Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice

Abstract

Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, eg. celastrol, might be a novel strategy for colorectal cancer treatment.

Neural Functions of Hypothalamic Oxytocin and its Regulation

“…As shown in rats, activation of this pathway can increase insulin levels (Bjorkstrand et al, 1996), reduce heart rate and cardiac contractility (Houshmand et al, 2015), suppress food and water intake of the digestive system (Niimi et al, 2001), slow gastric emptying (Tolentino et al, 2021) and regulate hepatic metabolic activity (Dos . Recently, it is also reported that activation of brain OT neurons inhibits colitis-associated cancer progression in association of suppression of sympathetic neuronal activity in the celiac-superior mesenteric ganglion as shown in mice (Pan et al, 2021). Thus, OT can modulate visceral activities by increasing parasympathetic nervous activity although the parasympathetic outflow function of endogenous OT remains to be studied.…”

Immune-related gene signature associates with immune landscape and predicts prognosis accurately in patients with Wilms tumour

“…OXT inhibited ovarian cancer metastasis by suppressing the expression of MMP-2 and VEGF ( 73 ). Interestingly, stimulation of hypothalamic OXT neurons inhibited the progression of colorectal cancer in mice ( 74 ). Thus OXT may be a new strategy for the treatment of colorectal cancer.…”

Psychological distress and eustress in cancer and cancer treatment: Advances and perspectives

“…To elucidate the mechanisms underlying the effects of psychological stress on malignant disease, multiomics studies, such as cytomics, genomics, metabolomics, proteomics, and bioinformatics analytical approaches, can be applied to explore the key mediators of psychological distress and eustress in malignant diseases and to develop relevant targeted therapies or to find prognostic biomarkers. In addition to the SNS and HPA axes, other molecules associated with stress coping may also have effects on malignant tumors, including dopamine, serotonin, and oxytocin ( 89 , 90 , 128 ). And the impact of these mediators on malignancies could be of interest in future studies.…”