Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer

Abstract

Patients with cancer experience a host of behavioral alterations that include depression, fatigue, sleep disturbances, and cognitive dysfunction. These behavioral comorbidities are apparent throughout the process of diagnosis and treatment for cancer and can persist well into the survivorship period. There is a rich literature describing potential consequences of behavioral comorbidities in patients with cancer including impaired quality of life, reduced treatment adherence, and increased disease-related morbidity and mortality. Medical complications of cancer and its treatment such as anemia, thyroid dysfunction, and the neurotoxicity of cancer chemotherapeutic agents account in part for these behavioral changes. Nevertheless, recent advances in the neurosciences and immunology/oncology have revealed novel insights into additional pathophysiologic mechanisms that may significantly contribute to the development of cancer-related behavioral changes. Special attention has been focused on immunologic processes, specifically activation of innate immune inflammatory responses and their regulation by neuroendocrine pathways, which, in turn, influence CNS functions including neurotransmitter metabolism, neuropeptide function, sleep-wake cycles, regional brain activity, and, ultimately, behavior. Further understanding of these immunologic influences on the brain provides a novel conceptual framework for integrating the wide spectrum of behavioral alterations that occur in cancer patients and may reveal a more focused array of translational targets for therapeutic interventions and future research. Such developments warrant complementary advances in identification of cancer patients at risk as well as those currently suffering, including an increased emphasis on the status of behavior as a "sixth vital sign" to be assessed in all cancer patients throughout their disease encounter.

Figure 1. Neuroendocrine-Immune Mechanisms and Mediators of Behavioral Co-Morbidities in Patients with Cancer

Various aspects of being diagnosed with and treated for cancer activate inflammation through tissue damage/destruction and/or psychological stress. Cytokines of the innate immune response along with life style changes, pain and other consequences of cancer and its treatment alter the sleep-wake cycle, which in turn contributes to disruption of the neuroendocrine system, in particular, the hypothalamic-pituitary-adrenal (HPA) axis. Given the role of the HPA axis and glucocorticoids in regulating inflammatory responses, altered HPA axis function may disrupt glucocorticoid-mediated negative regulation of inflammation. Unrestrained inflammation and the associated increased release of proinflammatory cytokines, in turn, interacts with central nervous system (CNS) pathways that regulate behavior, leading to pathophysiologic changes that underlie depression, fatigue, impaired sleep and cognitive dysfunction.