*2.1. Inflammatory Cytokines in Cancer*

Cancer is repeatedly accompanied by depression and cognitive difficulties, the etiology of which remains largely unknown. It is conceivable that the mere realization of the disease might cause changes in mood or that mood problems arise from the toxic side effects of chemotherapy and radiation. On the other hand, tumors themselves might have biological effects on the function of the CNS. In some rodent models, tumor and non-tumor cells in the TME (e.g., leukocytes, fibroblasts, endothelial cells) secrete inflammatory mediators such as interleukin (IL)-1, tumor necrosis factor (TNF)-α, IL-6, IL-8, IFN-α, IL-10, IL-12, TGF-β, and CXCR4 [4,5]. The latter promote tumor development, and, in some cases, transduced, among other tissues, into the brain, leading to neuroinflammation, which, in turn, influences behavior [6]. For example, as shown in rats [7], tumors by themselves are enough to induce impairments in working memory and CNS inflammation, cause a chronic increase in blood cytokine levels and in the expression of brain cytokines, enhance negative or positive feedback on glucocorticoid production, and as a result, generate depressive-like behavior.

Using a large cohort of newly diagnosed breast cancer patients, Patel and colleagues investigated the presence of cancer-related symptoms prior to onset of treatment and the association between symptoms, including neurocognitive performance, and circulating pro-inflammatory cytokine levels [8]. Tumor-induced memory impairment was found to be accompanied by increased expression of hippocampal TNFα mRNA in the brain (though not upregulation in peripheral plasma TNFα). They report that higher plasma levels of a marker of TNFα production was associated with poorer verbal memory but not with impaired executive functioning or processing speed performance. They also found higher IL-1 receptor antagonist (IL-1ra) but not IL-6 levels. Their results suggest that elevated pro-inflammatory cytokines elicited by the underlying disease may be sufficient to induce impaired memory performance.

Several studies [9–11] showed that cancer patients suffer from a high prevalence of depression, anxiety, and cognitive disorders. The fact that these disorders are common among other populations afflicted with chronic inflammatory disease stimulated discussion of potential shared biological mechanisms of neuroinflammation and depressed mood to precede major changes resulting, later, in diagnosis of cancer [12]. Potentially, two mechanisms may be involved—cytokine-related or glucocorticoid responses-related. The relative contribution of the two has yet to be understood. The increase observed in behavioral despair in the absence of important, measurable disease behaviors, indicates a selective effect of tumors on affective behaviors [13]. Together, increases in the production of hippocampal cytokines and GR gene expression suggest that the hippocampus may be a neural substrate in which the endocrine and the inflammation-related cytokines merge to induce depressive behavior in chronic disease, in general, and in cancer, in particular [7]. According to Molfino et al. [14] inflammation and cytokines affect the CNS, and the interaction between inflammatory mediators and the CNS may occur at the periphery, and may play a role in the activation of host inflammatory response which may lead to

cancer development. At the periphery, tumor growth might be sensed by the vagal nerve, perhaps by sensing the release of the pro-inflammatory cytokines. Several studies [11,15,16] emphasized that the majority of the postulated mechanisms of mental comorbidities within the cancer context (and other chronic inflammatory diseases) logically focuses on neuroinflammatory pathways. Peripheral tumors and their microenvironment provide the source of various cytokines and, potentially, use neural and/or humoral signaling pathways similar to peripheral infection to gain access to the brain. In addition, Dantzer et al., and Quan and Banks [16,17] focused on models of acute illness. The canonical acute bacterial infection model, a single, sub-toxic i.p. injection of a lipopolysaccharide (LPS) component of the cell wall of the gram-negative bacteria *E. coli*, causes pro-inflammatory cytokine production in the peritoneal cavity. Then, through both neural and humoral signaling pathways, cytokine production rapidly ensues in the brain (hippocampus, hypothalamus, forebrain) and stimulates the production or activation of other inflammatory effectors (IDO, iNOS, Nf-kB, COX). Three other studies [18–20] mentioned that the role of these inflammatory markers in cytokine-induced behavioral changes are consistent with clinical research in depressed patients. In summary, they claim that LPS treatment elicits acute sickness behaviors (e.g., lethargy, social withdrawal, fever, anorexia) akin to "somatic" or "vegetative" symptoms of depression and subsequent affective-like behaviors including impaired learning and memory. Experimental manipulation of cytokines in these models (e.g., pharmacologic blockade, cytokine gene knockout) suggests that brain-production of cytokines is necessary and sufficient for subsequent behavioral changes. A recent study in rats bearing bone cancer [21] reported elevated levels of IL-1β, IL-6, and TNF-α and of their respective receptors in the rats' periaqueductal gray brain region. Prolonged microglia activation leads to the release of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, which initiates a pro-inflammatory cascade and subsequently contributes to neuronal damage and losses [22]. Interestingly, blockade of the receptors alleviated the cancer-induced hyperalgesia. This recent report corroborates the previous above-mentioned studies, but further research is still required to improve basic scientific understanding of how activation of pro-inflammatory cytokine networks by cancer cells may increase cancer-related symptoms, to guide clinical interventions.
