Abstract
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.
Highlights
The tumor microenvironment (TME) is a dynamic and complex niche consisting of both cancer cells (CCs) and supporting stromal cells [1]
We show that Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a)-deficient tumor-associated ECs (TECs) are able to shape metabolism in CCs (Figure 7)
LLC cells treated with FLVCR1a-silenced Breast-tumor-derived endothelial cells (BTEC)-derived
Summary
The tumor microenvironment (TME) is a dynamic and complex niche consisting of both cancer cells (CCs) and supporting stromal cells [1]. Endothelial cells (ECs) are critical determinants of tumor progression and immune evasion [2]. Contribution to tumor development does rely on the formation of new blood vessels (angiogenic switch). Vascular networks are not just passive conduits, and ECs supply a specific pattern of membrane-bound and secreted elements to the surrounding cells (angiocrine switch), actively contributing to establishing a unique pro-tumorigenic milieu [3,4]. Accumulating evidence indicates that metabolic cooperation exists between CCs and stromal cells, the latter having a crucial role in shaping CC metabolism by shuttling 4.0/).
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