Endothelial Heme Dynamics Drive Cancer Cell Metabolism by Shaping the Tumor Microenvironment

Biomedicines

Luca Munaron¹  Tullio Genova¹  Chiara Riganti²  Joanna Kopecka²  Federico Mussano³  Anna Lucia Allocco⁴  Francesco De Giorgio⁴  Deborah Chiabrando⁴  Emanuela Tolosano⁴  Fiorella Altruda⁴  Veronica Fiorito⁴  Sara Petrillo⁴  Francesca Bertino⁴ 

[1] Department of Life Sciences and Systems Biology, University of Torino, 10123 Torino, Italy;Department of Oncology, University of Torino, 10126 Torino, Italy;Department of Surgical Sciences, C.I.R. Dental School, University of Torino, 10126 Torino, Italy;Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy;

关键词: cancer cell metabolism;    tumor microenvironment;    endothelial cell metabolism;    tumor endothelial cells;    heme metabolism;    FLVCR1a;   

DOI  :  10.3390/biomedicines9111557

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown