Nerves switch on angiogenic metabolism

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Science  20 Oct 2017:
Vol. 358, Issue 6361, pp. 305-306
DOI: 10.1126/science.aaq0365

Nerves release neurotransmitters to regulate most physiologic functions in the body. Recently, it has been recognized that nerves play dominant roles in organogenesis and tissue regeneration (1, 2). In addition, growing evidence suggests that cancer development in a variety of tissues is controlled by an assortment of nerve-mediated signals, including neurotransmitters and other molecules (35). The key molecules depend on the organ and the context, but the targets of neurotransmission appear to include both stem cells and the surrounding stromal cells. Both adrenergic and cholinergic nerves promote prostate cancer development, at least in part, by activating stromal cells (4). On page 321 of this issue, Zahalka et al. (6) expand on their previous findings (3) by elucidating the molecular mechanism of neurotransmission in prostate cancer, revealing that noradrenaline released from cancer-associated nerves triggers angiogenesis and thus cancer progression.

Nerves expand greatly in most solid tumors, and this increased nerve density is strongly associated with tumor growth and prognosis (3, 4). The authors found that surgical or chemical sympathectomy (where sympathetic nerves are destroyed locally in the surgical model and systemically in the chemical model), as well as knockout of β2-adrenergic receptor (Adrb2) and Adrb3 in stromal cells, efficiently inhibited prostate cancer progression in mouse models. Tumor regression appeared to coincide with reductions in blood vessel numbers, particularly at more advanced (high-grade) tumor stages, and endothelial cells (which form blood vessels) were found to have high expression of ADRβ2. Consequently, Zahalka et al. deleted the Adrb2 gene specifically in endothelial cells and found significant inhibition of both angiogenesis (new blood vessel formation) and tumor cell proliferation. Further analyses revealed that genes associated with mitochondrial cytochrome c activity, including cytochrome c oxidase assembly factor 6 (Coa6), exhibited significant upregulation in Adrb2-deleted endothelial cells. Given previous evidence for connections between endothelial cell metabolism and angiogenesis (7, 8), the authors performed a variety of metabolic analyses with or without Adrb2 expression. This led to the conclusion that ADRβ2 blockade in endothelial cells induced a “reverse metabolic shift,” whereby endothelial cell metabolism shifted such that oxidative phosphorylation became more predominant than glycolysis, by way of regulation of COA6 expression through a G protein S (GαS)–adenylyl cyclase–cyclic adenosine monophosphate (cAMP) pathway (see the figure). Interestingly, deletion of cytochrome c oxidase assembly homolog 10 (Cox10) blocked these metabolic alterations and restored both angiogenesis and prostate cancer progression, suggesting that the shift to oxidative phosphorylation regulated by the mitochondrial cytochrome c complex may be a key metabolic switch that controls angiogenesis and tumor progression.

In tumors, cancer cells preferentially metabolize glucose via glycolysis, rather than undertaking the dominant metabolic pathway, oxidative phosphorylation, as initially suggested by Otto Warburg. This metabolic switch has been attributed to prolonged hypoxia within the tumor microenvironment and subsequent adaptation of cancer cells. Such metabolic changes may also develop in stromal endothelial cells, and Zahalka et al. suggest that it is likely caused by amplified adrenergic inputs from cancer-associated nerves, the density of which is often increased through axonogenesis (expansion or generation of axon fibers from neurons) in response to neurotrophins produced by cancer cells (9, 10). The precise functions of COA6 and COX10 in endothelial cells, and their importance to various human cancers, requires further investigation.

These findings greatly improve our understanding of how cellular metabolism is regulated in the tumor microenvironment and point to a dominant role for nerves in this setting. Given the dependence on nerves in organogenesis and vascularization during development (1, 2), similar mechanisms may occur in tumor progression, with nerves promoting epithelial growth in part through stimulation of angiogenesis. The mechanism by which expansion and metabolic modulation of endothelial cells promote prostate cancer growth remains to be defined. Adequate blood flow is thought to be critical for the growth of cancer cells, but tumor-associated endothelial cells also signal to epithelial cells and/or immune cells through release of growth factors and cytokines (termed the perivascular niche) (11). Nonetheless, this dependence of blood vessel growth on adrenergic signaling raises the possibility that treatment with β-blockers, perhaps in combination with existing antiangiogenic drugs, may elicit profound and prolonged inhibition of tumor-associated angiogenesis and cancer growth. Indeed, given the requirement for ADRβ2 signaling for progression from low-grade prostatic intraepithelial neoplasia (LPIN) to high-grade PIN (HPIN) and the angiogenic switch, perhaps the use of nonselective β-blockers could prevent progression to prostate cancer.

Nerve–endothelium interaction in the tumor microenvironment

Nerves control the multistep endothelial cell metabolic pathway in cancer through ADRβ2. NADH, nicotinamide adenine dinucleotide reduced form; NAD, nicotinamide adenine dinucleotide; ADP, adenosine 5′-diphosphate; ATP, adenosine triphosphate.


Although the findings in this impressive study have considerably advanced our understanding of nerve–tumor interaction, several questions remain. First, what are the mechanisms that lead to increased nerve density and norepinephrine levels in the preneoplastic prostate? Second, as neural regulation of cancer development may go beyond angiogenesis, do ADRβ2 and adrenergic signals act in other cell types? In many organs, nerves directly regulate tissue-resident stem cell function (3, 5, 10). Given that ADRβ2 is also expressed in prostate cancer cells (12), the effects of ADRβ2 knockout or blockade in epithelial stem cells and tumor cells will need to be examined more closely. Others have suggested a role for adrenergic signaling and the “neural reflex” in the regulation of inflammation and immunity, which may contribute to cancer progression (13, 14). Thus, neuroimmune signaling may play a role in cancer and should also be investigated.

How other neurotransmitters such as acetylcholine are involved remains to be clarified. For example, cholinergic signaling in stromal cells exerted a tumor growth–promoting effect in prostate cancer models (4), whereas dopamine, a stress-inhibiting catecholamine, suppressed angiogenesis and tumor growth in ovarian cancer (15). Therefore, it seems likely that additional mechanisms are involved in nerve-mediated angiogenesis and tumor progression. Nonetheless, accumulating evidence suggests that various forms of denervation constitute promising approaches to cancer therapy, and further exciting discoveries on nerve–cancer interactions and clinical interventions targeting nerves may be expected in the near future.


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