A new role for extracellular vesicles: how small vesicles can feed tumors' big appetite

Abstract

Cancer cells must adapt their metabolism in order to meet the energy requirements for cell proliferation, survival in nutrient-deprived environments, and dissemination. In particular, FA metabolism is emerging as a critical process for tumors. FA metabolism can be modulated through intrinsic changes in gene expression or signaling between tumor cells and also in response to signals from the surrounding microenvironment. Among these signals, extracellular vesicles (EVs) could play an important role in FA metabolism remodeling. In this review, we will present the role of EVs in tumor progression and especially in metabolic reprogramming. Particular attention will be granted to adipocytes. These cells, which are specialized in storing and releasing FAs, are able to shift tumor metabolism toward the use of FAs and, subsequently, increase tumor aggressiveness. Recent work demonstrates the involvement of EVs in this metabolic symbiosis.

Keywords: adipocytes; cancer; fatty acid metabolism; fatty acid oxidation; fatty acid synthesis; tumor microenvironment • exosomes • microvesicles • obesity • biomarker.

Fig. 1.

EVs mediate a metabolic cross-talk between tumor cells and with the stroma. EVs secreted by aggressive tumor cells can transfer molecules involved in sugar-related pathways and lipid synthesis to more indolent tumor cells. Tumor-derived EVs can also decrease glycolysis within the pre-metastatic niche to increase nutrient availability to metastatic cells. EVs from CAFs increase glycolysis and glutamine-dependent reductive carboxylation, but decrease oxidative phosphorylation in tumors. They also transport metabolites required for lipid synthesis, such as acetate. ADSCs secrete EVs containing miR-126, which decreases lipid accumulation in mammary epithelial cells. Finally, adipocyte EVs transport proteins implicated at all stages of lipid metabolism, including lipogenesis, lipid transport and storage, lipolysis, and FAO. These EVs are able to increase FAO in tumor cells, which consequently promotes tumor aggressiveness. Pathways known to be impacted by the indicated EVs are shown in bold. Pathways that could be affected by the molecules transported by the indicated EVs are shown in italic. This figure summarizes most of the citations from (80) to (119).

Fig. 2.

Adipocyte EVs transport proteins involved in FA metabolism. Exogenous FAs are taken up by tumor cells, then transported (either as FAs by FABPs or after conversion to fatty acyl-CoAs by acyl-CoA binding proteins) to LDs to be stored as TGs. These lipids then undergo lipolysis to mobilize fatty acyl-CoAs, which can be transferred directly to mitochondria (for long and short chain fatty acyl-CoAs) or be processed first by peroxisomal FAO to shorten chain length before transfer to mitochondria (for very long chain fatty acyl-CoAs). These fatty acyl-CoAs then undergo mitochondrial FAO, producing one acetyl-CoA per cycle that enters the TCA cycle. The NADH and FADH2 produced by both FAO and the TCA cycle then fuel the electron transport chain to produce ATP. The proteins (gene names are indicated) that we identified in adipocyte EVs in our proteomic study (89), and which are implicated in every stage of exogenous FA metabolism, are shown. ABHD5, abhydrolase domain containing 5; ACAA, acetyl-CoA acyltransferase; ACADL, long-chain-specific acyl-CoA dehydrogenase; ACADM, medium-chain-specific acyl-CoA dehydrogenase; ACADS, short-chain-specific acyl-CoA dehydrogenase; ACADV, very long-chain-specific acyl-CoA dehydrogenase; ACSL1, acyl-CoA synthetase long-chain family member 1; CAV, caveolin; CPT2, carnitine palmitoyltransferase 2; DECR1, 2,4-dienoyl-CoA reductase; DHB4/HSD17B4, peroxisomal multifunctional enzyme type 2; HADHA, trifunctional enzyme subunit α HADHB, trifunctional enzyme subunit β LIPE, lipase E (hormone sensitive type); PTGFRN, prostaglandin F2 receptor inhibitor.