Extracellular Vesicle-Mediated Mitochondrial Reprogramming in Cancer: Comparison
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Tumors are complex systems in constant communication with their microenvironment on which they rely for growth and survival. EVs, as intercellular communicators, are involved in several hallmarks of cancers, being active players in the remodeling of the TME and priming metastatic niches to support tumor survival, progression, and invasion. Although the importance of mitochondrial state and reprogramming in cancer progression has been established, the underlying mechanisms and metabolic phenotypes are incredibly varied, and knowledge is still lacking. Thus, this entry focuses on the role of EVs in mitochondrial reprogramming to support tumor survival by modulation of the TME in the context of the hallmarks of cancer.

  • tumor-derived EVs (TEVs)
  • miRNA
  • mitochondrial dynamics
  • metabolism
  • tumor-derived exosomes (TEXs)
  • cancer
  • extracellular vesicles

1. Dysregulating Cellular Energetics

1.1. Metabolic Coupling with Cancer-Associated Fibroblasts (CAFs)

Among the different TME players, fibroblasts are key in metabolically supporting tumor progression [1]. Crosstalk between tumor cells and fibroblasts in the TME induces a phenotype change of the latter into cancer-associated fibroblasts (CAFs). CAFs display a hyperactive behavior facilitating tumor survival and migration [2]. During this transformation, fibroblasts switch to a glycolytic phenotype to provide cancer cells with energy-rich metabolic intermediates that fuel both mitochondrial ATP generation and biosynthesis [3]. This process, in which glycolytic CAFs support mitochondrial respiration in cancer cells, has been termed the reverse Warburg effect [4]. Reprogramming resulting from the crosstalk between cancer cells and local fibroblasts can occur through different mechanisms which can be mediated by TEVs [3].
One of these mechanisms is through the transfer of miRNAs affecting the expression of mitochondrial proteins. Melanoma TEVs have been found to contain miR-155 and miR-210 that lead to the reprogramming of stromal fibroblast metabolism by promoting glycolysis and inhibiting OXPHOS [5]. Similarly, miR-424, found in TEVs, downregulates the TCA enzyme IDH3a leading to the inhibition of OXPHOS through the upregulation of mitochondrial NDUFA4L2 [6][7]. Another mechanism of OXPHOS downregulation is through lung cancer TEVs transfer of miR-210 to CAFs [8]. Mechanistically, miR-210 directly downregulates ETC complex I subunit NDUFA4 and complex II subunit SDHD, resulting in mitochondrial dysfunction, as evidenced by an alteration in mitochondrial membrane potential. Interestingly, this miRNA also modifies mitochondria size and cristae organization [9]. In cancer associated with viral infection, it has been observed that TEVs contain viral proteins that, upon delivery to normal fibroblasts, induce their transformation into CAFs. This transformation is associated with a decrease in OXPHOS [10]. Moreover, further work on fibroblasts incubated with colorectal cancer (CRC) TEVs exhibited dysregulated expression of a number of mitochondrial proteins such as upregulation of a complex V subunit (ATP5H), TCA cycle enzyme IDH2 and the β-oxidation enzyme ECH1, as well as downregulation of mitochondrial protein translation factor TUFM and detoxifying enzyme ALDH2 [11].
In turn, CAF-derived EVs (CAF-EVs) also participate in cancer’s metabolic switch. For instance, breast cancer CAF-EVs transfer the lncRNA SNHG3 that inhibits OXPHOS and increases glycolysis, driving an increased tumor cell proliferation [12]. Similarly, Zhao and colleagues showed that CAF-EVs were able to inhibit OXPHOS through the transfer of miRNAs such as miR-22, let7a and miR-125b. Moreover, CAF-EVs can modulate mitochondrial metabolism by the transfer of lipids, amino-acids, and de novo complete TCA metabolites. Of note, the most abundant miRNAs found in CAF-EVs targeted OXPHOS genes with downregulation in the expression of subunits in complexes III and IV of the ETC [13]. The same group later demonstrated that CAF-EV-derived metabolites were able to support nutrient-deprived pancreatic cancer cell metabolism by modulating the TCA cycle [14]. Moreover, CAF-EVs delivered miR-92a to CRC [15]. Inhibition of this miRNA has been found to enhance oxygen consumption as well as increase the expression of mitochondrial proteins in adipocytes [16], suggesting a mitochondrial effect in cancer cells. However, fibroblasts metabolically reprogrammed by TEVs can also lead to increased OXPHOS, mitochondrial activity and number through the supply of energy-rich metabolites to cancer cells [10]. Consequently, the observed capacity of CAF-EVs to support the cancer cell TCA cycle while generally inhibiting OXPHOS, suggests a repurposing of mitochondria from an energy “powerhouse” to a biosynthetic “factory”.
EV-mediated mitochondrial reprogramming is bidirectional, the direction and nature of this reprogramming being dependent on cancer type and pathological stage. Supporting evidence for the changing role of EVs in the natural history of cancer comes from early and late-stage colorectal cancer TEVs being able to induce different phenotypes in fibroblasts, from protumorigenic to prometastatic phenotypes [11]. These observed differences in fibroblast function and phenotype suggest that the cargo of the TEVs can be adjusted to satisfy the varying needs of cancer cells throughout their developmental process.

1.2. Metabolic Coupling with Adipocytes

Adipose tissue, composed mainly of adipocytes, has been found to promote tumor progression [17]. The main role of adipocytes is to maintain a physiological energy balance by storing fat and releasing it according to energy demands. Adipocyte function depends on its differentiation status which is linked to mitochondrial changes. Typically, differentiation of white adipocytes into brown/beige adipocytes is characterized by an increase in mitochondrial number and activity, as well as an increase in the expression of mitochondrial uncoupling protein (UCP1) that uncouples respiration from ATP synthesis to generate heat and stimulate lipolysis [18]. This phenotype change leads to the release of metabolites that, upon uptake by cancer cells, promote tumor progression [19].
TEVs have been demonstrated to induce lipolysis and browning in adipocytes through the transfer of miRNAs such as miR-155, miR-144 and miR-126. Consequently, adipocytes release fatty acids, glutamine, pyruvate, lactate, and ketone bodies for cancer cell utilization [19][20][21]. In parallel, experimental work with adipocytes in melanoma and prostate cancer has shown that adipocytes secrete EVs (adEVs) that increase their malignant potential. This observed phenotypic change was related to metabolic reprogramming, characterized by an increase in fatty acid catabolism via FAO. This catabolic switch was also accompanied by an increase in mitochondrial number and density [22]. The same group also showed that adipocytes can influence tumor metabolism by EV transfer of mitochondrial FAO enzymes, OXPHOS subunits, mitochondrial ADP/ATP transporters, TCA cycle proteins, and fatty acids [23]. AdEVs have also been shown to transfer miR-23a/b to HCC cells [24] and, in the context of prostate cancer, these miRNAs have been found to target mitochondrial glutaminase [25].
In a similar way to CAFs, cancer cells and adipocytes develop a metabolic relationship, where TEVs induce a metabolic shift in adipocytes encouraging the formation and release of energy-rich metabolites to provide nutritional support to cancer cells, thereby promoting a metabolic remodeling favoring FAO for their progression and invasion. This experimental evidence supports the need for further studies to investigate EV-mediated molecular mechanisms by which adipocytes can support tumor growth metabolically.

1.3. Metabolic Subjugation of Neighboring Cells

The EV-mediated metabolic manipulation of healthy cells in cancer is not just limited to fibroblasts and adipocytes. Kaposi’s sarcoma-associated herpes virus-derived EVs transfer miRNA to uninfected cells resulting in reduced mitochondrial biogenesis and respiration, with an induction of aerobic glycolysis. The reduction in respiration observed was related to a decrease in mitochondrial volume in EV-treated cells by 40%. Overall, mitochondrial activity was also reduced as reflected by a lower level of TCA cycle metabolites [26]. Unfortunately, the underlying mechanisms leading to this alteration in mitochondrial biogenesis were not explored in greater depth. However, similarly to what occurs with CAFs and adipocytes, the purpose of this change in mitochondrial behavior is to turn EV recipient cells into feeder cells, by the release and transfer of glycolytic end products to infected cells to fuel their TCA cycle for growth advantage.

2. Resisting Cell Death

Resistance to apoptosis is a hallmark of cancer and apoptosis is a biological process that can be regulated by mitochondrial events. Chemotherapy ultimately exerts its function by inducing apoptosis which makes the mitochondrial state an important determinant of tumor response to therapy [27]. Mitochondrial dysfunction is associated with tumor cell resistance to both chemotherapy and radiotherapy by impeding apoptosis [28][29], with cancer cells being able to modulate mitochondrial apoptotic priming through EVs to benefit their survival.

2.1. Modulation of the Bcl-2 Pathway

Some of cancer’s EV strategies to evade apoptosis do not necessarily target mitochondrial proteins, but act indirectly on other aspects of the apoptotic cascade, for example transferring proteins such as survivin, which blocks cell death by inhibiting caspases [30], or miR-21 that targets the tumor suppressor programmed cell death 4 (PDCD4) [31]. However, there is also evidence that TEVs are taken up by melanoma and bladder cancer cells inhibiting apoptosis and favoring cell proliferation by targeting mitochondria through the regulation of the Bax/Bcl-2 signaling pathway [32][33]. However, the molecular basis of these observations needs further investigation.
EV-mediated resistance to apoptosis can also occur between cancer cells and other cell types in the TME. For instance, glioma cells transfer EVs containing lncRNA-CCAT2 to endothelial cells in order to promote angiogenesis by decreasing apoptosis in these cells through Bcl-2 increase and suppression of Bax and Caspase-3 expression [34]. The same effect also occurs in the opposite direction, such as between mesenchymal stem cells (MSCs) and cancer cells. MSCs are important players in maintaining tissue homeostasis as they promote processes involved in tissue regeneration, angiogenesis, and cell survival, and their EVs are one way they exert their function. However, MSC function can be hijacked by cancer to enhance its own survival [35]. MSC-derived EVs (MSC-EVs) have been found to contain lncRNA LINC00461 and, on uptake by multiple myeloma cells, it relieved the inhibitory effect of miR-15a/miR-16 on Bcl-2, therefore suppressing apoptosis and promoting myeloma proliferation [36].

2.2. Chemotherapy Resistance

The antiapoptotic effect of TEVs has a direct implication on determining the response of tumor cells to therapy. TEVs can spread resistance to chemotherapeutic agents by transferring ncRNAs such as lncRNA-SNHG14, lncRNA PART1 and miR-214, as well as proteins such as chloride intracellular channel 1 (CLIC1) and connexin 43 to chemosensitive cells by modulating components of the Bcl-2 family [37][38][39][40][41][42]. Although the development of chemoresistance caused by the modulation of the Bcl-2 family appears to be common and consistent across a number of cancer and drug types, many of the underlying molecular mechanisms remain unknown.
Besides acting on mitochondrial apoptotic pathways, TEVs have been shown to modulate chemoresistance via the metabolic regulation of drug-sensitive cells. For instance, in doxorubicin-resistant breast cancer cells, TEVs were able to affect the balance between glycolysis and OXPHOS in recipient cells via mechanisms involving heat shock protein-70 (Hsp70). After Hsp-70 delivery by TEVs, this protein translocates into mitochondria and induces mitochondrial damage through increasing reactive oxygen species (ROS) levels. Consequently, recipient cells with impaired mitochondrial respiration switch to an enhanced glycolytic activity [43].
EVs from other cells in the TME also enhance drug resistance. For instance, CAF-EVs transfer miR-92a-3p and miR-103a-3p to cancer cells inhibiting mitochondrial apoptosis [44][45]. In another study, the co-culture of MSCs with tumor cells activated the mitochondrial fission mediator Drp1, inducing an increased fragmentation of mitochondria in a T-cell lymphoblastic leukemia model. This alteration in mitochondrial fission dynamics was related to a decrease in mitochondrial ROS, a glycolytic switch and contributed to the development of chemoresistance [46]. Although the specific extracellular mechanism was not studied, EV capacity to promote mitochondrial fission has been previously demonstrated [23][47].

2.3. Enhancing Cancer Survival and Chemotherapy Resistance through EV Transfer of Functional Mitochondria and Mitochondrial Components

Besides the intercellular transfer of molecules such as miRNAs that regulate the expression of mitochondrial components, several studies have also described the transfer of whole functional organelles. The transfer of whole mitochondria has been proven to be a protective strategy for a range of conditions such as lung or stroke-induced injury which require a metabolic rescue [48][49]. There are a number of different mechanisms for horizontal transfer of mitochondria such as cell fusion, gap junctions, tunnelling nanotubes and EVs [50][51]. In the context of cancer, this is another strategy undertaken to alter mitochondrial respiration.
MSCs have been found to transfer whole mitochondria via big MSC-EVs to recipient cells and rescue their metabolic function (see Section 5). However, the mechanisms that are beneficial for regenerative medicine (e.g., cells with a metabolic disease) can also be exploited by cancer cells to increase their mitochondrial number for ATP production to favor their progression [52]. Genetic aberrations and high proliferation in tumor cells increase the likelihood of mitochondrial dysfunction and instability. Therefore, receiving functional mitochondria or mitochondrial components could help restore or enhance mitochondrial function. In the context of chemotherapy, it has been shown that the horizontal transfer of mitochondria from MSC to leukemic cells led to an increase in OXPHOS and cancer cell survival advantage [53].
Further evidence for EV transfer of mitochondria has been seen in the exchange from astrocytes to glioma cells. This was found to improve the metabolism of the recipient cancer cell and contribute to chemotherapy resistance. Mechanistically, mitochondria-derived NAD+ metabolic enzymes increase the availability of NAD+ in recipient cancer cells, inducing the PARP-mediated DNA repair pathway [54]. In turn, tumor-activated stromal cells were also found to transfer mitochondria to glioblastoma cells through a number of different mechanisms, including EVs, with the co-culture of both cell types increasing glioblastoma proliferation and resistance to anticancer treatments [55].
In addition to whole mitochondria, the transfer of mitochondrial components such as mtDNA [56], membrane proteins, and active mitochondrial enzymes also occurs. Mitochondrial proteins can account for up to 10% of the total protein content of small EVs [57]. TEVs from melanoma, ovarian, and breast cancer have all been found to contain mitochondrial components that were not present in healthy controls [58]. Interestingly, a recent study showed that trastuzumab was able to modulate the mitochondrial protein cargo of breast cancer cells with most of the affected proteins being involved in mitochondrial membrane organization. It was also observed that trastuzumab reduced mitochondrial cristae numbers. Therefore, the authors hypothesized that damaged mitochondrial components are packed into EVs for disposal. However, the effect of these EVs and their mitochondrial cargo on potential recipient cells needs further investigation [59].
mtDNA is also selectively packaged into EVs as demonstrated by the higher copy numbers found in EVs in blood compared to cell-free plasma and whole blood [60]. Specifically, cancer cells have been found to release TEVs carrying mtDNA [61]. Moreover, mtDNA copy numbers change according to cancer stage and when compared to healthy controls suggesting a potential role in cancer progression [56][62]. Further evidence for EV mtDNA involvement in cancer biology is from their ability to restore OXPHOS and induce resistance to hormonal therapy in breast cancer cells [63]. Tumor cells that lack mtDNA exhibit delayed tumor growth and cells in the TME can transfer mtDNA to mtDNA-depleted tumor cells thereby re-establishing mitochondrial respiration and enhancing tumorigenic potential. Although the transfer process was not studied, EVs were proposed as a potential mechanism [64]. In the context of chronic alcohol exposure, mitochondrial aldehyde dehydrogenase (Aldh2)-deficient hepatocytes produce oxidized mtDNA, which can be delivered into neighboring HCC cells via EVs activating multiple oncogenic pathways which promote HCC [65]. These results highlight a biological role for EV mtDNA cargo in cancer behavior.

3. Avoiding Immune Destruction

A relevant hallmark of cancer is immune evasion as cancer cells have the capacity to alter both immune surveillance and its response. Tumors utilize different strategies to silence the immune response in order to create a tolerant TME [66][67]. Cancer cells are known to produce immunosuppressive EVs that contain bioactive molecules with immunomodulatory effects [68]. Recent reviews extensively cover the various mechanisms of TEV-mediated immune suppression [69][70]. However, those affecting mitochondrial function remained largely unaddressed. Potential TEV-mediated immune suppression mechanisms involving the reprogramming of immune cell mitochondria include (i) modulating metabolism to inactivate their tumor suppressor function and (ii) triggering mitochondria mediated apoptosis. Interestingly, immunoregulatory effects can also be induced by the transfer of whole mitochondria via EVs [71].

3.1. Macrophage Mitochondrial Reprogramming in Cancer

In recent years, the link between metabolic reprogramming and immune cell function has attracted increasing attention, giving rise to the field of immunometabolism. The metabolic profile of immune cells can define their phenotype and antitumor capabilities [72]. One of the TEV-mediated mechanisms promoting immune evasion is through shifting macrophages towards an anti-inflammatory M2 phenotype [73][74][75]. Macrophage M2 polarization is considered a key component for tumor progression and is linked to mitochondrial metabolism [74]. However, little attention has been paid to TEVs and their role in mediating immune escape through macrophage mitochondrial reprogramming [75][76][77][78][79]. Proinflammatory M1 macrophages have suppressed mitochondrial function and increased glycolysis to support the shift in their energy demands. In contrast, M2 macrophages present an increase in mitochondrial respiration, a preserved TCA cycle and an enhanced fatty acid metabolism [74]. TEVs can alter mitochondrial respiration in non-committed M0 macrophages and polarize them to the M2 phenotype, and their miRNA cargo has been hypothesized as the basis for this observation [73]. Supporting experimental evidence comes from hypoxic TEV inducing M2-like polarization in infiltrating macrophages by enhancing mitochondrial OXPHOS through the transfer of let-7a miRNA which suppresses the insulin mediated mTOR signaling pathway [80]. Many of the underlying mechanisms of macrophage M2 polarization in cancer remain unexplored. Despite this, adaptations of the ETC complexes are recognized to play an important role in defining macrophage immune response by contributing to the immune metabolic switch [81]. Given the importance of bioenergetics in macrophage polarization and the ability of TEVs to modulate cell metabolism, further research is needed on EV-induced mitochondrial reprogramming of macrophages to potentially provide insight into how cancer promotes its own growth and immune escape.

3.2. EV-Related Immunosuppression of T Cells

Other cell types, such as T cells, play a significant role in the regulation of antitumor immune response [82], therefore becoming the target of immunomodulatory mechanisms aimed to reduce cancer cell killing. TEVs have been found to induce apoptosis of activated T cells [83][84] via modulation of the Bcl-2/Bax pathway [85]. TEVs are also responsible for driving antitumor CD8+ effector T cell apoptosis by the presence of FasL and MHC class I as cargo molecules that trigger caspase activation. This, in turn, initiates the release of cytochrome c from mitochondria, leading to a loss of mitochondrial membrane potential and subsequent DNA fragmentation [84][86]. This process is not only modulated by TEVs but also by myeloid-derived suppressor cells EVs (MDSC-EVs). These cells are found in the TME and are recognized for their role in tumor progression. MDSC-EVs contain protumorigenic factors, such as death receptor proteins Fas and TNF-1α, inherited from their parental cells that are capable of immunosuppression by promoting mitochondrial apoptosis in CD8+ T cells through enhanced ROS [87]. The levels of internal ROS in antigen-specific T cells determine cell fate through reciprocal modulation of FasL and antiapoptotic Bcl-2 [88]. In addition to death ligands, melanoma TEVs can eliminate CD4+ T cells by directly targeting mitochondrial apoptosis regulator Bcl-2 through miR-690 [89]. Beyond Bcl-2 family regulation, melanoma cells were also found to enrich their EVs with certain RNAs that, upon delivery, altered mitochondrial function of tumor infiltrating cytotoxic T lymphocytes [90].
Another strategy employed by cancer cells to induce immunosuppression is through EV-encapsulated mtDNA. Mitochondria are a key source of damage-associated molecular patterns (DAMPs) and mtDNA is a large contributing component of mitochondrial DAMPs [91]. As described earlier (Section 4.2.3), TEVs have been found to have a higher copy number of mtDNA compared to healthy controls [62]. Mitochondrial Lon protease (Lon) plays many roles in mitochondrial homeostasis including ROS regulation. Lon drives ROS-induced mtDNA damage which results in its translocation into the cytosol. In the context of cancer, cytosolic mtDNA can affect the immune checkpoint receptors (known as the gatekeepers of the immune response) by causing overexpression of PD-L1 and subsequent activation of immune inhibitory pathways. In parallel, Lon increases the production of TEVs enriched with mtDNA and PD-L1 which inhibit T-cell activation. These Lon-induced EVs further contribute to cancer immune escape by silencing CD9+ T-cell immunity by inducing production of IFN and IL-6 from macrophages [92]. A further link between mitochondria and checkpoint receptors has been shown in a recent study, where the activation of the T-cell surface receptor PD-1 has been associated with downregulation of Drp1 phosphorylation on Ser616 and the consequent reduction of mitochondrial fission in T cells. The effect on mitochondrial dynamics causes a crucial impairment of T-cell functionality and therefore significantly affects antitumor response [93].

4. Activating Invasion and Metastasis

4.1. Increased Motility and Migration

Alterations in mitochondrial dynamics play different roles in the TME by both inducing and supporting malignant transformation, and these effects can be mediated by TEVs. More specifically, EV-mediated dysregulation of mitochondrial dynamics appears to have a direct impact on cancer motility and migration capabilities. For instance, hypoxic breast cancer cells have been shown to release EVs containing integrin-linked kinase (ILK) that increase epithelial cell migration, a requirement for epithelial-to-mesenchymal transition (EMT). As a result, mitochondrial movement was stimulated by promoting their intracellular trafficking and accumulation in the cortical cytoskeleton of epithelial cells. This observation was mediated by the phosphorylation of Ser616 in mitochondrial fission protein Drp1 combined with the increased expression of mitochondrial fusion proteins Mfn-1 and Mfn-2 [47]. Wu and colleagues similarly showed that TEVs could induce malignant transformation in healthy cells. EV-treated cells were found to have a higher number of small-sized mitochondria. The authors proposed that this effect was related to the downregulation of Mfn-2 altering the balance of mitochondrial fusion/fission, but further research is needed to elucidate this process [94].
Conversely, EVs derived from cells within the TME can also affect cancer cell mitochondrial dynamics. Adipocytes have been found to induce a more aggressive phenotype and promote invasiveness of cancer cells [20]. This observation can be achieved by the adipocyte transfer of FA and FAO enzymes via EVs to enhance FAO in cancer cells. This, in turn, alters mitochondrial dynamics to drive increased tumor cell migration. Specifically, increased FAO induces mitochondrial fission and intracellular redistribution of mitochondria to cell protrusions to facilitate cancer cell migration. In parallel, observed mitochondrial size reduction was attributed to EV transfer of mitochondrial fission regulators FIS1 and OPA1, with mitochondrial fission events being identified as crucial for cell migration [23]. CAF-EVs have also been shown to transfer miR-106b to pancreatic cancer where it has been associated with chemotherapy resistance [95]. On a mechanistic level, this miRNA species has been found to induce mitochondrial dysfunction in skeletal muscle by targeting Mfn-2 [96] but more studies are required in the context of cancer.

4.2. Intravasation (Trans-Endothelial Migration into Vessels)

After increased cell motility, the next step in the metastatic cascade is the intravasation of tumor cells into the vasculature. TEVs have the capacity to destroy vessel barriers to promote this aspect. Breast cancer TEVs are able to destroy endothelial barriers by activating endothelial to mesenchymal transition [97], which can be driven by mitochondrial dysfunction [98] and is required for the preparation of the premetastatic niche. miR-34a, present in TEVs [99], can also induce breakdown of the blood–brain barrier (BBB) by inducing a reduction in endothelial OXPHOS, ATP production and cytochrome c, the latter being a downstream target of miR-34a [100]. Another miRNA delivered through EVs that can promote destruction of the BBB is miR-181c [101]. A target of miR-181c is COX1 [102], whose downregulation results in mitochondrial apoptosis [103]. These preliminary but interesting results encourage the need for further investigation that strengthens the knowledge in the link between TEV cargo and the loss of endothelial barrier integrity via manipulation of mitochondrial biology.

References

  1. Gentric, G.; Mechta-Grigoriou, F. Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective. Cancers 2021, 13, 399.
  2. Nurmik, M.; Ullmann, P.; Rodriguez, F.; Haan, S.; Letellier, E. In search of definitions: Cancer-associated fibroblasts and their markers. Int. J. Cancer 2019, 146, 895–905.
  3. Avagliano, A.; Granato, G.; Ruocco, M.R.; Romano, V.; Belviso, I.; Carfora, A.; Montagnani, S.; Arcucci, A. Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts. BioMed Res. Int. 2018, 2018, 6075403.
  4. Roy, A.; Bera, S. CAF cellular glycolysis: Linking cancer cells with the microenvironment. Tumor Biol. 2016, 37, 8503–8514.
  5. La Shu, S.; Yang, Y.; Allen, C.L.; Maguire, O.; Minderman, H.; Sen, A.; Ciesielski, M.J.; Collins, K.A.; Bush, P.J.; Singh, P.; et al. Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment. Sci. Rep. 2018, 8, 12905.
  6. Zhang, D.; Wang, Y.; Shi, Z.; Liu, J.; Sun, P.; Hou, X.; Zhang, J.; Zhao, S.; Zhou, B.P.; Mi, J. Metabolic Reprogramming of Cancer-Associated Fibroblasts by IDH3α Downregulation. Cell Rep. 2015, 10, 1335–1348.
  7. Albino, D.; Falcione, M.; Uboldi, V.; Temilola, D.O.; Sandrini, G.; Merulla, J.; Civenni, G.; Kokanovic, A.; Stürchler, A.; Shinde, D.; et al. Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer. Commun. Biol. 2021, 4, 119.
  8. Fan, J.; Xu, G.; Chang, Z.; Zhu, L.; Yao, J. Mir-210 Transferred by Lung Cancer Cell-Derived Exosomes May Act as Proangiogenic Factor in Cancer-Associated Fibroblasts by Modulating Jak2/Stat3 Pathway. Clin. Sci. 2020, 134, 807–825.
  9. Puissegur, M.-P.; Mazure, N.M.; Bertero, T.; Pradelli, L.; Grosso, S.; Robbe-Sermesant, K.; Maurin, T.; Lebrigand, K.; Cardinaud, B.; Hofman, V.; et al. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 2010, 18, 465–478.
  10. Wu, X.; Zhou, Z.; Xu, S.; Liao, C.; Chen, X.; Li, B.; Peng, J.; Li, D.; Yang, L. Extracellular vesicle packaged LMP1-activated fibroblasts promote tumor progression via autophagy and stroma-tumor metabolism coupling. Cancer Lett. 2020, 478, 93–106.
  11. Rai, A.; Greening, D.W.; Chen, M.; Xu, R.; Ji, H.; Simpson, R.J. Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome. Proteomics 2019, 19, 1800148.
  12. Li, Y.; Zhao, Z.; Liu, W.; Li, X. SNHG3 Functions as miRNA Sponge to Promote Breast Cancer Cells Growth Through the Metabolic Reprogramming. Appl. Biochem. Biotechnol. 2020, 191, 1084–1099.
  13. Zhao, H.; Yang, L.; Baddour, J.; Achreja, A.; Bernard, V.; Moss, T.; Marini, J.C.; Tudawe, T.; Seviour, E.G.; Lucas, F.A.S.; et al. Author response: Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 2015.
  14. Achreja, A.; Zhao, H.; Yang, L.; Yun, T.H.; Marini, J.; Nagrath, D. Exo-MFA—A 13C metabolic flux analysis framework to dissect tumor microenvironment-secreted exosome contributions towards cancer cell metabolism. Metab. Eng. 2017, 43, 156–172.
  15. Ham, I.-H.; Lee, D.; Hur, H. Cancer-Associated Fibroblast-Induced Resistance to Chemotherapy and Radiotherapy in Gastrointestinal Cancers. Cancers 2021, 13, 1172.
  16. Zhang, Z.; Jiang, H.; Li, X.; Chen, X.; Huang, Y. Mir-92a Regulates Brown Adipocytes Differentiation, Mitochondrial Oxidative Respiration, and Heat Generation by Targeting Smad7. J. Cell. Biochem. 2020, 121, 3825–3836.
  17. Lengyel, E.; Makowski, L.; DiGiovanni, J.; Kolonin, M.G. Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors. Trends Cancer 2018, 4, 374–384.
  18. Barquissau, V.; Beuzelin, D.; Pisani, D.F.; Beranger, G.E.; Mairal, A.; Montagner, A.; Roussel, B.; Tavernier, G.; Marques, M.-A.; Moro, C.; et al. White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways. Mol. Metab. 2016, 5, 352–365.
  19. Wu, Q.; Li, J.; Li, Z.; Sun, S.; Zhu, S.; Wang, L.; Wu, J.; Yuan, J.; Zhang, Y.; Sun, S.; et al. Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression. J. Exp. Clin. Cancer Res. 2019, 38, 223.
  20. Wu, Q.; Sun, S.; Li, Z.; Yang, Q.; Li, B.; Zhu, S.; Wang, L.; Wu, J.; Yuan, J.; Yang, C.; et al. Tumour-originated exosomal miR-155 triggers cancer-associated cachexia to promote tumour progression. Mol. Cancer 2018, 17, 155.
  21. Sah, R.P.; Sharma, A.; Nagpal, S.; Patlolla, S.H.; Sharma, A.; Kandlakunta, H.; Anani, V.; Angom, R.S.; Kamboj, A.K.; Ahmed, N.; et al. Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. Gastroenterology 2019, 156, 1742–1752.
  22. Lazar, I.; Clement, E.; Dauvillier, S.; Milhas, D.; Ducoux-Petit, M.; LeGonidec, S.; Moro, C.; Soldan, V.; Dalle, S.; Balor, S.; et al. Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer. Cancer Res. 2016, 76, 4051–4057.
  23. Clement, E.; Lazar, I.; Attané, C.; Carrié, L.; Dauvillier, S.; Ducoux-Petit, M.; Esteve, D.; Menneteau, T.; Moutahir, M.; Le Gonidec, S.; et al. Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells. EMBO J. 2020, 39, e102525.
  24. Liu, Y.; Tan, J.; Ou, S.; Chen, J.; Chen, L. Adipose-derived exosomes deliver miR-23a/b to regulate tumor growth in hepatocellular cancer by targeting the VHL/HIF axis. J. Physiol. Biochem. 2019, 75, 391–401.
  25. Gao, P.; Tchernyshyov, I.; Chang, T.-C.; Lee, Y.-S.; Kita, K.; Ochi, T.; Zeller, K.I.; De Marzo, A.M.; Van Eyk, J.E.; Mendell, J.T.; et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009, 458, 762–765.
  26. Yogev, O.; Henderson, S.; Hayes, M.J.; Marelli, S.S.; Ofir-Birin, Y.; Regev-Rudzki, N.; Herrero, J.; Enver, T. Herpesviruses shape tumour microenvironment through exosomal transfer of viral microRNAs. PLoS Pathog. 2017, 13, e1006524.
  27. Sarosiek, K.A.; Ni Chonghaile, T.; Letai, A. Mitochondria: Gatekeepers of response to chemotherapy. Trends Cell Biol. 2013, 23, 612–619.
  28. Elliott, R.L.; Jiang, X.P.; Head, J.F. Mitochondria organelle transplantation: Introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity. Breast Cancer Res. Treat. 2012, 136, 347–354.
  29. Sun, C.; Wang, Z.; Liu, Y.; Liu, Y.; Li, H.; Di, C.; Wu, Z.; Gan, L.; Zhang, H. Carbon ion beams induce hepatoma cell death by NADPH oxidase-mediated mitochondrial damage. J. Cell. Physiol. 2013, 229, 100–107.
  30. Kreger, B.T.; Johansen, E.R.; Cerione, R.A.; Antonyak, M.A. The Enrichment of Survivin in Exosomes from Breast Cancer Cells Treated with Paclitaxel Promotes Cell Survival and Chemoresistance. Cancers 2016, 8, 111.
  31. Cappellesso, R.; Tinazzi, A.; Giurici, T.; Simonato, F.; Guzzardo, V.; Ventura, L.; Crescenzi, M.; Chiarelli, S.; Fassina, A. Programmed cell death 4 and microRNA 21 inverse expression is maintained in cells and exosomes from ovarian serous carcinoma effusions. Cancer Cytopathol. 2014, 122, 685–693.
  32. Matsumoto, A.; Takahashi, Y.; Nishikawa, M.; Sano, K.; Morishita, M.; Charoenviriyakul, C.; Saji, H.; Takakura, Y. Accelerated growth of B16 BL 6 tumor in mice through efficient uptake of their own exosomes by B16 BL 6 cells. Cancer Sci. 2017, 108, 1803–1810.
  33. Yang, L.; Wu, X.-H.; Wang, D.; Luo, C.-L.; Chen, L.-X. Bladder cancer cell-derived exosomes inhibit tumor cell apoptosis and induce cell proliferation in vitro. Mol. Med. Rep. 2013, 8, 1272–1278.
  34. Lang, H.-L.; Hu, G.-W.; Zhang, B.; Kuang, W.; Chen, Y.; Wu, L.; Xu, G.-H. Glioma cells enhance angiogenesis and inhibit endothelial cell apoptosis through the release of exosomes that contain long non-coding RNA CCAT2. Oncol. Rep. 2017, 38, 785–798.
  35. Hmadcha, A.; Martin-Montalvo, A.; Gauthier, B.; Soria, B.; Capilla-Gonzalez, V. Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy. Front. Bioeng. Biotechnol. 2020, 8, 43.
  36. Deng, M.; Yuan, H.; Liu, S.; Hu, Z.; Xiao, H. Exosome-transmitted LINC00461 promotes multiple myeloma cell proliferation and suppresses apoptosis by modulating microRNA/BCL-2 expression. Cytotherapy 2019, 21, 96–106.
  37. Dong, H.; Wang, W.; Chen, R.; Zhang, Y.; Zou, K.; Ye, M.; He, X.; Zhang, F.; Han, J. Exosome-mediated transfer of lncRNA-SNHG14 promotes trastuzumab chemoresistance in breast cancer. Int. J. Oncol. 2018, 53, 1013–1026.
  38. Kang, M.; Ren, M.; Li, Y.; Fu, Y.; Deng, M.; Li, C. Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA. J. Exp. Clin. Cancer Res. 2018, 37, 171.
  39. Zhang, Y.; Li, M.; Hu, C. Exosomal transfer of miR-214 mediates gefitinib resistance in non-small cell lung cancer. Biochem. Biophys. Res. Commun. 2018, 507, 457–464.
  40. Zhao, K.; Wang, Z.; Li, X.; Liu, J.-L.; Tian, L.; Chen, J.-Q. Exosome-mediated transfer of CLIC1 contributes to the vincristine-resistance in gastric cancer. Mol. Cell. Biochem. 2019, 462, 97–105.
  41. Yang, Z.-J.; Zhang, L.-L.; Bi, Q.-C.; Gan, L.-J.; Wei, M.-J.; Hong, T.; Tan, R.-J.; Lan, X.-M.; Liu, L.-H.; Han, X.-J.; et al. Exosomal connexin 43 regulates the resistance of glioma cells to temozolomide. Oncol. Rep. 2021, 45, 44.
  42. Li, X.-Q.; Liu, J.-T.; Fan, L.-L.; Liu, Y.; Cheng, L.; Wang, F.; Yu, H.-Q.; Gao, J.; Wei, W.; Wang, H.; et al. Exosomes derived from gefitinib-treated EGFR-mutant lung cancer cells alter cisplatin sensitivity via up-regulating autophagy. Oncotarget 2016, 7, 24585–24595.
  43. Hu, W.; Xu, Z.; Zhu, S.; Sun, W.; Wang, X.; Tan, C.; Zhang, Y.; Zhang, G.; Xu, Y.; Tang, J. Small extracellular vesicle-mediated Hsp70 intercellular delivery enhances breast cancer adriamycin resistance. Free Radic. Biol. Med. 2021, 164, 85–95.
  44. Hu, J.L.; Wang, W.; Lan, X.L.; Zeng, Z.C.; Liang, Y.S.; Yan, Y.R.; Song, F.Y.; Wang, F.F.; Zhu, X.H.; Liao, W.J.; et al. CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer. Mol. Cancer 2019, 18, 91.
  45. Wang, H.; Huang, H.; Wang, L.; Liu, Y.; Wang, M.; Zhao, S.; Lu, G.; Kang, X. Cancer-associated fibroblasts secreted miR-103a-3p suppresses apoptosis and promotes cisplatin resistance in non-small cell lung cancer. Aging 2021, 13, 14456–14468.
  46. Cai, J.; Wang, J.; Huang, Y.; Wu, H.-X.; Xia, T.; Xiao, J.; Chen, X.; Li, H.; Qiu, Y.; Wang, Y.; et al. ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells. Cell Death Dis. 2016, 7, e2459.
  47. Bertolini, I.; Ghosh, J.C.; Kossenkov, A.V.; Mulugu, S.; Krishn, S.R.; Vaira, V.; Qin, J.; Plow, E.F.; Languino, L.R.; Altieri, D.C. Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment. Dev. Cell 2020, 55, 163–177.e6.
  48. Islam, M.N.; Das, S.R.; Emin, M.T.; Wei, M.; Sun, L.; Westphalen, K.; Rowlands, D.J.; Quadri, S.K.; Bhattacharya, S.; Bhattacharya, J. Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 2012, 18, 759–765.
  49. Hayakawa, K.; Esposito, E.; Wang, X.; Terasaki, Y.; Liu, Y.; Xing, C.; Ji, X.; Lo, E.H. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 2016, 535, 551–555.
  50. MohammadAlipour, A.; Dumbali, S.P.; Wenzel, P.L. Mitochondrial Transfer and Regulators of Mesenchymal Stromal Cell Function and Therapeutic Efficacy. Front. Cell Dev. Biol. 2020, 8, 603292.
  51. Hough, K.; Trevor, J.L.; Strenkowski, J.G.; Wang, Y.; Chacko, B.K.; Tousif, S.; Chanda, D.; Steele, C.; Antony, V.B.; Dokland, T.; et al. Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol. 2018, 18, 54–64.
  52. Dong, L.-F.; Kovarova, J.; Bajzikova, M.; Bezawork-Geleta, A.; Svec, D.; Endaya, B.; Sachaphibulkij, K.; Coelho, A.R.; Sebkova, N.; Ruzickova, A.; et al. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. eLife 2017, 6, e22187.
  53. Griessinger, E.; Moschoi, R.; Biondani, G.; Peyron, J.-F. Mitochondrial Transfer in the Leukemia Microenvironment. Trends Cancer 2017, 3, 828–839.
  54. Liu, Y.; Lu, Y.; Li, A.; Song, H.; Zhang, W.; Gilbert, M.; Yang, C. CBMT-46, Microenvironment-derived mitochondria prime glioma chemoresistance by augmenting Nad+ Metabolism and parp-dependent DNA repair. Neuro Oncol. 2018, 20, vi42.
  55. Salaud, C.; Alvarez-Arenas, A.; Geraldo, F.; Belmonte-Beitia, J.; Calvo, G.F.; Gratas, C.; Pecqueur, C.; Garnier, D.; Pérez-Garcià, V.; Vallette, F.M.; et al. Mitochondria transfer from tumor-activated stromal cells (TASC) to primary Glioblastoma cells. Biochem. Biophys. Res. Commun. 2020, 533, 139–147.
  56. Li, Y.; Guo, X.; Guo, S.; Wang, Y.; Chen, L.; Liu, Y.; Jia, M.; An, J.; Tao, K.; Xing, J. Next generation sequencing-based analysis of mitochondrial DNA characteristics in plasma extracellular vesicles of patients with hepatocellular carcinoma. Oncol. Lett. 2020, 20, 2820–2828.
  57. Schwarzenbach, H.; Gahan, P. Exosomes in Immune Regulation. Non-Coding RNA 2021, 7, 4.
  58. Jang, S.C.; Crescitelli, R.; Cvjetkovic, A.; Belgrano, V.; Bagge, R.O.; Sundfeldt, K.; Ochiya, T.; Kalluri, R.; Lötvall, J. Mitochondrial protein enriched extracellular vesicles discovered in human melanoma tissues can be detected in patient plasma. J. Extracell. Vesicles 2019, 8, 1635420.
  59. Marconi, S.; Santamaria, S.; Bartolucci, M.; Stigliani, S.; Aiello, C.; Gagliani, M.; Bellese, G.; Petretto, A.; Cortese, K.; Castagnola, P. Trastuzumab Modulates the Protein Cargo of Extracellular Vesicles Released by ERBB2+ Breast Cancer Cells. Membranes 2021, 11, 199.
  60. Ruivo, C.F.; Adem, B.; Silva, M.; Melo, S.A. The Biology of Cancer Exosomes: Insights and New Perspectives. Cancer Res. 2017, 77, 6480–6488.
  61. Guescini, M.; Genedani, S.; Stocchi, V.; Agnati, L.F. Astrocytes and Glioblastoma cells release exosomes carrying mtDNA. J. Neural Transm. 2010, 117, 1.
  62. Keserű, J.S.; Soltész, B.; Lukács, J.; Márton, É.; Szilágyi-Bónizs, M.; Penyige, A.; Póka, R.; Nagy, B. Detection of cell-free, exosomal and whole blood mitochondrial DNA copy number in plasma or whole blood of patients with serous epithelial ovarian cancer. J. Biotechnol. 2019, 298, 76–81.
  63. Sansone, P.; Savini, C.; Kurelac, I.; Chang, Q.; Amato, L.B.; Strillacci, A.; Stepanova, A.; Iommarini, L.; Mastroleo, C.; Daly, L.; et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl. Acad. Sci. USA 2017, 114, E9066–E9075.
  64. Tan, A.S.; Baty, J.W.; Dong, L.-F.; Bezawork-Geleta, A.; Endaya, B.; Goodwin, J.; Bajzikova, M.; Kovarova, J.; Peterka, M.; Yan, B.; et al. Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA. Cell Metab. 2015, 21, 81–94.
  65. Seo, W.; Gao, Y.; He, Y.; Sun, J.; Xu, H.; Feng, D.; Park, S.H.; Cho, Y.-E.; Guillot, A.; Ren, T.; et al. ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles. J. Hepatol. 2019, 71, 1000–1011.
  66. Kim, R.; Emi, M.; Tanabe, K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007, 121, 1–14.
  67. Bates, J.P.; Derakhshandeh, R.; Jones, L.; Webb, T.J. Mechanisms of Immune Evasion in Breast Cancer. BMC Cancer 2018, 18, 556.
  68. Whiteside, T.L. Exosomes and tumor-mediated immune suppression. J. Clin. Investig. 2016, 126, 1216–1223.
  69. Li, Q.; Cai, S.; Li, M.; Salma, K.I.; Zhou, X.; Han, F.; Chen, J.; Huyan, T. Tumor-Derived Extracellular Vesicles: Their Role in Immune Cells and Immunotherapy. Int. J. Nanomed. 2021, 16, 5395–5409.
  70. Sheehan, C.; D’Souza-Schorey, C. Tumor-derived extracellular vesicles: Molecular parcels that enable regulation of the immune response in cancer. J. Cell Sci. 2019, 132, jcs235085.
  71. She, Z.; Xie, M.; Hun, M.; Abdirahman, A.S.; Li, C.; Wu, F.; Luo, S.; Wan, W.; Wen, C.; Tian, J. Immunoregulatory Effects of Mitochondria Transferred by Extracellular Vesicles. Front. Immunol. 2021, 11, 628576.
  72. Biswas, S.K. Metabolic Reprogramming of Immune Cells in Cancer Progression. Immunity 2015, 43, 435–449.
  73. Pritchard, A.; Tousif, S.; Wang, Y.; Hough, K.; Khan, S.; Strenkowski, J.; Chacko, B.K.; Darley-Usmar, V.M.; Deshane, J.S. Lung Tumor Cell-Derived Exosomes Promote M2 Macrophage Polarization. Cells 2020, 9, 1303.
  74. Russell, D.G.; Huang, L.; VanderVen, B.C. Immunometabolism at the Interface between Macrophages and Pathogens. Immunology 2019, 19, 291–304.
  75. Raimondo, S.; Pucci, M.; Alessandro, R.; Fontana, S. Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives. Int. J. Mol. Sci. 2020, 21, 2286.
  76. Graner, M.W.; Schnell, S.; Olin, M.R. Tumor-Derived Exosomes, Micrornas, and Cancer Immune Suppression. Semin. Immunopathol. 2018, 40, 505–515.
  77. Syed, S.N.; Frank, A.-C.; Raue, R.; Brüne, B. Microrna-a Tumor Trojan Horse for Tumor-Associated Macrophages. Cells 2019, 8, 1482.
  78. Kwon, Y.; Kim, M.; Kim, Y.; Jung, H.S.; Jeoung, D. Exosomal MicroRNAs as Mediators of Cellular Interactions Between Cancer Cells and Macrophages. Front. Immunol. 2020, 11, 1167.
  79. Yi, M.; Xu, L.; Jiao, Y.; Luo, S.; Li, A.; Wu, K. The role of cancer-derived microRNAs in cancer immune escape. J. Hematol. Oncol. 2020, 13, 25.
  80. Park, J.E.; Dutta, B.; Tse, S.W.; Gupta, N.; Tan, C.F.; Low, J.K.; Yeoh, K.W.; Kon, O.L.; Tam, J.P.; Sze, S.K. Hypoxia-Induced Tumor Exosomes Promote M2-Like Macrophage Polarization of Infiltrating Myeloid Cells and Microrna-Mediated Metabolic Shift. Oncogene 2019, 38, 5158–5173.
  81. Garaude, J.; Acín-Pérez, R.; Martínez-Cano, S.; Enamorado, M.; Ugolini, M.; Nistal-Villán, E.; Hervás-Stubbs, S.; Pelegrín, P.; Sander, L.E.; Enríquez, J.A.; et al. Mitochondrial Respiratory-Chain Adaptations in Macrophages Contribute to Antibacterial Host Defense. Nat. Immunol. 2016, 17, 1037–1045.
  82. Zaini, R.G.; Al-Rehaili, A.A. The Therapeutic Strategies of Regulatory T Cells in Malignancies and Stem Cell Transplantations. J. Oncol. 2019, 2019, 5981054.
  83. Robbins, P.D.; Dorronsoro, A.; Booker, C.N. Regulation of chronic inflammatory and immune processes by extracellular vesicles. J. Clin. Investig. 2016, 126, 1173–1180.
  84. Whiteside, T.L. Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem. Soc. Trans. 2013, 41, 245–251.
  85. Yang, L.; Wu, X.; Wang, D.; Luo, C.; Chen, L. Renal Carcinoma Cell-Derived Exosomes Induce Human Immortalized Line of Jurkat T Lymphocyte Apoptosis in vitro. Urol. Int. 2013, 91, 363–369.
  86. Czystowska-Kuźmicz, M.; Han, J.; Szczepanski, M.J.; Szajnik, M.; Quadrini, K.; Brandwein, H.; Hadden, J.W.; Signorelli, K.; Whiteside, T.L. IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death. Cell Death Differ. 2009, 16, 708–718.
  87. Rashid, M.H.; Borin, T.F.; Ara, R.; Piranlioglu, R.; Achyut, B.R.; Korkaya, H.; Liu, Y.; Arbab, A.S. Critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment. Oncol. Rep. 2021, 45, 1171–1181.
  88. Hildeman, D.A.; Mitchell, T.; Kappler, J.; Marrack, P. T cell apoptosis and reactive oxygen species. J. Clin. Investig. 2003, 111, 575–581.
  89. Zhou, J.; Yang, Y.; Wang, W.; Zhang, Y.; Chen, Z.; Hao, C.; Zhang, J. Melanoma-released exosomes directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo. Exp. Cell Res. 2018, 371, 364–371.
  90. Bland, C.L.; Byrne-Hoffman, C.N.; Fernandez, A.; Rellick, S.L.; Deng, W.; Klinke, D.J. Exosomes derived from B16F0 melanoma cells alter the transcriptome of cytotoxic T cells that impacts mitochondrial respiration. FEBS J. 2018, 285, 1033–1050.
  91. West, A.P.; Shadel, G.S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 2017, 17, 363–375.
  92. Cheng, A.N.; Cheng, L.-C.; Kuo, C.-L.; Lo, Y.K.; Chou, H.-Y.; Chen, C.-H.; Wang, Y.-H.; Chuang, T.-H.; Cheng, S.-J.; Lee, A.Y.-L. Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles. J. Immunother. Cancer 2020, 8, e001372.
  93. Simula, L.; Antonucci, Y.; Scarpelli, G.; Cancila, V.; Colamatteo, A.; Manni, S.; De Angelis, B.; Quintarelli, C.; Procaccini, C.; Matarese, G.; et al. Pd-1-Induced T Cell Exhaustion Is Controlled by a Drp1-Dependent Mechanism. Mol. Oncol. 2022, 16, 188–205.
  94. Wu, C.-H.; Silvers, C.R.; Messing, E.M.; Lee, Y.-F. Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells. J. Biol. Chem. 2019, 294, 3207–3218.
  95. Fang, Y.; Zhou, W.; Rong, Y.; Kuang, T.; Xu, X.; Wu, W.; Wang, D.; Lou, W. Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer. Exp. Cell Res. 2019, 383, 111543.
  96. Zhang, Y.; Yang, L.; Gao, Y.-F.; Fan, Z.-M.; Cai, X.-Y.; Liu, M.-Y.; Guo, X.-R.; Gao, C.-L.; Xia, Z.-K. MicroRNA-106b induces mitochondrial dysfunction and insulin resistance in C2C12 myotubes by targeting mitofusin-2. Mol. Cell. Endocrinol. 2013, 381, 230–240.
  97. Kim, J.; Lee, C.; Kim, I.; Ro, J.; Kim, J.; Min, Y.; Park, J.; Sunkara, V.; Park, Y.-S.; Michael, I.; et al. Three-Dimensional Human Liver-Chip Emulating Premetastatic Niche Formation by Breast Cancer-Derived Extracellular Vesicles. ACS Nano 2020, 14, 14971–14988.
  98. Hua, W.; Dijke, P.T.; Kostidis, S.; Giera, M.; Hornsveld, M. TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer. Cell. Mol. Life Sci. 2019, 77, 2103–2123.
  99. Ge, L.; Wu, Y.; Wan, M.; You, Y.; Zhai, Z.; Song, Z. Metformin Increases Sensitivity of Melanoma Cells to Cisplatin by Blocking Exosomal-Mediated miR-34a Secretion. J. Oncol. 2021, 2021, 5525231.
  100. Bukeirat, M.; Sarkar, S.N.; Hu, H.; Quintana, D.D.; Simpkins, J.W.; Ren, X. Mir-34a Regulates Blood-Brain Barrier Permeability and Mitochondrial Function by Targeting Cytochrome C. J. Cereb. Blood Flow Metab 2016, 36, 387–392.
  101. Tominaga, N.; Kosaka, N.; Ono, M.; Katsuda, T.; Yoshioka, Y.; Tamura, K.; Lötvall, J.; Nakagama, H.; Ochiya, T. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier. Nat. Commun. 2015, 6, 6716.
  102. Gusic, M.; Prokisch, H. Ncrnas: New Players in Mitochondrial Health and Disease? Front. Genet. 2020, 11, 95.
  103. Ding, L.; Gu, H.; Lan, Z.; Lei, Q.; Wang, W.; Ruan, J.; Yu, M.; Lin, J.; Cui, Q. Downregulation of Cyclooxygenase-1 Stimulates Mitochondrial Apoptosis through the Nf-Κb Signaling Pathway in Colorectal Cancer Cells. Oncol. Rep. 2019, 41, 559–569.
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