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Page 2 of 18 Borniger. J Cancer Metastasis Treat 2019;5:23 I http://dx.doi.org/10.20517/2394-4722.2018.107

Figure 1. A simplified schematic of reciprocal tumor-host interactions. Tumors promote aberrant physiology via alterations to the immune
system and secretion of metabolic “waste” which contributes to further inflammation and altered function of distal organs, including
the brain. Feedback from the brain (neural or humoral) can subsequently exacerbate tumor-associated immune and metabolic changes,
ultimately facilitating tumor growth, angiogenesis, metastasis, or cancer-associated co-morbidities

[1-5]
of poor prognoses and reduced quality of life . Tumors are capable of altering local macronutrient contents
that modulate infiltrating immune cell function resulting in aberrant inflammation. Additionally, they secrete
metabolic “waste”, which can promote inflammation and alter the function of distal organs and tissues such
as the liver and brain [6-10] . As evidence accumulates, we are learning that many of these cancer-associated
co-morbidities are (at least in part) due to deregulation of normal brain function by the cancer itself, cancer
treatment(s), or other factors.

Reciprocally, the host system can influence tumor growth and metastasis via immune, endocrine, and neural
pathways. For example, chronic stress, which results in dysregulation of glucocorticoid and adrenergic
signaling, exacerbates tumor growth and angiogenesis [11,12] . Additionally, chronic sleep fragmentation,
[13]
resulting in top-down impairments to the immune system, further promotes tumor growth . The objective
of this review is to provide an up-to-date overview of cancer as a systemic disease from a basic science
perspective [Figure 1]. Special focus will be given to subcortical neural populations that are sensitive to
signals arriving from peripheral tissues and the environment, as well as those that send long-range projections
to modulate immune or metabolic function, ultimately facilitating cancer growth and/or metastasis.
Through understanding these brain-tumor interactions, potential undescribed drug or lifestyle targets will
be uncovered. Additionally, these studies would open up space for existing therapies to be repurposed for
effective cancer treatment (as is the case with the anti-obesity drug Metformin [14,15] .

NEURAL CIRCUITRY DEREGULATED IN CANCER
Sleep disruption
Disruption of sleep and/or circadian rhythms in physiology and behavior are frequently observed in cancer
patients. Indeed, 35%-80% of cancer patients report poor sleep quality [16,17] , as compared to 29%-32% of
the general population [Table 1]. These problems may stem from the cancer itself, the stress or stigma
[18]