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Borniger. J Cancer Metastasis Treat 2019;5:23 I http://dx.doi.org/10.20517/2394-4722.2018.107 Page 11 of 18

Thaker, Sood & colleagues provided empirical evidence that psychological stress can facilitate tumor growth
in multiple animal models via its promotion of glucocorticoid and adrenergic signaling [12,93] . These studies
demonstrated that multiple ovarian cancer tumor cell lines (e.g., EG, SKOV3, 222, HeyA8…) enhance
invasiveness when exposed to norepinephrine and/or glucocorticoids (in part) via the upregulation of matrix
metalloproteinases (MMPs), critical regulators of angiogenesis and tissue remodeling. Blockade of adrenergic
signaling or inhibition of MMPs prevented elevations in cell invasiveness. In vivo experiments demonstrated
that chronic behavioral stress (restraint) increased tissue catecholamines, tumor growth, vascularization, and
invasiveness in an orthotopic mouse model of ovarian cancer. These effects were driven by adrenergic signaling
(through the b2-adrenoceptor), resulting in downstream cAMP-protein kinase A (PKA) pathway activation.
This subsequently promoted the transcription of vascular endothelial growth factor and the MMPs (-2 and -9).
These findings highlight adrenergic-receptor signaling as a potential target for reducing tumor angiogenesis and
growth. Indeed, perioperative cyclo-oxygenase 2 and beta-adrenergic blockade was shown to improve measures
[94]
of metastasis in breast cancer patients, offering a safe and effective adjuvant treatment strategy .
Energy balance and feeding
Disrupted energy balance resulting in enhanced capacity to sustain proliferative growth is a hallmark of
[9]
cancer . Indeed, one of the first major breakthroughs in cancer research was the discovery that tumor
cells are biased towards aerobic glycolysis rather than oxidative phosphorylation to produce energy (i.e., the
Warburg effect [95-97] ). Therefore, a common finding in malignant cancers is a strong upregulation of lactate
and catalytic enzymes required for lactate production from pyruvate (e.g., lactate dehydrogenase) [98-101] .
Lactate normally acts to aide in glucose sensing and food intake, where it is transported into the brain via
[102]
monocarboxylate transporters present on endothelial cells lining the blood-brain barrier . After entering the
brain, lactate is able to interact with neurons that normally promote food intake, such as those that produce
agouti-related peptide (AgRP) within the arcuate nucleus. Lactate’s mechanism of action on orexigenic cells
is via its effects on the adenosine monophosphate kinase/methylmalonyl CoA signaling pathway within the
hypothalamus [103] . Lactate alone, however, does not seem to be responsible for cancer-associated anorexia
[104]
(discussed below) .

Anorexia is a common phenomenon in cancer patients with weight loss, and even when patients attempt to
eat enough to compensate, they frequently cannot maintain a healthy weight. Although significant evidence
suggests that inflammatory signaling secondary to tumor growth or cancer-treatment associates with
[99]
anorexia, a specific neural population and mechanism governing this common problem is lacking . An
attractive candidate neural population that may underlie these traits (in part) is the calcitonin-gene-related-
peptide (CGRP) expressing population of cells in the parabrachial nucleus (PBN CGRP ). These cells powerfully
suppress appetite and promote the termination of feeding behavior [105,106] . CGRP neurons are activated by
upstream circuits that respond to cancer-associated signals, and are inhibited by those that promote feeding,
including hypothalamic AgRP/neuropeptide Y neurons [107] . These neurons are also sensitive to peripheral
[108]
noxious and painful stimuli, which are other aspects of cancer progression .
In a mouse model of Lewis lung carcinoma, Schwartz and colleagues investigated how peripheral tumors
modulate CGRP neural activity and their role in cancer-associated anorexia/cachexia [109] . CGRP neurons
were strongly activated in tumor-bearing mice compared with controls, a phenotype typically found after
ingestion of a large meal. This suggests that tumors activate cells normally responsible for meal termination
and cessation of feeding behavior. Using a cre-dependent tetanus toxin transgene, they demonstrated that
inactivation of these cells prevented cancer-associated anorexia/cachexia. Additionally, this manipulation
normalized the activity of neurons in circuits downstream from the PBN, namely the central amygdala (CeA)
and oval subnucleus of the bed nucleus of the stria terminalis (ovBNST), which may play additional roles in
cancer-associated behavioral phenotypes. To control the activity of PBN CGRP neurons with better temporal
precision, they used Gi-coupled DREADDs to transiently inhibit these neurons in anorexic/cachexic mice.
This manipulation was able to recapitulate the effects seen with their previous approach using tetanus toxin.