Di Rosso María Emilia, Sterle Helena Andrea, Cremaschi Graciela Alicia, Genaro Ana María
Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Católica Argentina (UCA), Ciudad de Buenos Aires, Argentina.
Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Ciudad de Buenos Aires, Argentina.
Front Immunol. 2018 Jun 19;9:1341. doi: 10.3389/fimmu.2018.01341. eCollection 2018.
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.
临床数据和实验研究表明，心理社会因素与癌症预后之间存在关联。压力对免疫系统和肿瘤生物学的影响曾分别进行过分析。然而，关于压力对免疫系统与肿瘤生物学之间相互作用的影响，相关研究较少。此外，抗抑郁药已被用于癌症患者以缓解情绪障碍。尽管如此，关于它们对癌症预后的作用，存在相互矛盾的证据。在此背景下，我们研究了慢性应激对肿瘤进展的影响，同时考虑了其对免疫系统和肿瘤生物学的影响。此外，我们分析了选择性5-羟色胺再摄取抑制剂氟西汀和舍曲林在这些影响中的作用。为此，将接受或未接受慢性应激模型且接受或未接受氟西汀或舍曲林治疗的C57BL/6J小鼠皮下接种EL4细胞以形成实体瘤。我们的结果表明，慢性应激会导致肿瘤生长和肿瘤细胞扩散增加。对细胞周期调节蛋白的分析表明，应激诱导细胞周期蛋白A2、D1和D3的mRNA水平升高，细胞周期抑制剂p15、p16、p21、p27的mRNA水平降低，从而刺激细胞周期进程。此外，在应激动物的肿瘤中发现金属蛋白酶（MMP-2和MMP-9）的mRNA水平升高，金属蛋白酶抑制剂mRNA水平（TIMP 1、2和3）降低，迁移能力增强。此外，发现应激动物的抗肿瘤免疫反应显著降低。过继性淋巴细胞转移实验表明，应激动物免疫反应降低会影响肿瘤生长和肿瘤细胞的转移能力。最后，我们发现氟西汀或舍曲林治疗对癌症进展有重要的有益作用。我们的结果强调了免疫系统在应激情况下肿瘤进展中的关键作用。尽管不能排除应激和药物治疗对肿瘤生物学的直接影响，但氟西汀和舍曲林的有益作用似乎主要归因于抗肿瘤免疫反应的恢复。
