Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

Abstract

Cancer patients suffer high levels of affective and cognitive disturbances, which have been attributed to diagnosis-related distress, impairment of quality of life, and side effects of primary treatment. An inflammatory microenvironment is also a feature of the vast majority of solid tumors. However, the ability of tumor-associated biological processes to affect the central nervous system (CNS) has only recently been explored in the context of symptoms of depression and cognitive disturbances. In this review, we summarize the burgeoning evidence from rodent cancer models that solid tumors alter neurobiological pathways and subsequent behavioral processes with relevance to affective and cognitive disturbances reported in human cancer populations. We consider, in parallel, the evidence from human clinical cancer research demonstrating that affective and cognitive disturbances are common in some malignancies prior to diagnosis and treatment. We further consider the underlying neurobiological pathways, including altered neuroinflammation, tryptophan metabolism, prostaglandin synthesis and associated neuroanatomical changes, that are most strongly implicated in the rodent literature and supported by analogous evidence from human cancer populations. We focus on the implications of these findings for behavioral researchers and clinicians, with particular emphasis on methodological issues and areas of future research.

Depression in cancer: The many biobehavioral pathways driving tumor progression

“…There is also some accumulating evidence indicating that affective and somatic depressive symptoms may occur prior to the establishment of a cancer diagnosis 22,23 .…”

“…In keeping with this view, elevated concentrations of cytokines (e.g., IL-6 and TNF-α) have been associated with later cancer stages, poor differentiation and tumor size/volume across a variety of malignancies. Therefore, the detrimental prognostic impact of depression in comorbidity with cancer may be at least in part mediated by the activation inflammatory cascades 22 . For example, increased plasma levels of IL-6 were observed in association with depressive symptoms in individuals with advanced ovarian cancer as compared to subjects with tumors of low-grade malignant potential 27 .…”

“…A large body of preclinical data indicates that stress promotes inflammatory dysregulation and affect immune response in cancer models of depressive-like behavior 22 . These data were also confirmed in clinical settings.…”

“…Stress-induced processes can directly modulate these tumor hallmarks and a large body of preclinical and clinical evidence supports the role of inflammation as an essential factor for tumor growth and progression 1 . Pro-inflammatory cytokines are produced by tumor and stromal cells, as well as by tumor-associated macrophages and infiltrating T-cells, and play an important role in tumor angiogenesis, metastatic spread, and possibly resistance to therapy 22,33 . In addition, stress-related effects on angiogenesis may be regulated by neural control mechanisms.…”

Euflammation Attenuates Central and Peripheral Inflammation and Cognitive Consequences of an Immune Challenge after Tumor Development

“…These cognitive impairments can persist as much as 20 years after cancer treatment [10] and significantly reduce quality of life [11] and employability [12]. While cancer treatments and stress contribute to mental health issues associated with cancer, pretreatment clinical findings and tumor models indicate that tumor biology also plays a significant role [13,14]. Cognitive issues are documented in the oral cancer population specifically [15,16], even prior to cancer treatments (chemotherapy, radiation) [17], indicating a causal role of tumor biology alone.…”