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Another research area that is rapidly growing in scope is that of brain-gut and gut-cancer interactions.
Changes in systemic microbial diversity can influence brain function, alter immune phenotypes, and dictate
subsequent cancer development or a tumor’s response to immunotherapy [110,111] . In a proof-of-principle
[112]
experiment, Lakritz et al. demonstrated that Helicobacter hepaticus, a pathogenic gut microbe, promotes
distal breast tumorigenesis in a neutrophil-dependent manner. Cancer-prone female mice (FVB-Tg(C3-1-
TAg)cJeg/JegJ) were infected with H. hepaticus (via gastric gavage) at 3 months of age, and then assessed for
subsequent mammary tumorigenesis. Mice infected with these bacteria developed significantly more tumors
than their counterpart controls that were not infected. Additionally, mammary intraepithelial neoplasias were
associated with strong neutrophil invasion (myeloperoxidase staining). Chronic depletion of neutrophils (via
anti-Ly6-G antibodies) prevented H. hepaticus-induced cancer development. These data suggest that host-
microbe interactions may drive cancer in distal tissues through an immune-mediated mechanism.

CONCLUSIONS AND IMPLICATIONS
Together, the studies discussed above aim to provide an understanding of the types of inputs the brain
receives, the signals it propagates, and the effects of these messages on tumor growth and metastasis.
Reciprocally, tumor-induced changes in physiology are relayed to the brain via endocrine, immune, or
neural signals that ultimately change the activity of discrete neural populations important for maintaining
homeostasis. Resolving the “conflict of interest” between cancer and the brain will undoubtedly lead to
improvements in patient quality of life and unlock a novel means for cancer treatment. A summary of these
findings from basic science are presented in Table 2.

In this vein, treatments targeting the circadian system (i.e., chronotherapy) have gained significant traction
in recent years [113,114] . These approaches leverage natural circadian rhythms in metabolism and detoxification
systems to schedule chemotherapy or radiotherapy to coincide with times of peak effectiveness with the lowest
potential for side-effects. Animal models have further demonstrated that this approach can effectively limit
hepatic toxicity and the inflammatory response to chemotherapeutics [115,116] . Artificially boosting circadian
[64]
rhythms (e.g., with nobiletin) adds an additional prospective anti-cancer strategy .
Alternatively, targeted stimulation of specific brain areas deregulated in cancer may help overcome resistance
to more traditional treatment strategies. As discussed above, stimulation of the dopaminergic ventral
[87]
tegmental area promotes tumor suppression via the sympathetic nervous system . If findings such as these
translate to humans, deep brain stimulation protocols could be adapted for adjuvant cancer treatment. For
example, deep brain stimulation of the subthalamic nuclei for Parkinson’s disease promotes sympathetic
activation in a safe and reversible manner [117,118] , a procedure that could be repurposed in the context of
advanced cancer. Alternatively, biobehavioral therapies can be designed to promote positive thinking
and rewarding experiences (to activate the dopaminergic system) to aide in cancer suppression. Indeed,
mindfulness meditation has been demonstrated to improve mood, reduce stress, and attenuate inflammation
[119]
in patients with breast cancer .

As cancer drastically alters energy balance, influencing the activity of specific brain nuclei regulating
metabolism and food intake (e.g., hypocretin, AgRP, POMC, CGRP neurons) represents a strategy to not only
improve quality of life, but limit energy availability to the cancer. Indeed, inhibition of aberrant hypocretin/
orexin signaling promotes sleep and attenuates tumor-induced metabolic abnormalities in a mouse model
[6]
of breast cancer . Repurposing drugs that modify food intake and energy balance (e.g., metformin) further
provides additional avenues for adjuvant cancer therapy. However, significant more research is needed to
understand both (1) how the brain influences cancer-associated immune populations and (2) how the tumor
communicates with the brain to deregulate homeostasis and health. Only then can we begin to manipulate
this cross-talk to facilitate cancer elimination.