Episodes of severe depression affect up to 5% of the general population and occur with a threefold higher frequency in patients with cancer. Effective drug therapy for depression is especially important for patients with cancer, where quality of life is often already compromised from the side effects of surgery, radiation, and chemotherapy. Disturbance of the hypothalamic-pituitary-adrenal axis with high cortisol levels and or resistance to dexamethasone suppression is the most and best documented biochemical feature of major depression.Under normal circumstances, adrenal steroids help to contain responses to stress, maintain stability within the organism, control a wide range of membrane and genomic effects on cells, including those of the immune system, and perform critical signaling roles within the brain. As long as steroid levels are contained, the beneficial effects predominate; however, when adrenal corticosteroid levels are persistently elevated, then a series of events begins in which neural and peripheral systems start to show abnormalities resulting from excess exposure to corticosteroids. Then various types of pathology may ensue, such as depression or certain autoimmune diseases. A persistently elevated concentrations of glucocorticoids result in down-regulation of glucocorticoid receptors leading to glucocorticoid hypersecretion. In the immune system, glucocorticoids inhibit the cascade of immune and inflammatory responses at multiple levels, both directly via an action on immunocompetent cells, and indirectly via effects on leukocyte migration.A healthy cell has a well-defined shape and fits neatly within the ordered array of cells surrounding it. It responds to the instructions imposed by its environment, giving rise to healthy daughter cells solely when the balance of stimulatory and inhibitory signals from the outside favors normal cell division. Defective glucocorticoid feedback inhibition resulting in persistent glucocorticoid hypersecretion then might provoke aberrant immunosuppressive effects. Consequently, the complex dynamic equilibrium needed for normal cell growth and division is threatened and subsequently, might put the organism at risk for the development of opportunistic diseases such as cancer, when presented with a carcinogenic event.Recently a transgenic animal model dealing with the neuroendocrine aspects of depression has been developed, and is characterized by partial knockout of GR gene expression, caused by GR antisense RNA expression (Pepin et al. 1992, Nature 355:725). These transgenic mice display a hyperactive hypothalamic-pituitary adrenal (HPA) axis and dysfunctional glucocorticoid inhibitory feedback similar to that seen in 60% of depressed patients. Based on the fact that glucocorticoids affect the immune system and that both depression as well as immunosuppression play a potential important role in the onset and progress of cancer, the hypothesis was tested that disruption of GR gene expression, accompanied by alterations in immune functioning, may result in enhanced susceptibility to chemically induced tumorigenesis. Adult female transgenic mice and intact controls were injected s.c. with the chemical carcinogen 9, 10 dimethylbenzanthracene (DMBA, 50 mg/kg) or with the vehicle (DMSO).DMBA-induced tumorigenesis. Transgenic mice treated with DMBA displayed a significant higher incidence of tumor growth and development than control mice treated with DMBA. None of the mice treated with DMSO developed tumors. Furthermore, tumor appearance was accelerated in transgenic mice as compared to their counterpart controls. Tumor appearance was anticipated by two weeks. Twenty percent of the transgenic mice developed tumors within 7 days post DMBA injection. Tumor rate increased during the second week post treatment, to 50% and by the end of the third week, 73% of the transgenic mice had developed tumors. In contrast to the transgenic animals only 23% of the normal control animals developed tumors. Furthermore, tumor incidence correlated positively with altered immune responsiveness, as measured by lymphocyte cell number and lymphoproliferative assays.Cell number. Thymocyte and splenocyte numbers were assessed as a basis for any direct cytotoxic effects caused by DMBA or the level of circulating glucocorticoids. DMBA treated transgenic mice had a significant lower number of thymocytes than transgenic mice treated with the vehicle alone. Thymocyte number did not change between DMBA or vehicle treated controls. Furthermore, there was no significant difference between both normal control groups and the vehicle treated transgenic group. In the spleen, an other pattern could be observed. Cell numbers were significantly elevated in transgenic mice, both DMBA-treated as well as vehicle treated and the DMBA-treated control mice as compared to vehicle-treated controls. Among these three groups, splenocyte number did not differ.Lymphocyte proliferation. Thymocyte proliferation remained unchanged when stimulated with PHA. However, proliferation in basal RPMI conditions or in the presence of Con A or LPS was markedly reduced, up to two- or threefold, in DMBA-treated transgenic mice as compared to DMBA treated normal mice. Proliferative responsiveness of splenocytes was enhanced in DMBA treated transgenic mice when compared to controls treated with DMBA after stimulation with Con A and LPS but not in basal RPMI 1640 medium or when stimulated with PHA.These results indicate that suppression of the immune system enhances susceptibility to chemically-induced tumors, and that disruption of the glucocorticoid negative feedback loop and the HPA-immune axis can increase the risk of developing cancer if coincident with a carcinogenic event. Finally, as normalization of the hyperactive HPA system occurs during successful antidepressant treatment of depressive illness, the possibility will be discussed that treatment of these transgenic mice with an antidepressant such as desimipramine might restore general host defense mechanisms and consequently lower the susceptibility to develop opportunistic diseases such as cancer.