Neuropsychiatric manifestations of prostate cancer and its treatment: Biological mechanisms and psycho-oncology perspectives

Figure 1 Represents hypothalamic-pituitary-adrenal axis and sympathetic signalling in the context of prostate cancer cellular processes. Author-assembled schematic integrating hypothalamic-pituitary-adrenal axis activation, sympathetic/adrenergic signaling, cortisol-glucocorticoid receptor signaling and downstream prostate cancer (PCa)-associated responses. Direct evidence from PCa patients includes altered stress/cortisol profiles[18], associations of circulating interleukin-6 and tumor necrosis factor-α with disease extent and progression[73] and clinical evidence linking glucocorticoid receptor expression/signaling with antiandrogen resistance[74-76]. PCa preclinical/cellular evidence supports stress-induced β-adrenergic signaling, tumor growth, migration, and dissemination[13,77,78]. Asterisks indicate downstream links that have not been established as causal pathways in PCa patients and are supported predominantly by PCa cellular/preclinical studies or broader mechanistic cancer literature. CRH: Corticotropin releasing hormone; ACTH: Adrenocorticotropic hormone; NK: Natural killer; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; TGF: Transforming growth factor; ROS: Reactive oxygen species; AR: Androgen receptor; EMT: Epithelial-mesenchymal transition.

Figure 2 Depicts the brain-tumor communication through autonomic, hormonal, extracellular-vesicle, and inflammatory signaling in prostate cancer. Author-assembled schematic illustrating likely bidirectional communication pathways between the prostate tumor, systemic signalling and the brain. Published human data in prostate cancer (PCa) include observations of decreased medial prefrontal activation with a relationship between Medial P-F activation and connectivity and treatment with androgen deprivation therapy[70,92], as well as altered systemic inflammation and symptom burden during treatment[98], a pilot of neuroinflammation in androgen deprivation therapy recipients[42] and circulating PCa extracellular vesicle miRNAs, like miR-21-5p[99]. From PCa cell and animal studies come evidence that autonomic innervation regulates tumor function[78] and the role of exosomal miR-146a-5p signaling within the prostate tumor environment[100]. Asterisked neuroinflammatory links – including microglial activation, astrogliosis, and their relationship with behavioral or neural effects – have not been established in PCa patients and are extrapolated primarily from non-prostate-cancer tumor-bearing animal models[101,102]. The therapeutic implications shown are exploratory research directions rather than established psycho-oncology interventions; β-blocker evidence in PCa is observational rather than interventional[96]. CNS: Central nervous system; ADT: Androgen deprivation therapy; HPA: Hypothalamic-pituitary-adrenal; EVs: Extracellular vesicles; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; CCL2: Chemokine (C-C motif) ligand 2.