Moro Marianna, Balestrero Federica Carolina, Colombo Giorgia, Torretta Simone, Clemente Nausicaa, Ciccone Valerio, Del Grosso Erika, Donnini Sandra, Travelli Cristina, Condorelli Fabrizio, Sangaletti Sabina, Genazzani Armando A, Grolla Ambra A
Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
Division of Hematology/Oncology Department of Medicine, Weill Cornell Medicine, Cornell University, New York, USA.
Angiogenesis. 2024 Dec 5;28(1):4. doi: 10.1007/s10456-024-09956-2.
Tumour angiogenesis supports malignant cells with oxygen and nutrients to promote invasion and metastasis. A number of cytokines released in situ participate in the recruitment of endothelial cells and pericytes to trigger the formation of novel blood vessels, which are often abnormal, leaky, and disorganized. Nicotinamide phosphoribosyltransferase is a key intracellular enzyme involved in NAD metabolism and is up regulated in many cancers to meet bioenergetic demands. Yet, the same protein is also secreted extracellularly (eNAMPT), where it acts as a pro-inflammatory cytokine. High plasma eNAMPT levels have been reported in breast cancer patients and correlate with aggressiveness and prognosis. We now report that in a triple-negative breast cancer model, enriching the tumour microenvironment with eNAMPT leads to abundant angiogenesis and increased metastatization. Atypically, the eNAMPT-mediated pro-angiogenic effect is mainly directed to NG2 pericytes. Indeed, eNAMPT acts as chemoattractant for pericytes and coordinates vessel-like tube formation, in synergism with the classical factor PDGF-BB. Stimulation of pericytes by eNAMPT leads to a pro-inflammatory activation, characterized by the overexpression of key chemokines (CXCL8, CXCL1, CCL2) and VCAM1, via NF-κB signalling. All these effects were ablated by the use of C269, an anti-eNAMPT neutralizing antibody, suggesting that this might represent a novel anti-angiogenic pharmacological approach for triple-negative breast cancer.
肿瘤血管生成通过为恶性细胞提供氧气和营养物质来促进侵袭和转移。原位释放的多种细胞因子参与内皮细胞和周细胞的募集，从而触发新生血管的形成，这些新生血管通常是异常的、有渗漏且结构紊乱的。烟酰胺磷酸核糖转移酶是参与烟酰胺腺嘌呤二核苷酸（NAD）代谢的关键细胞内酶，在许多癌症中上调以满足生物能量需求。然而，同一蛋白也会分泌到细胞外（eNAMPT），在细胞外它作为一种促炎细胞因子发挥作用。乳腺癌患者血浆中eNAMPT水平较高，且与侵袭性和预后相关。我们现在报告，在三阴性乳腺癌模型中，用eNAMPT丰富肿瘤微环境会导致大量血管生成和转移增加。非典型的是，eNAMPT介导的促血管生成作用主要针对NG2周细胞。事实上，eNAMPT作为周细胞的趋化因子，并与经典因子血小板衍生生长因子-BB（PDGF-BB）协同作用，协调类血管管的形成。eNAMPT对周细胞的刺激通过核因子κB（NF-κB）信号传导导致促炎激活，其特征是关键趋化因子（CXCL8、CXCL1、CCL2）和血管细胞黏附分子1（VCAM1）的过表达。使用抗eNAMPT中和抗体C269可消除所有这些效应，这表明这可能代表一种针对三阴性乳腺癌的新型抗血管生成药理学方法。
