Petrillo Sara, De Giorgio Francesco, Kopecka Joanna, Genova Tullio, Fiorito Veronica, Allocco Anna Lucia, Bertino Francesca, Chiabrando Deborah, Mussano Federico, Altruda Fiorella, Munaron Luca, Riganti Chiara, Tolosano Emanuela
Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Department of Oncology, University of Torino, 10126 Torino, Italy.
Biomedicines. 2021 Oct 28;9(11):1557. doi: 10.3390/biomedicines9111557.
The crosstalk among cancer cells (CCs) and stromal cells within the tumor microenvironment (TME) has a prominent role in cancer progression. The significance of endothelial cells (ECs) in this scenario relies on multiple vascular functions. By forming new blood vessels, ECs support tumor growth. In addition to their angiogenic properties, tumor-associated ECs (TECs) establish a unique vascular niche that actively modulates cancer development by shuttling a selected pattern of factors and metabolites to the CC. The profile of secreted metabolites is strictly dependent on the metabolic status of the cell, which is markedly perturbed in TECs. Recent evidence highlights the involvement of heme metabolism in the regulation of energy metabolism in TECs. The present study shows that interfering with endothelial heme metabolism by targeting the cell membrane heme exporter Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a) in TECs, resulted in enhanced fatty acid oxidation (FAO). Moreover, FAO-derived acetyl-CoA was partly consumed through ketogenesis, resulting in ketone bodies (KBs) accumulation in FLVCR1a-deficient TECs. Finally, the results from this study also demonstrate that TECs-derived KBs can be secreted in the extracellular environment, inducing a metabolic rewiring in the CC. Taken together, these data may contribute to finding new metabolic vulnerabilities for cancer therapy.
肿瘤微环境（TME）中癌细胞（CCs）与基质细胞之间的相互作用在癌症进展中起着重要作用。在此情况下，内皮细胞（ECs）的重要性依赖于多种血管功能。通过形成新血管，内皮细胞支持肿瘤生长。除了其血管生成特性外，肿瘤相关内皮细胞（TECs）建立了一个独特的血管生态位，通过向癌细胞输送特定模式的因子和代谢物来积极调节癌症发展。分泌代谢物的谱严格依赖于细胞的代谢状态，而肿瘤相关内皮细胞的代谢状态明显受到干扰。最近的证据强调了血红素代谢参与肿瘤相关内皮细胞能量代谢的调节。本研究表明，通过靶向肿瘤相关内皮细胞中的细胞膜血红素输出蛋白猫白血病病毒C亚群受体1a（FLVCR1a）来干扰内皮血红素代谢，会导致脂肪酸氧化（FAO）增强。此外，脂肪酸氧化产生的乙酰辅酶A部分通过生酮作用被消耗，导致FLVCR1a缺陷的肿瘤相关内皮细胞中酮体（KBs）积累。最后，本研究结果还表明，肿瘤相关内皮细胞衍生的酮体可以分泌到细胞外环境中，诱导癌细胞的代谢重编程。综上所述，这些数据可能有助于找到癌症治疗新的代谢弱点。
