Abstract 1835: Mechanisms of psychological stress on the adaptive immune system and disease progression in a novel double transgenic ovarian cancer mouse model
Authors: Flint Melanie S. , Budiu Raluca A. , Conrads Thomas P. , Vlad Anda M. 
Published: June 2012

It is estimated that 21,880 women will be diagnosed with ovarian cancer in 2010 with 13,850 patients dying of this disease. In addition, gynecologic cancer is one of the most stressful diseases because patients need to receive repeated chemotherapy treatments, and young patients in particular fear their impending loss of fertility. It is becoming increasingly apparent that the immune system plays a global role in cancer initiation and progression. We have previously defined a novel mechanism through which stress, via release of glucocorticoids and catecholamines, impacts the cellular actin cytoskeleton; a dynamic structure intimately involved in cell activation and migration in healthy mice. However, studies using disease-specific preclinical models are sorely needed to unravel molecular mechanisms underlying the stress response and cancer in disease pathogenesis. We hypothesize that psychological stress and stress hormones significantly impact T cell activation and trafficking which directly contribute to disease outcome. To determine if stress influences tumor initiation and progression we used a LSLS-KrasG12D/+PtenloxP/loxp conditional transgenic mouse model for endometrioid ovarian cancer. Four weeks post tumor induction via intrabursal Adcre injection, a group (n = 6) of mice were restrained for 1h, 3 times per week for four weeks. Non-restrained (control, n = 5) mice remained in their home cages in a noise-free environment for 1 h. Following the 4 week restraint stress protocol, mice were monitored for weight loss and for signs of tumor formation and ascites accumulation. All mice were sacrificed at 8 weeks and all primary (ovarian) and metastatic (peritoneal) tumors, regional (para-aortic) lymph nodes and spleens were harvested at necropsy. All tumors were histologically confirmed by H & E staining of injected ovaries. Contralateral (non-injected) ovaries were kept as controls. The spleens and regional lymph nodes were immune phenotyped using T cells markers for activation. We found that stress decreased overall mouse weight (control median 24.1g vs. stress median 22.5g) and observed that stressed mice demonstrated early onset and more confined to the ovary than non stressed mice. We also demonstrated that restraint stress resulted in decreased activation of CD3+cells isolated from the spleen and para-aortic lymph nodes. More specifically, there was a significant decrease in CD3+CD69+ (p = 0.006) in stressed mice and these changes were independent of the mouse tumor burden. These findings link the effect of stress on T cell immunity in mice with orthotopic de novo ovarian tumors and substantiate the use of the KrasPten mice as a suitable model for in vivo studying the stress-induced immune regulation in ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1835. doi:10.1158/1538-7445.AM2011-1835