Controlling nerves

Sympathetic nerves associate with tumours and promote tumorigenesis; however, the mechanisms behind this are poorly understood. New research published in Science shows that adrenergic innervation controls the angiogenic switch in prostate cancer by regulating vascular metabolism.

tumours in βAdR^KO mice stopped growing after 18 days and had reduced tumour vessel density

The researchers implanted prostate cancer xenografts orthotopically into mice lacking β-adrenergic receptors Adrb2 and Adrb3 (βAdR^KO). Whereas tumours in control mice (βAdR^WT) grew exponentially, tumours in βAdR^KO mice stopped growing after 18 days and had reduced tumour vessel density. βAdR^WT mice treated with the neurotoxin 6-hydroxydopamine had reduced ability to recruit vasculature to an orthotopically transplanted collagen type I matrix that resembles the extracellular matrix in prostate cancer, suggesting that β-adrenergic signalling could regulate angiogenesis in prostate cancer.

To corroborate this finding, the researchers analysed tumours in the Hi-MYC spontaneous autochthonous prostate cancer mouse model. Upon overexpression of human MYC, this model recapitulates the progression of prostate cancer from the low-grade pre-neoplastic stage to the high-grade malignant stage and, subsequently, invasive cancer. In high-grade tumours, they found increased nerve and vessel densities and higher levels of noradrenaline compared with low-grade tumours. Deletion of Adrb2 in endothelial cells (ECs) of Hi-MYC mice (MYC;Adrb2^ECKO), but not its deletion in other stromal cells, inhibited the progression from low-grade to high-grade tumours.

Functionally, ECs isolated from prostates of MYC;Adrb2^ECKO mice showed increased expression of mitochondrial metabolism genes compared with control ECs isolated from MYC;Adrb2^WT mice, including cytochrome c oxidase assembly factor 6 (Coa6), which is required for the assembly of the terminal enzyme of the electron transport chain. In addition, these ADRB2-deficient ECs had features consistent with increased oxidative phosphorylation activity, including a high mitochondrial membrane potential and high glucose uptake.

The researchers continued their functional analysis by using primary mouse prostate ECs that are capable of long-term survival through expression of the adenoviral E4ORF1 gene (E4ORF1⁺ ECs) and by using lentiviral transduction of short hairpin RNA (shRNA) that targets Adrb2. ADRB2-depleted E4ORF1⁺ ECs grown in noradrenaline (NA)-containing media were less able to migrate than, and had a similar oxidative phosphorylation profile to, ECs from MYC;Adrb2^ECKO mice. Stable-isotope tracing analysis of [¹³C]glucose revealed an increased contribution of glucose to the tricarboxylic acid (TCA) cycle in ADRB2-depleted E4ORF1⁺ ECs, which was accompanied by increased oxygen consumption, production of mitochondrial ATP and expression of Coa6. When overexpressing Coa6 in E4ORF1⁺ ECs, oxidative phosphorylation was upregulated and the ability of these ECs to form vessels in co-transplanted prostate cancer xenografts was reduced. As the protein encoded by Coa6 cooperates with cytochrome c oxidase assembly protein 10 (encoded by Cox10), the researchers deleted Cox10 specifically in ECs of MYC;Adrb2^ECKO mice, which prevented the oxidative switch in ECs, rescued angiogenesis in prostate tumours and enabled cancer progression.

Credit: Carl Conway/Macmillan Publishers Limited

Overall, this study shows that angiogenesis in prostate cancer is promoted by adrenergic innervation, and this control is mediated by suppressing oxidative metabolism in ECs.