The proposed project has the primary goal of testing the hypothesis that ovarian tumors cause behavioral signs of depression. The secondary goal is to assess whether ovarian tumors mediate this depressive effect via tumor-secreted proinflammatory cytokines. Depression is commonly comorbid with cancer, with about one third of cancer patients reporting depression around the time of diagnosis and up to one fourth suffering from Major Depression. Additionally, several studies suggest that depression predisposes cancer patients to a worsened clinical outcome. It has been assumed that cancer patients become depressed in reaction to the psychological stress of cancer diagnosis. However, recent research suggests that the tumor itself may also be a cause of depression. Elevations in the proinflammatory cytokine cascade of tumor necrosis factor alpha (TNF-a), interleukin 1 (IL-1), and interleukin 6 (IL-6) are causally related to """"""""sickness behaviors,"""""""" which overlap with the signs and symptoms of depression, and these cytokines are produced by ovarian tumor microenvironments. Because limitations inherent in correlational research with human cancer patients preclude thorough investigation of a causal pathway between ovarian tumor and depression, we have defined two specific aims to test this pathway using a well- characterized, animal model of ovarian cancer.
Specific Aim 1 : Experimentally determine the extent to which depressive behaviors are a result of tumor burden.
Specific Aim 2 : Experimentally identify the proinflammatory cytokines that may account for depressive behaviors in the model. C57BL6 mice will be injected intraperitoneally with ID8 ovarian carcinoma cells or vehicle only and allowed to develop clinical tumor. Major Depression requires that a person demonstrate loss of interest in pleasure or depressed mood, which includes a sense of hopelessness. These criteria, referred to as anhedonia and behavioral despair in animal models of depression, will be assayed in mice using reliable and validated measures including sucrose preference tests, self-stimulation of reward areas in the brain, and the tail suspension test both before and after injection with carcinoma cells. The findings of this study will have great potential for translational application in pharmacological and behavioral interventions that treat the comorbidity of depression in patients with ovarian cancer. News of a cancer diagnosis can be traumatic to the patient and lead to depression, including the core symptoms of feeling hopeless and losing interest in activities the patient once found pleasurable. This research plans to examine another scenario, however, that the tumor itself is a contributor to these depressive symptoms, and that it accomplishes these effects by secreting certain physiological factors that are known to cause depression.
| Lamkin, Donald M; Lutgendorf, Susan K; Lubaroff, David et al. (2011) Cancer induces inflammation and depressive-like behavior in the mouse: modulation by social housing. Brain Behav Immun 25:555-64 |
