Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) drives abnormal pericyte-rich vasculature in triple-negative breast cancer
- PMID: 39636369
- DOI: 10.1007/s10456-024-09956-2
Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) drives abnormal pericyte-rich vasculature in triple-negative breast cancer
Abstract
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.
Keywords: Angiogenesis; Breast cancer; Cytokines; Pericytes; Tumour microenvironment.
© 2024. The Author(s), under exclusive licence to Springer Nature B.V.
Conflict of interest statement
Declarations. Conflicts of interest: The authors declare no potential conflicts of interest. Ethical approval: All procedures involving animals were approved by the Italian Ministry of Health (120/2018 DB064.30; 1047/2023-PR, DB064.84; 81/2024-PR DB064.86).
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