Dual Role of MSC-Derived Exosomes in Tumor Development

Abstract

Mesenchymal stem cells (MSCs) are a class of adult stem cells derived from the mesoderm. They can self-renew, have multidirectional differentiation potential, and can differentiate into a variety of mesenchymal tissues. MSCs can produce a large number of exosomes, which can mediate information exchange and transmission between cells in the tumor microenvironment under conditions of rest or stress. Recent studies have reported conflicting findings regarding the effect of MSC-derived exosomes on tumors. Some studies have suggested that MSC-derived exosomes can promote tumor growth and metastasis, but others have reported that they can inhibit tumor cell growth. Here, we investigate the two sides of the debate regarding the effect of MSC-derived exosomes on tumors and analyze the reasons for the divergent findings.

Figure 1

Exosome biogenesis and secretion. Cell membrane inward budding leads to the formation of early endosomes, and these transform into multivesicular bodies (MVBs) with a dynamic subcellular structure. MVBs can be fused with lysosomes or the plasma membrane and secreted exosomes. Finally, exosomes release cargo such as DNA, microRNA, and proteins to cancer cells through (a) direct fusion with recipient cell plasma, (b) surface protein binding, or (c) endocytosis.

Figure 2

Promotional roles of MSC-derived exosomes in tumors. MSC-derived exosomes can promote tumor growth and cell migration and confer drug resistance on gastric cancer by activating the Akt, ERK1/2, CaM-Ks, and Hedgehog pathways and transporting miR-221 to cancer cells. MSC-derived exosomes support multiple myeloma progression by shuttling LINC00461. Moreover, MSC-derived exosomes support breast cancer cell proliferation, metastasis, and reorganization through Hippo and Wnt pathways and by delivering exosomal TGF-b, C1q, semaphorins, MMP-2, miR-21, and miR-34a. MSC-derived exosomes promote osteosarcoma growth through the Hedgehog pathway. MSC-derived exosomes facilitate nasopharyngeal carcinoma progression through the delivery of FGF19. MSC-derived exosomes enhance the aggressiveness of glioblastoma and growth of glioma stem cells through the delivery of miR-1587.

Figure 3

Inhibitory roles of MSC-derived exosomes in tumors. MSC-derived exosomes suppress angiogenesis and promote dormancy of breast cancer by shuttling miR-100, miR-16, miR-23b, and miR-222/223. MSC-derived exosomes suppress cell migration, invasion, and progression by shuttling miR-143 and miR-145. MSC-derived exosomes induce bladder cancer cell apoptosis and necrosis by transporting PLK-1 siRNA and inhibit osteosarcoma cell migration by shuttling miR-143. MSC-derived exosomes render hepatocellular carcinoma cells sensitive to chemotherapeutic agents through delivery of miR-122. MSC-derived exosomes enhance human leukemia cell imatinib-induced apoptosis through the caspase pathway. MSC-derived exosomes hinder the progression of glioblastoma and the progression and metastasis of glioma stem cells by transporting miR-124, miR-145, anti-miR-9, and miR-146b. MSC-derived exosomes inhibit pancreatic cancer activity and suppress glioma progression by shuttling miR-1231 and miR-133b. MSC-derived exosomes reduce breast cancer cell viability and the ablation of HeLa cells by transporting PTX and iron oxide.

Figure 4

MSC-derived exosomes shuttle various bioactive molecules to inhibit or promote tumor growth. Black areas are inhibitory bioactive molecules, and white areas are promotional bioactive molecules.