Adrenergic nerves activate an angio-metabolic switch in prostate cancer

Abstract

Nerves closely associate with blood vessels and help to pattern the vasculature during development. Recent work suggests that newly formed nerve fibers may regulate the tumor microenvironment, but their exact functions are unclear. Studying mouse models of prostate cancer, we show that endothelial β-adrenergic receptor signaling via adrenergic nerve-derived noradrenaline in the prostate stroma is critical for activation of an angiogenic switch that fuels exponential tumor growth. Mechanistically this occurs through alteration of endothelial cell metabolism. Endothelial cells typically rely on aerobic glycolysis for angiogenesis. We found that the loss of endothelial Adrb2, the gene encoding the β2-adrenergic receptor, leads to inhibition of angiogenesis through enhancement of endothelial oxidative phosphorylation. Co-deletion of Adrb2 and Cox10, a gene encoding a cytochrome IV oxidase assembly factor, prevented the metabolic shift induced by Adrb2 deletion and rescued prostate cancer progression. This cross-talk between nerves and endothelial metabolism could potentially be targeted as an anti-cancer therapy.

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

“…PanINs), and thus cancer development in a susceptible host could be inhibited by ADRB2-antagonists. ADRB2 signaling likely promotes tumorigenesis through effects on both the epithelial and the stromal compartment (Hayakawa and Wang, 2017; Magnon et al, 2013; Zahalka et al, 2017). Although the effects of stress in promoting cancer have been linked in the past to suppression of the immune response (Partecke et al, 2016) or to recruitment of M2 macrophages (Madden et al, 2011; Pérez Piñero et al, 2012), we show here that many of the effects of circulating catecholamines are indeed direct, with stimulation of ADRB2-dependent pancreatic epithelial growth.…”

“…While some of these stimulatory factors are likely provided by inflammatory leukocytes, the role of the nervous system in supporting tumor growth needs to be considered. Recent studies have shown the importance of the autonomic nervous system in tumorigenesis for prostate cancer (Magnon et al, 2013; Zahalka et al, 2017), ovarian cancer (Thaker et al, 2006), gastric cancer (Hayakawa et al, 2017; Zhao et al, 2014), and basal cell carcinoma (Peterson et al, 2015). …”

Sympathetic nerve tissue in milky spots of the human greater omentum

“…; Zahalka et al. ). Although further studies are needed to elucidate the exact anti‐tumour mechanism, these findings suggest a potential role for β‐blockers in the treatment of cancer.…”

“…The sympathetic nerve system and specifically its neurotransmitter noradrenaline are known (1) to contribute to a favourable tumour microenvironment, for example by affecting stromal cells, endothelial cells, and tumour-associated macrophages (Magnon et al 2013), and (2) to stimulate tumour cell proliferation, via beta (b) adrenergic receptors on tumour cells (Coelho et al 2017). As since all of these processes are mediated via adrenergic receptors, the effects of b adrenergic blocking as a potential anti-tumour therapy have been investigated in in vitro, animal, and retrospective patient studies with promising results (Magnon et al 2013;Coelho et al 2017;Zahalka et al 2017). Although further studies are needed to elucidate the exact anti-tumour mechanism, these findings suggest a potential role for b-blockers in the treatment of cancer.…”

β‐Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3‐adrenoceptors

“…In addition to directly acting on tumour cells, β‐adrenoceptors play a major role in mediating the intimate crosstalk between tumour cells and their environment that has a profound influence on tumour growth and progression (Finotello and Eduati, ). In this respect, it has been demonstrated that propranolol counteracts the stress‐induced formation of new blood vessels in a mouse model of colorectal carcinoma and that the deletion of the gene encoding for β 2 ‐adrenoceptors leads to inhibition of angiogenesis in a mouse model of prostate cancer (Liu et al ., ; Zahalka et al ., ). In addition, propranolol prevents both macrophage recruitment into the tumour mass in a model of ovarian carcinoma and macrophage M2 polarization in a model of breast cancer (Armaiz‐Pena et al ., ; Qin et al ., ).…”