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.

María Emilia Di Rosso,Ana María Genaro,Graciela Alicia Cremaschi,Helena Andrea Sterle

doi:10.3389/fimmu.2018.01341

Abstract

Clinical data and experimental studies have suggested a relationship between psychosocial factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progression taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer progression. Our results emphasize the crucial role of the immune system in tumor progression under stress situations. Although a direct effect of stress and drug treatment on tumor biology could not be ruled out, the beneficial effect of fluoxetine and sertraline appears to be mainly due to a restoration of antitumor immune response.

Highlights

Nowadays, stress affects thousands of people around the world
To investigate the effect of chronic stress on tumor growth, 5-week-stressed and control mice were subcutaneously inocu lated with EL4 syngeneic lymphoma cells to develop a solid tumor and tumor volume was determined every day
To ascertain if proteins involved in the regulation and prog ression of cell cycle could be altered in parallel with tumor growth, we evaluated the tumor mRNA expression of A2, D1, and D3 cyclins and their inhibitors p15/Ink4b, p16/Ink4a, p21/ Cip1, and p27/Kip1

Summary

Introduction

Stress affects thousands of people around the world. Stress is defined as a critical, real, or apparent, situation that rep resents a challenge for homeostasis. To restore this state, a coor dinated adaptive response is triggered. Stress mediators involve catecholamines and glucocorticoids (the characteristic neuroendocrine hormones of the stress response) and several other neurotransmitters, cytokines, and growth factors [1]. It is important to note that stress response is an essential survival mechanism, when it is prolonged over time, may affect endocrine, immunological, and behavioral function [1]. In par ticular, epidemiological studies indicate that chronic stress might constitute a risk factor for cancer onset and progression [2, 3]

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