The Role of Extracellular Vesicles in Metabolic Reprogramming of the Tumor Microenvironment

Abstract

The tumor microenvironment (TME) includes a network of cancerous and non-cancerous cells, together with associated blood vessels, the extracellular matrix, and signaling molecules. The TME contributes to cancer progression during various phases of tumorigenesis, and interactions that take place within the TME have become targets of focus in cancer therapy development. Extracellular vesicles (EVs) are known to be conveyors of genetic material, proteins, and lipids within the TME. One of the hallmarks of cancer is its ability to reprogram metabolism to sustain cell growth and proliferation in a stringent environment. In this review, we provide an overview of TME EV involvement in the metabolic reprogramming of cancer and stromal cells, which favors cancer progression by enhancing angiogenesis, proliferation, metastasis, treatment resistance, and immunoevasion. Targeting the communication mechanisms and systems utilized by TME-EVs is opening a new frontier in cancer therapy.

Keywords: cancer metabolism; exosomes; extracellular vesicles (EVs); glycolysis; tumor microenvironment (TME).

Figure 1

Tumor microenvironment metabolic reprogramming by tumor-derived extracellular vesicles. Tumor-derived EVs (TDEVs) have been implicated in almost all tumor aspects, including cell proliferation and metastasis, angiogenesis, immunoescape, and therapy resistance. TDEVs transfer cargo into endothelial cells that increase arginine metabolism and glycolysis, which promotes endothelial proliferation and angiogenesis. TDEVs transfer glycolytic enzymes and genetic material from treatment-resistant cancer cells to sensitive cancer cells, which thereby enhances glycolysis, causes a decrease in ROS, and increases chemotherapy metabolism, thus conferring treatment resistance. EVs carry and deliver purine metabolites, genetic material, and glycolytic enzymes that increase glycolysis in MDSC and polarize macrophages to TAMs, which, together with TDEVs, have a direct effect on inhibiting the immunoresponse to cancer. TDEVs activate fibroblasts to CAFs, which induces glycolysis in CAFs and, in turn, promotes proliferation and metastasis. TDEVs act on cancer cells to increase glucose uptake while suppressing glucose uptake by premetastatic niche cells, which promotes metastasis. TDEVs travel beyond the immediate TME to inhibit glycolysis and enhance OXPHOS in myoblasts, which disrupts myotube differentiation and partly explains cachexia. TDEVs induce insulin resistance in skeletal muscle cells and transfer AM to induce lipolysis and β-cell dysfunction, which is manifested as cancer-related diabetes. NK cell—natural killer cell; TAM—tumor-associated macrophage; MDSC—myeloid-derived suppressor cell; CAF—cancer-associated fibroblast; TME—tumor microenvironment; AM—adrenomedullin; ROS—reactive oxygen species; OXPHOS—oxidative phosphorylation. Dashed arrow—transferred EV cargo.

Figure 2

Tumor microenvironment metabolic reprogramming by stromal-derived extracellular vesicles. There is crosstalk between stromal cells and cancer cells. The metabolic landscape is dynamic and depends upon the availability of nutrients and complex TME communication. This can result in opposing effects for EVs. Stromal EVs transfer different metabolites to support cancer cells. CAFs transfer amino acids and TCA cycle intermediates to cancer cells to induce glycolysis and reductive glutamine metabolism. On the other hand, CAF EVs also enhance the cancer cell OXPHOS via the transfer of mtDNA. Immune cells transfer miRNA and HISLA to augment glycolysis. MSC EVs have dual effects—supplying metabolites (lactate and glutamine) to replenish cancer cells and support angiogenesis, as well as hydrolyzing ATP to adenosine, which can inhibit angiogenesis. Adenosine hydrolyzation by B and Treg cells binds to T cells, prompting immunoevasion. Adipocytes shed EVs that can increase glycolysis but can also increase OXPHOS and FAO levels without changing that activity. TAM—tumor-associated macrophage; CAF—cancer-associated fibroblast; TME—tumor microenvironment; OXPHOS—oxidative phosphorylation; MSC—mesenchymal stem cell; PSC—pancreatic stellate cell; FA—fatty acid; FAO—fatty acid oxidation; NO—nitric oxide; TCA—tricarboxylic acid; HISLA—HIF-1α-stabilizing long noncoding RNA MC—monocarboxylic acid; CAA—cancer-associated adipocytes. Dashed arrow—transferred EV cargo.