Beneficial Effect of Fluoxetine and Sertraline on Chronic Stress-Induced Tumor Growth and Cell Dissemination in a Mouse Model of Lymphoma: Crucial Role of Antitumor Immunity

DI ROSSO, MARÍA EMILIA; STERLE, HELENA ANDREA; CREMASCHI, GRACIELA ALICIA; GENARO, ANA MARÍA

Frontiers in Immunology

Frontiers

Lugar: Lausanne; Año: 2018 vol. 9

Clinical data and experimental studies have suggested a relationship between psychosocialfactors and cancer prognosis. Both, stress effects on the immune system and ontumor biology were analyzed independently. However, there are few studies regardingthe stress influence on the interplay between the immune system and tumor biology.Moreover, antidepressants have been used in patients with cancer to alleviate mooddisorders. Nevertheless, there is contradictory evidence about their action on cancerprognosis. In this context, we investigated the effect of chronic stress on tumor progressiontaking into account both its influence on the immune system and on tumor biology.Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetineand sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to achronic stress model and treated or not with fluoxetine or sertraline were subcutaneouslyinoculated with EL4 cells to develop solid tumors. Our results indicated that chronicstress leads to an increase in both tumor growth and tumor cell dissemination. Theanalysis of cell cycle regulatory proteins showed that stress induced an increase in themRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycleinhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augmentof mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors ofmetalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability werefound in tumors from stressed animals. In addition, a significant decrease of antitumorimmune response in animals under stress was found. Adoptive lymphoid cell transferexperiments indicated that the reduced immune response in stressed animals influencedboth the tumor growth and the metastatic capacity of tumor cells. Finally, we found animportant beneficious effect of fluoxetine or sertraline treatment on cancer progression.Our results emphasize the crucial role of the immune system in tumor progression understress situations. Although a direct effect of stress and drug treatment on tumor biologycould not be ruled out, the beneficial effect of fluoxetine and sertraline appears to bemainly due to a restoration of antitumor immune response.