Mesenchymal stem cell exosomes: a two-edged sword in cancer therapy

Figures & data

Figure 1 Exosome biogenesis and secretion.

Note: Reprinted from Schorey JS, Cheng Y, Singh PP, Smith VL. Exosomes and other extracellular vesicles in host–pathogen interactions. EMBO Rep. 2015;16(1):24–43, with permission from John Wiley and Sons.²¹

Abbreviation: MVB, multivesicular body.

Table 1 Natural or modified MSC EVs/exosomes that promote tumors or extend their metastatic effect

Source of exosome	Study mode	Therapeutic agent	Target cancer/cells	Outcome	Reference
Stressed EVs derived from BM MSCs	In vitro and in vivo	No	Breast cancer cell	Supported breast cancer cell proliferation and metastasis possibly by transferring miR-21 and miR-34a	^Citation30
Human BM MSC-derived exosomes	In vitro	No	Osteosarcoma and gastric cancer cell lines	Supported cancer cell growth by promoting the Hedgehog signaling pathway	^Citation31
Human umbilical cord MSC-derived exosomes	In vitro	No	Ovary and breast cancer cells	Supported cancer cell reorganization and growth by transferring MMP-2 enzyme	^Citation32
Multiple myeloma BM MSC-derived exosomes	In vitro and in vivo	No	Multiple myeloma	Supported tumor progression possibly by transferring lower amount of exosomal tumor inhibitor miR-15a	^Citation36
Exosomes derived from BM MSCs	In vitro and in vivo	No	Gastric cancer	Stimulated tumor angiogenesis by inducing VEGF expression via activating ERK1/2 and p38 mitogen-activated protein kinase pathways	^Citation37
Placental exosomes derived from MSCs	In vitro	No	Placental microvascular endothelial cells	Promoted migration and angiogenesis	^Citation38
Adipose MSC-derived exosomes	In vitro and in vivo	No	Human microvascular endothelial cells	Promoted angiogenesis	^Citation39
Exosomes derived from gastric cancer tissue-derived MSCs	In vitro and in vivo	No	Gastric cancer	Facilitated growth and migration of tumor cells	^Citation44
Exosomes derived from MSCs	In vitro	No	Breast cancer	Induced Wnt signaling activation, hence facilitating migration and growth of the tumor cell line	^Citation45

Abbreviations: BM, bone marrow; EV, extracellular vesicle; miR, microRNA; MMP-2, matrix metalloproteinase-2; MSC, mesenchymal stem cell; VEGF, vascular endothelial growth factor.

Table 2 Natural or modified MSC EVs/exosomes that have an inhibitory effect on tumors

Source of exosome	Study mode	Therapeutic agent	Target cancer/cells	Outcome	Reference
Human umbilical cord Wharton’s jelly MSC-derived EVs	In vitro and in vivo	No	Bladder carcinoma	Inhibited tumor growth by down-regulating phosphorylation of Akt protein kinase and up-regulating cleaved caspase-3	^Citation33
Adipose MSC-derived exosomes	In vitro and in vivo	No	Prostate cancer	Inhibited tumor growth possibly by transferring miR-145 to reduce the activity of Bcl-xL and promote apoptosis through the caspase-3/7 pathway	^Citation34
Human BM MSC-derived EVs	In vitro and in vivo	No	Hepatoma/Kaposi’s sarcoma/ovarian tumor cell lines	Inhibited tumor growth	^Citation35
Exosomes derived from normal BM MSCs	In vitro and in vivo	No	Multiple myeloma	Inhibited tumor promotion	^Citation36
Mouse exosomes derived from BM MSCs	In vitro and in vivo	No	Mouse breast cancer cell line (4T1)	Suppressed angiogenesis via delivery of miR-16 and down-regulation of VEGF in the tumor	^Citation41
Exosomes derived from MSCs	In vivo	No	N/A	Cancer cells targeting capability using the exosome-mediated transfer of proteasomes	^Citation48
Exosomes derived from MSCs	In vitro	Paclitaxel	Pancreatic adenocarcinoma	Mediated powerful antitumorigenic outcomes	^Citation53
Exosomes derived from MSCs	In vitro	Anti-miR-9	Glioblastoma multiforme	Reversed the expression of multidrug transporters and reversed the chemoresistance	^Citation54
Exosomes derived from MSCs	In vitro and in vivo	miR-146b	Glioma	Decreased glioma xenograft progress in a rat brain tumor model and declined in vitro progression and metastasis	^Citation55
Exosomes derived from MSCs	In vitro	miR-143	Osteosarcoma cells	Decreased the migration of osteosarcoma cells	^Citation56
Exosomes derived from adipose MSCs	In vitro and in vivo	miR-122	Hepatocellular carcinoma	Increased tumor cell sensitivity to chemotherapeutic agents and tumor growth	^Citation57
Exosomes derived from adipose MSCs	In vitro and in vivo	miR-379	Breast cancer	Reduced tumor activity over the 6 weeks of monitoring	^Citation58
MSC-derived EVs	In vitro	TRAIL	Various cancer cell lines	Increased cell death in a range of cancer cell lines	^Citation59
Exosomes derived from MSCs	In vitro	PLK-1 siRNA	Bladder cancer	Successfully applied as a delivery vector to transfer PLK-1 siRNA to cancer cells of the bladder	^Citation50
Exosomes derived from MSCs	In vitro and in vivo	miR-124/miR-145 mimics	Glioma	Reduced the tumor cells migration and the stem cell properties of glioma cells	^Citation60
Human foreskin fibroblast-like/MSCs	In vivo	siRNA for oncogenic Kras	Mouse model of pancreatic cancer	Repressed cancer in multiple models of pancreatic cancer in the mouse and improved overall survival	^Citation61

Abbreviations: BM, bone marrow; EV, extracellular vesicle; miR, microRNA; MSC, mesenchymal stem cell; N/A, not available; siRNA, small interfering RNA; VEGF, vascular endothelial growth factor.

Figure 2 Strategies for targeting extracellular vesicles to particular target cells can be achieved by genetic modification of exosomes to express targeting moieties fused with exosome native membrane proteins, such as lysosomal-associated membrane protein 2 (Lamp2b), tetraspanins, glycosylphosphatidylinositol (GPI), and lactadherin C1C2.

Figure 3 Schematic of the procedure used to engineer the exosome–liposome hybrids. Reprinted from Sato YT, Umezaki K, Sawada S, et al. Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep. 2016;6:21933.⁸⁴

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