*2.2. Cancer, Cytokines and Stress*

Psychosocial stress is highly prevalent in cancer patients and can increase neuroinflammation. Therefore, stress is considered a likely contributor to neurotoxic symptoms. According to Pyter, Brydon, and Woon [13,23,24], in newly diagnosed cancer patients, acute psychological stress is often elevated. Plausible causes are that patients undergo staging and other medical testing, make treatment decisions, cope with current or anticipated physical symptoms, and grapple with existential concerns, all considered to have a major role in neuroinflammation, a predictor of neurotoxic symptoms, both during and after treatment, which may not only affect performance on neurocognitive tests but may themselves activate pro-inflammatory pathways. Indeed, psychological stress may interact with inflammatory pathways to synergistically increase cognitive changes and other behavioral symptoms. Psychological stress may also have direct effects on the CNS, including decreased neurogenesis and hippocampal volume. The latter could be exacerbated by additional biological insults of cancer and its treatment.

The growing tumor is sensed by the brain via neural, humoral, and inflammatory input. These signals activate the behavioral and metabolic response to stress by activating microglial cells. In turn, microglial activation triggers and perpetuates neuroinflammation by the release of inflammatory mediators within hypothalamic areas. Experimental data suggest that neuroinflammation may contribute to tumor growth and aggressiveness by modulating the peripheral immune response through autonomic output [2].

In breast cancer survivors, Kesler et al. reported an association between lower left hippocampal volume (measured by MRI), higher levels of circulating TNF-α, and lower levels of IL-6 [25]. Similarly, Jenkins et al. reported higher soluble TNF receptor (sTNFR)- 2 and IL-6 levels associated with decreased gray matter volume in specific regions in eight breast cancer patients who underwent chemotherapy during the study [26].

Based on the above, it is tempting to suggest that some of the variance in human mood disorders is comparable to that in cancer, attributable to the effects of tumors by themselves on emotional states. These potential interactions between stress and physiological reactions to cancer warrant further research.
