Is Neuronal Histamine Signaling Involved in Cancer Cachexia? Implications and Perspectives

Abstract

In this paper, we present evidence in support of our hypothesis that the neuronal histaminergic system might be involved in cancer cachexia. To build our premise, we present the research and the reasonable inferences that can be drawn from it in a section by section approach starting from one of the key issues related to cachexia, increased resting energy expenditure (REE), and progressing to the other, anorexia. Based on an extensive survey of the literature and our own deliberations on the abovementioned topics, we investigate whether histamine signaling might be the mechanism used by a tumor to hijack the body's thermogenic machinery. Our hypothesis in short is that hypothalamic histaminergic neurons are stimulated by inputs from the parasympathetic nervous system (PSNS), which senses tumor traits early in cancer development. Histamine release in the preoptic area of the hypothalamus primarily activates brown adipose tissue (BAT), triggering a highly energy demanding mechanism. Chronic activation of BAT, which, in this context, refers to intermittent and/or low grade activation by the sympathetic nervous system, leads to browning of white adipose tissue and further enhances thermogenic potential. Aberrant histamine signaling not only triggers energy-consuming processes, but also anorexia. Moreover, since functions such as taste, smell, and sleep are governed by discrete structures of the brain, which are targeted by distinct histaminergic neuron populations even relatively minor symptoms of cachexia, such as sleep disturbances and taste and smell distortions, also might be ascribed to aberrant histamine signaling. In late stage cachexia, the sympathetic tone in skeletal muscle breaks down, which we hypothesize might be caused by a reduction in histamine signaling or by the interference of other cachexia related mechanisms. Histamine signaling thus might delineate distinct stages of cachexia progression, with the early phase marked by a PSNS-mediated increase in histamine signaling, increased sympathetic tone and symptomatic adipose tissue depletion, and the late phase characterized by reduced histamine signaling, decreased sympathetic tone and symptomatic muscle wasting. To support our hypothesis, we review the literature from across disciplines and highlight the many commonalities between the mechanisms underlying cancer cachexia and current research findings on the regulation of energy homeostasis (particularly as it relates to hypothalamic histamine signaling). Extrapolating from the current body of knowledge, we develop our hypothetical framework (based on experimentally falsifiable assumptions) about the role of a distinct neuron population in the pathophysiology of cancer cachexia. Our hope is that presenting our ideas will spark discussion about the pathophysiology of cachexia, cancer's devastating and intractable syndrome.

Keywords: anorexia; cancer cachexia; central histaminergic system; energy expenditure; food intake; histamine signaling; histaminergic neurons; parasympathetic nervous system.

Figure 1

Body weight loss due to fasting (A) and in cancer cachexia (B). Histamine signaling is downstream and an integral part of the anorexigenic effect of leptin. As an adiposity sensor, leptin plasma levels, and thus histamine signaling, mirror the course of weight loss during fasting and in cancer cachexia. Analogously, average ghrelin levels are increased in (A,B). However, whereas histamine signaling is determined by leptin levels in fasting, it is uncoupled from it in cancer cachexia. Thus, relative levels of leptin and ghrelin promote appetite in fasting, but not in cancer cachexia. Increased histamine signaling overrules the hormonal regulatory mechanisms in food intake, allowing anorexia to be established as the default state.

Figure 2

Overview of the hypothesis concerning the involvement of the neuronal part of the histaminergic system in cancer cachexia. Muscle wasting is suggested to involve the loss of SNS tone. The mechanism and the time of onset in the course of cancer cachexia is still not clear, although the switch from increased to reduced neuronal histamine signaling might delineate the late phase (muscle wasting). The notion of histaminergic neurons in the TMN mediating cancer cachexia is consistent with a mechanism involving the sensing of tumor-derived signals (including those reflecting changes in its local tissue environment via the PSNS). Since this mechanism does not rely on systemic inflammation as a trigger of neuroinflammation, it represents an alternative route for tumors to affect systemic metabolism and cause cancer cachexia (BAT, brown adipose tissue; POA, preoptic area; PSNS, parasympathetic nervous system; PVN, paraventricular nucleus; REE, resting energy expenditure; SNS, sympathetic nervous system; TMN, tuberomamillary nucleus; VMN, ventromedial nucleus; WAT, white adipose tissue). Solid lines originating from the TMN indicate that connections have already been shown although in other contexts than cancer cachexia. Dashed lines indicate that while there is no direct evidence, it can be inferred indirectly. Solid lines between circles (hypothalamic nuclei and the periphery, BAT and WAT) indicate that increased SNS tone has been shown to be decisive in the respective physiological context. Central effects of tumor-induced changes of neuronal histamine signaling are shown in blue font, peripheral effects in red.