How cancer hijacks the body's homeostasis through the neuroendocrine system

Abstract

During oncogenesis, cancer not only escapes the body's regulatory mechanisms, but also gains the ability to affect local and systemic homeostasis. Specifically, tumors produce cytokines, immune mediators, classical neurotransmitters, hypothalamic and pituitary hormones, biogenic amines, melatonin, and glucocorticoids, as demonstrated in human and animal models of cancer. The tumor, through the release of these neurohormonal and immune mediators, can control the main neuroendocrine centers such as the hypothalamus, pituitary, adrenals, and thyroid to modulate body homeostasis through central regulatory axes. We hypothesize that the tumor-derived catecholamines, serotonin, melatonin, neuropeptides, and other neurotransmitters can affect body and brain functions. Bidirectional communication between local autonomic and sensory nerves and the tumor, with putative effects on the brain, is also envisioned. Overall, we propose that cancers can take control of the central neuroendocrine and immune systems to reset the body homeostasis in a mode favoring its expansion at the expense of the host.

Keywords: biogenic amines; hypothalamic–pituitary axis; melatonin; stress; survival; tumor progression.

Fig. 1.. How malignant tumors can hijack body homeostasis.

Malignant tumors can putatively affect body homeostasis through the production of neurohormonal modulators entering the circulation, neurotransmitters activating receptors on nerve ending, or through priming circulating immune cells to regulate other organ functions. For example, tumor-derived classical hypothalamic or related neuropeptides such as corticotropin releasing hormone (CRH), urocortins (URC), growth hormone releasing hormone (GHRH) or thyroid releasing hormone (TRH) may control the anterior pituitary gland via production of corresponding POMC-peptides, growth hormone (GH) and thyroid stimulating hormone (TSH). These will then affect body homeostasis directly through corresponding receptors or indirectly through activation of the adrenal glands, liver, or thyroid gland with the production of cortisol, IGF1/2 or thyroid hormones, respectively as proposed previously for various pathological conditions[26,37,73,74]. Tumors can also release biogenic amines, melatonin, acetylcholine or glucocorticoids (see Table 1) that could regulate body functions either directly or indirectly through actions on endocrine organs, brain, the parasympathetic and sympathetic systems, or through nerves reflexes. Additional regulatory elements relevant in this context are IL1, IL6 and TNFα[26,33,90] that would dysregulate the anterior pituitary or hypothalamus, or other brain centers when blood-brain-barrier (BBB) is disrupted. Figure 1 was created with BioRender.