the levels of inflammatory factors, changed the tryptophan metabolism direction, and caused changes in immune cells. Collectively, 1,25(OH)2D3 might improve CRF in tumor-bearing mice by changing the direction of tryptophan metabolism and inflammatory factor levels. This study provided a possible solution for patients with clinical CRF.

Solid peripheral tumor leads to systemic inflammation, astrocyte activation and signs of behavioral despair in mice.

Prevalence of depression is higher in patients with cancer than in the general population. Sustained systemic inflammation has been associated with depressive behavior and it has been reported that depressed patients commonly display alterations in their immune system. We previously showed that cancer in mice induces a systemic environment that promotes neutrophil activation and leukocytosis. We thus hypothesized that the peripheral systemic response to a solid tumor leads to endothelial activation, which may promote inflammatory changes in the brain with behavioral consequences. Using the Lewis lung carcinoma (LLC) model, we show that tumor growth induces a progressive increase in peripheral inflammation as observed by elevated interleukin-6 (IL-6). In behavioral studies, tumor-bearing mice showed no sign of motor, coordination or short term working memory deficits as assessed by rotarod, balance-beam, and novel object recognition tests. However, there was an impairment in the grip strength test and interestingly, an anxious and despair-like phenotype in the elevated plus-maze, and tail suspension tests, respectively. Immunostaining of perfused brains revealed fibrin accumulation in the vasculature with some leakage into the parenchyma, a process known to activate endothelial cells. Taken together, our results suggest that the inflamed and prothrombotic systemic environment created by the growth of a peripherally-located solid tumor induces endothelial activation, accumulation of fibrin in the brain and astrocyte activation, perhaps leading to depressive-like behavior.

[The effect of psychoemotional state on Lewis lung carcinoma metastasis].

The effect of a depression-like status formed by chronic stress on development of Lewis lung carcinoma metastases in C57Bl/6J mice was investigated. Two types of acute stress (restraint and social stress) were used for comparison. The depression-like status was induced by eight-week exposure to repeated but unpredictable stressors (chronic mild stress model) and was assessed in the forced swim test. Tumor cells were inoculated an hour after the onset of social stressor or immediately after physical or chronic stressor impacts. The number of metastases was counted 17 days after the inoculation. The results indicate that chronic mild stress provokes the development of a depression-like state in mice and causes a twofold increase in the number of metastases in the lungs, while both types of acute stress have no such effects. Thus, a depression-like psychoemotional status of animals enhances the metastasis of Lewis lung carcinoma.

Effect of vasopressin V1b receptor antagonist, SSR149415, on anxiety-like behavior and Lewis lung carcinoma metastasis in mice.

AIM: To study the effect of new vasopressin V1b receptor antagonist, SSR149415, on anxiety-like behavior and Lewis lung carcinoma metastasis in the anxious adult male mice of C57Bl/6J strain. This type of receptors was thought to act as potential targets mediating the effect of negative psychoemotional state on tumor progression. METHODS: Anxiety-like psychoemotional state of the animals was produced using chronic social conflict model. Used behavioral tests were elevated plus-maze, social interaction test and open field test. Tumor cells were administrated on background of double or sixfold SSR149415 injections and the number of metastases in the lung were calculated 17 days later. RESULTS: SSR149415 reduced the anxiety-like behavior measured in the elevated plus-maze and social interaction tests and did not affect locomotor activity in the open field test. Double and sixfold administration of the compound to such mice before and after inoculation of the tumor cells produced no effect on the metastasis rate. CONCLUSION: vasopressin V1b receptor is involved in the mediation of anxious behavior of animals but is not involved in the mechanism underlying the influence of negative psychoemotional state on Lewis lung carcinoma metastasis.

Depressive-like psychoemotional state versus acute stresses enhances Lewis lung carcinoma metastasis in C57BL/6J mice.

AIM: The effect of a depression-like status formed by chronic stress on the development of Lewis lung carcinoma metastases in C57Bl/6J mice was investigated. Two types of acute stress (restraint and social stress) were used for comparison. METHODS: The depression-like status was induced by eight-week exposure to repeated but unpredictable stressors (chronic mild stress model) and was assessed in the forced swim test. Tumor cells were inoculated an hour after the onset of social stressor or immediately after physical or chronic stressor impacts. The number of metastases was counted 17 days after the inoculation. RESULTS: Chronic mild stress provokes the development of a depression-like state in mice and causes a twofold increase in the number of metastases in the lungs, while both types of acute stress have no such effects. CONCLUSION: Depressive-like psychoemotional state of animals enhances the metastasis of Lewis lung carcinoma.

Limiting effect of diazepam on Lewis Lung carcinoma metastasis in anxious male mice.

AIM: It has been shown previously that chronic social defeat stress produces development of strong anxiety and increases intensity of experimental metastasis in the losers in comparison with the winners and control mice. The question was: is it possible to decrease the number of metastases in the losers by chronic or acute diazepam treatment. MATERIALS AND METHODS: Sensory contact model was used for generating male mice with repeated experience of social victories or defeats in daily agonistic interactions. Tumor cells of Lewis Lung Carcinoma (LLC) were injected into the tail vein of animals after 10 days of agonistic interactions. Then mice were treated acutely or chronically (7 days) with diazepam (1 mg/kg, i. p). Number of metastases in the lung was calculated in 16 days after tumor cell transplantation. RESULTS: Diazepam decreased the number of LLC metastases in anxious losers, whereas in the winners and control mice, without anxiety state, diazepam was ineffective. CONCLUSION: Well-known anxiolytic diazepam may decrease intensity of metastasis in anxious mice.

The influence of psychoemotional status on metastasis of Lewis lung carcinoma and hepatocarcinoma-29 in mice of C57BL/6J and CBA/Lac strains.

AIM: To study the influence of psychoemotional status on the development of experimental lung metastases of strain-specific murine Lewis lung carcinoma in C57BL/6J mice and hepatocarcinoma-29 in CBA/Lac male mice. MATERIALS AND METHODS: Sensory contact model was used for generating animals with repeated experience of social victories or defeat in daily agonistic interactions. Tumor cells were injected into the tail vein after 20 days of aggressive confrontations and the number of metastases in the lung was calculated 16 days later. RESULTS: The experimental metastasis is shown to develop differently in mice with opposing social experience: the winners of both strains had significantly less metastases in the lung than the losers. CONCLUSION: The results obtained indicate that psychoemotional status affects Lewis lung carcinoma and hepatocarcinoma-29 metastasis in male mice.

Time-dependent effects of stressor application on metastasis of tumor cells in the lung and its regulation by an immunomodulator in mice.

The effects of the timing of stressor application on transplanted tumor cells and its possible regulation by an immunomodulator was investigated. Male C57 BL/6N mice were subjected to rotational stressor for 7 days relative to tumor cell inoculation: stressor after inoculation of Lewis lung cancer cells, stressor during inoculation and stressor before inoculation. Stressor application and tumor cell inoculation induced transient decreases in body weight, particularly in mice stressed after inoculation. The mice exposed to the stressor during inoculation or before inoculation showed significant increases in the number of metastatic foci relative to control mice. Early administration of an immunomodulator, PSK, significantly attenuated the increase of metastatic foci in stressed mice. The weights of thymus gland and spleen at 14 days after inoculation were similar in the three stressor groups and the control group. Application of the stressor reduced NK cell activity of the normal mice as well as tumor bearing mice. The lowest pre-inoculation NK cell activity was observed in mice stressed for 7 days beginning on the day of inoculation. The NK cell activity decreased in the tumor bearing mice which were stressed at the time of tumor inoculation. Decreased NK cell activity was reversed at day 14 after tumor inoculation. The mice exposed to the stressor after inoculation showed lowest level of NK cell activity relative to mice exposed to the stressor before or during inoculation. The treatment of mice with PSK reduced these changes significantly. The present results suggest that the rotational stress reduces splenic NK cell activity, which may influence the magnitude of tumor metastasis, depending on the time of tumor cell injection. Further, administration of an immunomodulator may counteract the reduction of the NK cell activity.