*2.5. The HPA Axis in Cancer in Relation with Inflammation*

Cortisol is released by the hypothalamic-pituitary-adrenal (HPA) axis in response to psychosocial stress. Preliminary evidence indicates that tumors can affect endocrine function [12]. Studies by Pyter et al. [13,35] showed that corticosterone (the primary glucocorticoid in most animals) levels are generally higher in tumor-bearing rodents than in tumor-free controls, and that the hormone's responsivity to stress is reduced in these animals. Moreover, they reported that growth rates of tumors can be predicted by the production of cytokines, from the constitutive HPA function and according to depressive behavior. The same group made similar observations in patients, although they might have been caused by a combination of psychosocial stress and the tumor. Bower reported a blunted cortisol response in breast cancer survivors along with enhanced inflammatory response to psychological stress [36].

Moderate change in the HPA axis has also been found in a variety of CNS-related disorders caused by tumors [37]. In parallel, tumor-bearing mice developed depressive-like behavior along with higher plasma levels of corticosterone, the stress-related hormone [38].

In summary, although the mechanism of the interaction between neuroinflammation, systemic inflammation, and tumor growth has not yet been unraveled in full, the relationship between neuroinflammation and cancer-related neuro-toxicities is well-established. Association between inflammatory markers and neuro-toxicities seems to exist even when inflammation is low. It cannot be ruled out that inflammation is only an important mediator in individuals with a genetic vulnerability for exaggerated inflammatory responses to internal (tumor, stress) and external (cancer therapy) stressors.
